NEUROLOGY IN PRACTICE: SERIES EDITORS: ROBERT A. GROSS, DEPARTMENT OF , UNIVERSITY OF ROCHESTER MEDICAL CENTER, ROCHESTER, NY, USA JONATHAN W. MINK, DEPARTMENT OF NEUROLOGY, UNIVERSITY OF ROCHESTER MEDICAL CENTER, ROCHESTER, NY, USA

Emergency Management in Neurocritical Care

EDITED BY EDWARD M. MANNO MD, FCCM, FAAN, FAHA Head, Neurological Intensive Care Unit Cleveland Clinic Cleveland, OH, USA This edition first published 2012, Ó 2012 by John Wiley & Sons, Ltd. Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s global Scientific, Technical and Medical business with Blackwell Publishing. Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

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Emergency management in neurocritical care / edited by Edward M. Manno. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-65473-6 (pbk. : alk. paper) I. Manno, Edward M. [DNLM: 1. Central Diseases–. 2. Emergencies. 3. Critical Care–methods. 4. Intensive Care Units. WL 301]

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Set in 8.75/11.75 pt Utopia by Thomson Digital, Noida, India

1 2012 Contents

List of Contributors vi Series Foreword viii Preface ix

PART I: ACUTE MANAGEMENT OF NEUROLOGICAL EMERGENCIES

1 Hypertensive Emergency 3 Laurie McWilliams

2 Airway Management in the Neurological and Neurosurgical Patient 12 Michael J. Souter

3 and Intracranial Hypertension 21 Iain J. McCullagh and Peter J.D. Andrews

4 Critical Care Management of Acute 32 Edward M. Manno

5 37 Muhammad A. Taqi and Michel T. Torbey

6 Acute Management of Cerebral Ischemia 45 Leonid Groysman and Gene Sung

7 Neurocritical Care of Intracerebral Hemorrhage 55 James M. Gebel Jr

8 Acute Management of 63 Jan Claassen

PART II: CEREBROVASCULAR CRITICAL CARE

9 Post-procedural Management of Patients with Aneurysmal Subarachnoid Hemorrhage 73 Tomoko Rie Sampson and Michael N. Diringer

10 Care of the Neurointerventional Patient in the Neurointensive Care Unit 84 Rishi Gupta

iii iv . Contents

11 New Treatment Strategies in the Management of Large Hemispheric and Intracerebral Hemorrhages 92 Edward M. Manno

12 Presentation and Management of Acute Cerebral Venous Thrombosis 99 Patrı´cia Canha˜o and Jose´ M. Ferro

PART III: INFECTIONS OF THE NERVOUS SYSTEM

13 Infections in the Neurocritical Care Unit 111 Denise H. Rhoney, Karen J. McAllen, and Dennis Parker

14 Diagnosis and Management of Bacterial and Viral 123 Maxwell S. Damian

15 : Presentation and Management 132 Ali E. Elsayed and Barnett R. Nathan

PART IV: NEUROMUSCULAR COMPLICATIONS ENCOUNTERED IN THE INTENSIVE CARE UNIT

16 Practical Management of Guillain–Barre´ Syndrome and Myasthenic Crisis 143 Alejandro A. Rabinstein

PART V: NEUROLOGICAL COMPLICATIONS AND CONSULTATIONS IN GENERAL INTENSIVE CARE UNITS

17 Metabolic Encephalopathies 155 Edward M. Manno

18 Delirium and Sedation in the ICU 162 Jennifer A. Frontera

19 Neurologic Complications of Cardiac 174 Cathy Sila

20 Neurological Complications of Medical Illness: Critical Illness Neuropathy and Myopathy 182 Edward M. Manno

21 : Application and Use in Neurocritical Care 188 Edward M. Manno

22 Etiologies of Posterior Reversible Encephalopathy Syndrome and Forms of Osmotic Demyelination Syndrome 197 J. Javier Provencio Contents . v

PART VI: ACUTE AND NEUROMONITORING IN NEUROCRITICAL CARE

23 Application of MR Diffusion, CT and Perfusion Imaging in Neurocritical Care 207 Carlos Leiva-Salinas, Wade Smith and Max Wintermark

24 Advanced Monitoring of Brain Oxygenation and Metabolism 214 Bharath R. Naravetla and J. Claude Hemphill III

Index 225

The color plate can be found facing page 54. Contributors

Peter J.D. Andrews, MD, MB, ChB, FRCA Jennifer A. Frontera, MD Centre for Clinical Brain Sciences Intensive Care Unit University of Edinburgh Departments of and Neurology Edinburgh, UK Mount Sinai School of Medicine New York, NY, USA Patrı´cia Canhao,~ MD, PhD Department of James M. Gebel, Jr, MD, MS, FAHA Servico¸ de Neurologia Cerebrovascular Center Hospital de Santa Maria Cleveland Clinic University of Lisbon Cleveland, OH, USA Lisboa, Portugal Leonid Groysman, MD Jan Claassen MD, PhD Neurocritical Care and Stroke Division Division of Neurocritical Care and University of Southern California the Comprehensive Center Los Angeles, CA, USA Department of Neurology Rishi Gupta, MD Columbia University Department of Neurology, Neurosurgery New York, NY, USA and Maxwell S. Damian, MD, PhD Emory University School of Medicine Department of Neurology and Marcus Stroke and Neuroscience Center the Neurocritical Care Unit Grady Memorial Hospital Cambridge University Hospitals Atlanta, GA, USA Cambridge, UK J. Claude Hemphill III, MD, MAS Department of Neurology Michael N. Diringer, MD University of California Neurology/Neurosurgery Intensive San Francisco, CA, USA Care Unit Department of Neurology and Carlos Leiva-Salinas, MD Neurological Surgery Department of Radiology Washington University School Division of Medicine University of Virginia Saint Louis, MO, USA Charlottesville, VA, USA

Ali E. Elsayed, MD Karen J. McAllen, Pharm.D Mountainside Hospital Department of Services Montclaire, NJ, USA Spectrum Health Hospitals Grand Rapids, MI, USA Jose M. Ferro, MD, PhD Department of Neurosciences Iain J. McCullagh, MBChB, FRCA Servico¸ de Neurologia Department of Anaesthesia, Critical Care Hospital de Santa Maria and Management University of Lisbon University of Edinburgh Lisboa, Portugal Edinburgh, UK

vi Contributors . vii

Edward M. Manno, MD, FCCM, Tomoko Rie Sampson, MD, MPH FAAN, FAHA Neurology/Neurosurgery Intensive Care Unit Neurological Intensive Care Unit Department of Neurology and Neurological Cleveland Clinic Surgery Cleveland, OH, USA Washington University School of Medicine Saint Louis, MO, USA Laurie McWilliams, MD Neurocritical Care Unit Cathy Sila, MD Cerebrovascular Center Department of Neurology Department of Neurology and Neurosurgery Case Western Reserve University Cleveland clinic School of Medicine Cleveland, OH, USA and Stroke & Cerebrovascular Center, Neurological Institute Bharath R. Naravetla, MD University Hospitals–Case Medical Center Department of Neurology Cleveland, OH, USA Neurovascular Service University of California, San Francisco Wade Smith, MD, PhD San Francisco, CA, USA Department of Neurology University of California Bartnett R. Nathan, MD San Francisco, CA, USA Departments of Neurology and Michael J. Souter, MB, ChB, FRCA NeuroCritical Care and NeuroInfectious Department of & Pain Medicine; Disease and Department of Neurological Surgery University of Virginia University of Washington; Charlottesville, VA, USA Department of Anesthesiology Harborview Medical Center Dennis Parker, Jr, Pharm.D Seattle, WA, USA Eugene Applebaum College of Pharmacy & Health Sciences Gene Sung, MD, MPH Wayne State University Neurocritical Care and Stroke Division Detroit, MI, USA University of Southern California Los Angeles, CA, USA J. Javier Provencio, MD Cerebrovascular Center Muhammad A. Taqui, MD Cleveland Clinic Department of Neurology and Neurosurgery Cleveland, OH, USA The Ohio State University Columbus, OH, USA Alejandro A. Rabinstein, MD Department of Neurology Michel T. Torbey, MD, MPH, FAHA, FCCM Mayo Clinic College of Medicine Department of Neurology and Neurosurgery Rochester, MN, USA The Ohio State University Columbus, OH, USA Denise H. Rhoney, Pharm.D, FCCP, FCCM Max Wintermark MD Eugene Applebaum College of Pharmacy & Department of Radiology Health Sciences Neuroradiology Division Wayne State University University of Virginia Detroit, MI, USA Charlottesville, VA, USA Series Foreword

The genesis for this book series started with the “Bibliography” sections that guide the reader proposition that, increasingly, physicians want to additional material. direct, useful information to help them in clinical We welcome feedback. As additional volumes care. Textbooks, while comprehensive, are useful are added to the series, we hope to refine the primarily as detailed reference works but pose content and format so that our readers will be challenges for uses at the point of care. By con- best served. trast, more outline-type references often leave Our thanks, appreciation, and respect go out to out the “hows and whys” – pathophysiology, our editors and their contributors, who conceived pharmacology – that form the basis of manage- and refined the content for each volume, assuring ment decisions. Our goal for this series is to a high-quality, practical approach to neurological present books, covering most areas of neurology, conditions and their treatment. that provide enough background information to Our thanks also go to our mentors and students allow the reader to feel comfortable, but not so (past, present, and future), who have challenged much as to be overwhelming; and to associate and delighted us; to our book editors and their that with practical advice from experts about contributors, who were willing to take on addi- care, combining the growing evidence base with tional work for an educational goal; and to our best practices. publisher, Martin Sugden, for his ideas and sup- Our series will encompass various aspects of port for wonderful discussions and commisera- neurology, with topics and the specific content tion over baseball and soccer teams that might chosen to be accessible and useful. not quite have lived up to expectations. We would Chapters cover critical information that will like to dedicate the series to Marsha, Jake and inform the reader of the disease processes and Dan; and to Janet, Laura and David. And also to mechanisms as a prelude to treatment plan- Steven R. Schwid, MD, our friend and colleague, ning. Algorithms and guidelines are presented, whose ideas helped to shape this project and when appropriate. “Tips & Tricks” boxes pro- whose humor brightened our lives, but he could vide expert suggestions, while other boxes not complete this goal with us. present cautions and warnings to avoid pit- falls. Finally, we provide “Science Revisited” Robert A. Gross sections that review the most important and Jonathan W. Mink relevant science background material, and Rochester, July 2011

viii Preface

Since its beginning in the early 1980s the field of ders, epilepsy, and neurological consultations in neurocritical care hasexpanded at a dramaticrate. general intensive care unit are included. A final In the last decade there has been the development section on neuroimaging and neuromonitoring of an international society with over 1000 mem- reflects the growing reliance on technology in bers, a specialized journal with a growing impact neurological critical care. factor, accredited fellowship programs, and a The chapters are written by experts in their board certification process through the United respective areas and represent a worldwide dis- Council of Neurological . To date tribution of multidisciplinary authors. The book there areclose to 100neurocritical care units inthe contains more detailed information than a hand- United States, a similar number in Europe, and a book, but is presented in a concise and user- growing presence in South America and Asia. The friendly manner to serve as a quick reference inclusion of a textbook of Neurocritical Care in the when needed. The “Tips & Tricks” and “Science Neurology in Practice series is a testimony to the Revisited” sections are designed to increase the field’s growing influence. readability of the chapters. The rapid growth of neurocritical care has en- Endeavors of this size are not undertaken with- couraged a commensurate growth of literature in out help, and I would like to thank Jonathan the field. Interestingly, this has mostly taken the Mink MD, one of the series editor, for including form of single author texts or handbooks primarily this topic. I would also like to thank Lewis designed to disseminate information quickly and O’Sullivan, Martin Sugden, Michael Bevan, and systematically tokeeppacewiththisgrowingfield. Lucinda Yeates at Wiley–Blackwell Publishing This book, Emergency Management in Neuro- who were instrumental in guiding me through critical Care is the first multi-authored textbook this process. in the field since the first text, Neurological and Finally, my father passed away during the edit- Neurosurgical Intensive Care, was edited by Allan ing of this text, and on retrieving his personal Ropper and Sean Kennedy in 1983. The primary items I discovered a number of medals of valor he aim is to provide a comprehensive guide to the received during World War II. He never spoke of management of acutely ill neurological or neu- these and my family was unaware of his posses- rosurgical patients wherever they may be located sions. This book is dedicated to him and to all the in the hospital. The scope of the book will include physicians, nurses, and personnel in the neuro- basic principles in emergency neurology and logical intensive care unit and elsewhere who critical care, which will review the underlying perform daily acts of valor with no expectation basic science and cerebrovascular physiology of of recognition. the critically ill neurological patient. Later sec- tions will focus more on the critical aspects of the Edward M. Manno neurologically ill. Specific sections dedicated to Cleveland cerebrovascular disease, neuromuscular disor-

ix Plate 7.1 Congo red staining of cerebral amyloid angiopathy showing thickened sub- cortical arteriole wall (left) which demonstrates apple green birefringence (right) which is neuropathologically diagnostic of the condition.

Plate 23.1 Mismatch between PCT MTT and CBV defects in a 63-year-old man evaluated 3 hours after sudden onset of right face-arm-leg weakness. CTA images show occlusion of the distal M1 segment of the left middle cerebral artery. CTA curved multiplanar reconstruction shows a calcified plaque at the origin of the left internal carotid artery (arrowhead) with a bypass from the left common carotid artery to the distal left internal carotid artery. PCT parametric maps show a mismatch between the region with prolonged MTT (white arrows) and the absence of decreased CBV (CBV is increased) (gray arrow). PCT source images (PCT SI) show good collateral flow in the tissue with prolonged MTT and no area showing paucity of vessels. The patient was treated with intravenous tPA. Follow up DWI image performed 12 hours later (Follow-up) show two small infarcts in the watershed territories, represented by the small foci of restricted water diffusion (purple arrows). Plate 23.2 Example of obscuration of the lentiform nucleus sign, and mismatch between PWI and DWI in a 66-year-old woman evaluated for left face-arm-leg weakness. NCT of the brain obtained 4 hours after symptom onset show obscuration of the right lentiform nucleus. MRI was performed 4.5 hours after symptom onset. There is a mismatch between the region with prolonged MTT (involving the entire right MCA territory) (white arrows) and the region of DWI abnormality (limited to the head of the caudate and lentiform nuclei)(purplearrows),whichrepresentstheinfarctcore.NotehowtheDWIabnormalityin not completely apparent on FLAIR sequence. MR angiography (MRA) shows occlusion of the M1 segment of the right middle cerebral artery. The patient was treated with intravenous tPA. The final infarct volume on the follow up MRI performed 24 hours later corresponded to the area of baseline restricted diffusion (not shown). Plate 23.3 MTT-CBV match in a 62-year-old man evaluated after sudden onset of right face, arm and leg weakness consistent with acute ischemic stroke. CTA images (CTA) show occlusion of the M1/M2 junction segment of the left MCA. PCT parametric maps (CBV and MTT) show a complete match between the areas of prolonged MTT and decreased CBV (involving the posterior superficial right MCA territory), consistent with infarcted tissue (white arrows). CTA and PCT source images (PCT-SI) show poor collateral flow an area of paucity of vessels that outlines the infarct core (purple arrows). Follow-up NCT (Follow-up) show that the final infarct corresponds to the area of predicted infarct core as represented by the area of decreased CBV. Hemorrhagic transformation was present. Plate 23.4 Imaging for Blood-brain permeability in a 73-year-old man with acute ischemic stroke and hemorrhagic transformation. Non-contrast CT (NCT) of the brain acquired 2 hours after symptom onset show slight obscuration of the right insular ribbon. CTA images acquired at that time (CTA) show occlusion of the distal M1 segment of the right middle cerebral artery. CBV ant MTT parametric maps (CBV and MTT) show a mismatch between the region with prolonged MTT and the absence of decreased CBV. The map of microvascular permeability (BBB) shows a region of blood brain barrier disruption involving the right insula (white arrow). The patient was treated with intra- venous rt-PA. Follow-up NCT (Follow-up) obtained 24 hours later show hemorrhagic transformation. Note how the intracranial hemorrhage is centered in the predicted region of blood brain barrier permeability disruption. Part I Acute Management of Neurological Emergencies 1 Hypertensive Emergency Laurie McWilliams

Neurocritical Care Unit, Cerebrovascular Center, Department of Neurology and Neurosurgery, Cleveland Clinic, Cleveland, OH, USA

Introduction insufficiency. The remaining text of the chapter will focus on the management of blood pressure Hypertension and neurologic disease coexist in the specified acute neurologic diseases. frequently, either as a cause or consequence Hypertensive crisis is defined as an abrupt of the underlying neurologic disease. In addition, elevation of blood pressure, to a point that the the management of elevated blood pressures in blood vessels are unable to maintain constant this setting has significant impact on outcomes. blood flow in the setting of increasing perfusion Hypertension is defined as systolic blood pres- pressures to specific organs, also known as dis- sure greater than 140 mmHg or diastolic blood ruption of autoregulation. The end result leads to pressure greater than 90 mmHg. The National end-organ damage from ischemia or hemor- Health and Nutrition Survey (NHANES) is con- rhage. The end result leads to end-organ damage ducted by the Centers for Disease Control and from ischemia or hemorrhage. Prevention obtaining data from US household Patients with blood pressure elevations greater individuals regarding health and nutrition for the than 180/110 mmHg are categorized into the fol- purpose of improving the US health through lowing diagnoses: policy. The NHANES 2005 to 2006 data reported that 29% of the United States population 18 years and older are diagnosed with hypertension. Of 1. Severe hypertension: no to mild symptoms the population with treated hypertension, greater and no acute end-organ damage than 64% has controlled hypertension. Men have 2. Hypertensive urgency: significant symptoms a higher rate of hypertension until the age of 45 and mild acute end-organ damage. Mild when the incidence of hypertension equalizes end-organ damage is defined as dyspnea and between men and women. headaches. In 2006 the mortality from hypertension was 3. Hypertensive emergency: severe symptoms reported in 56,561 individuals. Both the preva- with life-threatening end-organ damage. lence from hypertension and mortality has in- creased from the late 1990s to the 2000s. The Life-threatening end-organ damage is defined as estimated direct and indirect cost of hyperten- acute ischemic stroke, intracerebral hemorrhage, sion for the year 2010 was 76.6 billion US dollars. subarachnoid hemorrhage, acute aortic dis- The sequelae of hypertension include strokes, section, myocardial infarction, acute heart fail- myocardial ischemia, aortic dissection, and renal ure, eclampsia, renal insufficiency, and acute

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

3 4 . Acute Management of Neurological Emergencies pulmonary edema, to name a few. The first limits that lead to a disruption of this system instinct when dealt with this situation as a prac- with resultant ischemia or titioner is to acutely correct the problem. How- (Figure 1.1). ever, there are some considerations prior to The underlying mechanisms of autoregulation acutely correcting the blood pressure in a hyper- that allow for vessel caliber changes are myo- tensive crisis. The remainder of the chapter will genic and metabolic. When the MAP decreases, discuss these considerations in relation to neu- the arterioles constrict to increase the CBF; rologic emergencies. however, if hypotension persists beyond the Hypertensive urgencies include 25% of ED lower limit threshold, resultant cerebral ische- medical visits, while hypertensive emergencies mia exists. If the blood pressure continues to are one-third of the cases. CNS complications increase above the higher limit threshold, the are the most frequent of the hypertensive emer- result is hyperemia and cerebral edema. How- gencies. The hypertensive emergent patient with ever, in brain dysfunction, the blood–brain neurologic sequelae needs urgent attention, with barrier and cerebral endothelium is disrupted, hourly blood pressure monitoring and neurologic leading to leaky blood vessels with subsequent examination in an intensive care unit. Prior to fibrinoid deposition into the cerebral vas- discussing blood pressure management, a dis- culature. This results in vascular narrowing, with cussion of cerebral autoregulation and the pa- compensatory vasodilation. In these circum- rental antihypertensive agents will be reviewed. stances the autoregulation curve follows a more linear pattern with the CBF being dependent on Cerebral Autogregulation perfusion pressures. Cerebral blood flow (CBF) is tightly controlled Normal CBF is 50 mL/100 g brain tissue per under the normal conditions, with cerebral per- minute. Reversible injury, occurs at 15–20 mL/ fusion pressures (CPP) ranging from 50 to 150 100 g/min, and irreversible injury is less than mgHg. Cerebral perfusion pressures can be cal- 15 mL/100 g/min. The occurrence of cell death culated from mean arterial pressure (MAP) minus is based on the product of the degree and length jugular vein pressure (JVP). Intracracranial pres- of time of ischemia. The ischemic penumbra is sure (ICP) is substituted for JVP under conditions vulnerable tissue with impaired autoregulation where the ICP is greater than the JVP. Cerebral and low blood flow despite high oxygen extrac- autogregulation involves arteriole caliber tion. Therefore the tissue is salvageable but has a changes in response to changes in the blood high risk of becoming ischemic if the blood flow pressure; however, there are upper and lower is not recovered in a short period of time.

Figure 1.1. Autoregulation maintains cerebral blood flow relatively constant between 50 and 150 mmHg mean arterial pressure. The range is right shifted in chronically hypertensive patients. (Reproduced from Ruland and Aiyagari. Hypertension 2007; 49: 978, with permission from Wolters Kluwer Health.) 1 Hypertensive Emergency . 5

SCIENTIFIC EVIDENCE hypertensive effect can last for 2–4 hours. Beta action does cause a decrease in heart rate but An EEG is a useful tool for monitoring maintains the cardiac output. Similarly, cerebral , but also for detecting cerebral perfusion is maintained with the use of beta blood flow. In the operation room, older blockers. studies have shown that EEG can detect Start with a loading dose of 20 mg, increasing real-time ischemia. When cerebral blood subsequent doses from 20 to 80 mg every 10 min- flow reaches 25–30 mL/100 g/min, an EEG utes to the desired effect. In the author’s institu- demonstrates a change in morphology, tion, if repeat labetalol boluses do not result in amplitude, and frequency. When the CBF the desired effect, an infusion is initiated starting decreases to less than 15 mL/1006/min, the at 1–2 mg/min. EEG becomes isoelectric. The neurons that Esmolol is a short-acting beta antagonist, with produce the excitatory post-synaptic po- no direct affect on the peripheral vasculature. tential (EPSP) and inhibitory post-synaptic Decreased blood pressure is secondary by de- potential (IPSP) for the electrodes are the creasing cardiac output. The onset of action is same neurons (pyramidal neurons) that are 60 seconds, with a duration of action of 10–20 sensitive to hypoxia. minutes. esmolol has a unique metabolic profile, being metabolized by red blood cell (RBC) es- terases. In the setting of anemia, Esmolol can have a prolonged effect. Due to its pure beta Antihypertensive Agents action, caution should be used in patients with Hypertensive emergency can be fatal, and needs COPD. Similarly it should be avoided in patients prompt treatment. The initial treatment is blood in decompensated heart failure, due to com- pressure control, in a reliable and controlled promising myocardial function. fashion, therefore oftentimes, requiring parental Start with a loading dose of 500–1000 mg/kg, agents and arterial blood pressure monitoring. with a continuous infusion at 50 mg/kg/min to a There are multiple classes of antihypertensives maximum of 300 mg/kg/min. one has to choose from; however, there are also many factors to consider prior to administration. The most important factor to consider in neuro- TIPS & TRICKS logic damage is increased . A few class of antihypertensive agents work Beta blocker toxicity can present with via vasodilatory mechanisms, which can lead to bradycardia, hypotension, bronchospasm, further increases in intracranial pressure and and hypoglycemia. An ECG can be helpful potentially further worsening of neurologic inju- with detecting PR prolongation. QT ry. Another factor is the onset and duration of prolongation can sometimes be detected. action. Rapid fluctuations of hypotension and It should be treated with atropine for hypertension can lead to worsening cerebral in- bradycardia, intravenous fluids and jury. An agent that can be turned off and out of vasopressors for hypotension. Glucagon is the system quickly is more desirable in case of an a well-known antedote for the treatment of acute hypotensive episode. beta blocker toxicity.

Preferred Agents for Hypertensive Emergencies with Brain Calcium Channel Blockers Dysfunction Three types of calcium channel blocker exist: Beta Blockers dihydropyridines, phenylalkylamines, and ben- Labetalol is a selective alpha-1 and nonselective zothiapines. The two types of calcium channels beta antagonist. The onset of action is 2–5 min- that exist in the vasculature are L-type and utes with a peak effect seen in 5–15 minutes. The T-type. 6 . Acute Management of Neurological Emergencies

The action of calcium channel blockers on Other Agents Used for L-type channels decrease calcium influx, result- Hypertensive Emergencies ing in elevated GMP levels. The elevated GMP Nitric Oxide Vasodilators levels lead to vascular smooth muscle relaxa- tion, vasodilation and decrease systolic blood Sodium nitroprusside is a potent arterial and pressure. venous vasodilator, leading to significant preload Nicardipine and clevidipine are the preferred and afterload reductions. However, ICP eleva- parental calcium blocker agents for cerebro- tions can occur in patients with neurologic injury. vascular hypertensive emergencies. Nicardipine The first studies were performed on neurosurgi- crosses the blood brain barrier, leading to vaso- cal patients under anesthesia revealing vasodila- dilation of the small-resistance arterioles, with tion of large-capacitance vessels leading to vaso- little to no increases in intracranial pressure. dilation and increased intracranial pressure. An- The infusion rate starts at 5 mg/h, with incre- other negative consequence is cyanide toxicity. mental increases 2.5 mg/h every 5 minutes for a Sodium nitroprusside contains 44% of cyanide, maximum infusion 30 mg/h. The onset of action which is further metabolized to thiocyanate by is 5–15 minutes, with duration of action 4 to the liver, and eliminated by the kidneys. There is 6 hours. an increased risk for cyanide toxicity in patients Of note, nicardipine has other properties that with liver and kidney dysfunction. Cyanide tox- make it attractive in neurological diseases. It has icity leads to cellular hypoxia with neurologic a high affinity to ischemic cerebral tissue due to consequences and cardiac arrest. The neurologic the acidic pH of ischemic tissue. Once in the cell, consequences include encephalopathy, seizures, it is transformed to its active form, which may and . Thus, the use of sodium nitroprusside lead to a direct neuroprotective effect. and other nitric oxide drugs are discouraged due The effect of nicardipine on intracranial pres- to the potential for worsening intracranial sure has been studied. Narotam et al. (2008) pressures. performed a prospective case-control study of Diuretics have no role in the acute manage- 30 patients with hypertensive emergencies in ment of hypertensive emergencies in neurologi- acute brain disease. Nicardipine was the first-line cal and nonneurological disorders due to the antihypertensive agent. The results supported increased frequency of volume depletion. Specif- the ability to maintain cerebral perfusion pres- ically in the neurological patient, altered mental sures above 70 with no increase in ICP and status and dysphagia can further exacerbate vol- increased parenchymal brain tissue oxygenation. ume depletion, leading to increased fluid admin- Clevidipine is a third-generation dihydropyr- istration in the acute setting to prevent further idine calcium channel blocker, recently used in a dehydration and kidney injury. trial of blood pressure management in acute A list of medications used to treat acute hyper- intracerebral hemorrhage. The drug acts by ar- tensive emergencies and the doses used are listed teriole dilation, with an onset of action 2–4 min- in Table 1.1. utes and a duration of action 5–15 minutes. It is metabolized by red blood cell esterases. Clevi- Acute Ischemic Stroke dipine has antioxidative properties as a free- Blood pressure management in acute ischemic radical scavenger. Continuous infusions start at stroke is complex; lowering blood pressure could 1–2 mg/h, and is increased every 90 seconds un- potentially worsen the infarct size and cause til blood pressure goals are attained. However, neurologic deterioration, while allowing blood there are a few less attractive features of the drug: pressures to remain elevated could lead to hem- 1) infused in a lipid emulsion, requiring triglyc- orrhagic transformation and worsening brain eride monitoring during infusion, 2) contraindi- edema. If the patient is a thrombolytic candidate cated in patients with to soy and egg or received thrombolytics, pressures excessively products, and patients with lipid metabolism elevated can also lead to hemorrhagic transforma- disorders, and 3) can develop microbial growth tion. Retrospective analysis of outcomes post- in solution. thrombolysis has also shown a worse outcome in Table 1.1. Antihypertensives and management of neurologic emergencies

Drug Mechanism of action Dosage Onset Duration Contraindications Labetalol a1b antagonist Loading doses 20 mg with 2–5 min 2–4 h Reactive airway disease repeated boluses every 10 min COPD Infusion rates 1–2 mg/min for Decompensated heart failure target blood pressure Bradycardia Second or third degree heart block Esmolol b1 antagonist Loading dose 0.5–1.0 mg/kg 60 s 10–20 min Reactive airway disease Infusion rates 50 ug/kg/min COPD to max 300 ug/kg/min Decompensated heart failure Bradycardia Second or third degree heart block Nicardipine Dihydropyridine calcium Initial infusion 5 mg/h, 5–15 min 4–6 h Severe aortic stenosis channel antagonist increasing 2.5 mg/h every 5 min. Maximum 15 mg/h Clevidipine Dihydropyridine calcium Initial infusion 1–2 mg/h, 6 min Defective lipid metabolism channel antagonist increasing the dose x2 every disorders 90 s to max 32 mg/h Enalaprilat ACE inhibitor Initial dose of 0.625 with 15 min 12–24 h Acute renal failure

repeated doses 1.25 mg Acute MI Emergency Hypertensive 1 every 6 h Bilateral renal artery stenosis Pregnancy hyperkalemia Sodium Nitric oxide donor leading Initial dose of 0.3–0.5 mg/kg/min, 1–3 min 1–3 min Increased intracranial pres- nitroprusside to vascular smooth muscle increasing 0.5 mg/kg/min sures relaxation via intracellular for desired effect, max dose Acute MI second messenger systems 2 mg/kg/min. Hepatic or renal failure due to increase risk for cyanide toxicity . 7 8 . Acute Management of Neurological Emergencies patientswithahistoryofhypertension, despitethe blood pressures less than 140 mmHg if present- administration of thrombolysis. Studies focusing ing systolic blood pressures are less than on blood pressure management in acute ischemic 220 mmHg. However, there is insufficient data for stroke have shown that patients with lower blood a defined blood pressure target. pressure on admission had poor outcomes. Kazui et al. (1997) examined the risk factors for Vemmos and colleagues examined the mortality hematoma enlargement. 83% of the subjects had at 1 month and 12 months after ischemic and a pre-existing diagnosis of hypertension and 76% hemorrhagic strokes in relation to admission of the hemorrhages were in classical, hyperten- blood pressures. Their findings concluded that sive locations. In their study population, Kazui patients with ischemic strokes had the best out- et al. (1997) noted that admission systolic blood comes with an admission systolic blood pressure pressure greater than 200 mmHg was significant- of120–140 mmHg,andpatientswithanadmission ly associated with hematoma enlargement. systolic blood pressure less than 101 mmHg or The INTERACT trial randomized 404 patients greater than 220 mmHg had the highest mortality to intensive blood pressure control of systolic rates. Therefore, current guidelines recommend blood pressure less than 140 mmHg or guide- maintaining systolic blood pressure less than line-based blood pressure control of systolic 220 mmHg and diastolic blood pressure less than blood pressure less than 180 mmHg for the first 120 mmHg. The majority of patients will reset to 24 hours to 7 days after stroke onset. 296 patients normotensive days after their stroke. had all CT scans available for full statistical anal- In regards to blood pressure augmentation ysis. Patients in the intensive blood pressure during an acute stroke, there are no good studies lowering group showed reduced hematoma vo- to date to support artificially raising blood pres- lumes, 3.15 cc and 2.45 cc at 24 and 72 hours, sures in an acute stroke. Current recommenda- respectively. However, the results have been tions are to discontinue home blood pressure questioned due to enrollment bias with patients medications and allow the blood pressures to with smaller hemorrhage volumes than previous rise to their specific targets irrespective of throm- trials, less acuity based on NIHSS and GCS: bolysis. If thrombolytics have been instituted, NIHSS ranged from 5 to 15 and GCS ranged 13 patients need monitoring in an intensive care to 15. The patient population was more diverse unit, preferably a neurocritical care unit, with due to hospitals located in Australia, China, and the use of short-acting parental antihyperten- South Korea, with possible different etiologies sives if patients’ blood pressures are raised out- and pathophysiologies involved. side their specific targets. The ATACH trial enrolled 60 patients to one of three tiers of blood pressure goals within 6 hours Intracerebral Hmorrhage of symptom onset. The primary outcomes Intracerebral hemorrhages represent 15% of all included neurologic deterioration and serious strokes. Despite more sophisticated medical in- adverse events. They did not analyze hematoma terventions, neurological outcome and mortality growth or perihematoma edema. The most seri- continue to significantly impact patients with ous adverse events and neurologic deterioration intracerebral hemorrhages. More specifically, occurred in the most intensive tier, systolic blood patients with a decrease in the neurologic exami- pressure less than 140 mmHg. There was no nation prior to hospital admission have a signifi- difference in mortality between the groups. cantly greater mortality. The initial neurologic The ATACH trial produced opposite results to deterioration is frequently due to rebleeding of the INTERACT trial, showing more negative out- the initial hemorrhage. comes in patients with systolic blood pressures There has been poor evidence for guiding less than 140 mmHG after stroke onset. However, blood pressure goals in intracerebral hemor- as pointed out, ATACH did not analyze the he- rhages; however, the 2010 Stroke Guidelines has matoma volumes and both studies had different a new recommendation based on two clinical patient populations. trials: INTERACT and ATACH. The new guidelines There is still no correct answer for the low end state that it is “probably safe” to lower systolic of systolic blood pressure in intracerebral 1 Hypertensive Emergency . 9 hemorrhage, or if patients have a worse outcome controlled. For blood pressure management, with high or low blood pressure. We still need the use of short-acting parental antihypertensive high-powered studies to assist with this funda- agents should be instituted. mental management of intracerebral hemor- After securing the , the goal of blood rhage in the acute setting. pressure focuses on vasospasm management. Vasospasm is the arterial narrowing secondary to inflammatory changes from blood products TIPS & TRICKS from the initial subarachnoid hemorrhage. Vaso- spasm can lead to neurologic deficits by reduced Elevated blood pressures in intracerebral blood flow and ischemic brain tissue, collectively hemorrhage are frequently seen. However, termed “delayed cerebral ischemia.” Nimodi- persistent elevated blood pressures hours pine, a calcium channel blocker, is the only prov- after the initial insult can be an indicator en drug that improves the outcomes in patients of rebleeding or worsening edema. If blood with cerebral vasospasm in the context of sub- pressures are not responding to antihyper- arachnoid hemorrhage. Detecting cerebral vaso- tensives, a dose of mannitol or hypertonic spasm will be discussed in another chapter of this saline can be given with close blood pressure textbook, and the hypertensive management of monitoring. If blood pressures decrease, the vasospasm will be discussed only briefly here. persistent hypertension is an indicator of a The goal of management of vasospasm is worsening edema. optimizing oxygenation to the brain. During the management of vasospasm, patients require in- tensive care monitoring for arterial catheteriza- tion and triple lumen catheters. This is performed Blood Pressure and Aneurysmal by reducing cerebral metabolism and intracere- bral pressures, and optimizing cerebral perfu- SAH sion. Blood pressure management is paramount Subarachnoid hemorrhage is a devastating dis- in optimizing cerebral perfusion pressures, ease, with a high mortality depending on the which is achieved through the use of hemody- severity of the hemorrhage. The risk factors for namic augmentation. Considerable controversy aneurysmal subarachnoid hemorrhage include exists as to the best method to achieve increased hypertension, alcohol use, tobacco use, Adult cerebral blood flow in the patient with severe Polycystic Kidney Disease, and connective tissue vasospasm. However, it is known that during disorders. 30-day mortality from subarachnoid the acute period of vasospasm cerebral autore- hemorrhage has been reported as high as 50% gulation is disturbed. Methods to induce hyper- in the AHA guidelines, with the amount of blood, tension or increased cardiac output have been medical comorbidities, and time to treatment advocated and may require additional intravas- being important factors affecting the outcome. cular monitoring. When these measures have not However, the goal of this chapter is to discuss resulted in reversal of delayed cerebral ischemia, blood pressure management in subarchnoid patients are referred for intra-arterial opening of hemorrhage. Blood pressure goals depend on the the vessels. state of the aneurysm – unsecured or secured. Many factors are thought to contribute to the risk of rebleeding in the unsecured aneurysm and Dysautonomia in Guillain–Barre the literature is currently unsure of the role of Syndrome (GBS) blood pressure and rebleeding risk. However, Dysautonomia is now one of the leading causes most centers in America will maintain a systolic of increased mortality in GBS. It is a very common blood pressure of less than 160 mmHg. The cur- phenomenon in GBS, with increased risk when rent stroke guidelines do not give an absolute patients present with , tetra- value for blood pressure control; however, they plegia, or bulbar involvement. It is defined as recommend that the blood pressure should be overactivity or underactivity of the sympathetic 10 . Acute Management of Neurological Emergencies system, causing either extreme hypertension and Bibliography tachycardia and/or extreme hypotension and Anderson CS, Huang Y, Arima H, et al. Effects bradycardia. of early intensive blood pressure-lowering Cortelli et al. (1990) have found pathological treatment on the growth of hematoma and lesions in the intermediolateral horns of the perihematomal edema in acute intracerebral spinal cord, sympathetic chains of white rami, and hemorrhage: The intensive blood pressure involvement of glossopharyngeal and vagus nerves reduction in acute cerebral hemorrhage trial inpatientswithdysautonomiafrom GBS. Durocher (INTERACT). Stroke 2010; 41: 307–312. et al. (1980) examined the catecholamine levels of Anderson CS, Huang Y, Wang JG, et al. Intensive patients with dysautonomia, resulting in the high blood pressure reduction in acute cerebral urinary catecholamine secretion of VMA, HVA, and haemorrhage trial (INTERACT): a randomised 5 HIA; high CSF dopamine and serotonin levels; pilot trial. Lancet Neurol 2008; 7: 391–399. and normal serum serotonin levels. Antihypertensive Treatment of Acute Cerebral These studies provide evidence for the under- Hemorrhage (ATACH) investigators. Antihy- lying sympathetic presenting with the pertensive treatment of acute cerebral hemor- signs of dysautonomia; however, the literature is rhage. Crit Care Med 2010; 38: 637–648. scarce in the management of dysautonomia. Due to concerns for hypotension, it has been recom- Bartynski WS. Posterior reversible encephalopa- mended to allow patients to maintain elevated thy syndrome, Part 2: Controversies surround- blood pressures unless end-organ failure pro- ing pathophysiology of vasogenic edema. Am J ceeds. When patients do progress to hypotension, Neuroradiol 2008; 29: 1043–1049. pressors are indicated, and with severe bradycar- Bath P, Chalmers J, Powers W, et al. International dia, transcutaneous pacing may be indicated. Society of Hypertension (ISH): Statement on the management of blood pressure in acute Hypertensive Encephalopathy stroke. J Hypertens 2003; 21: 665–672. Hypertensive encephalopathy is an entity seen Cortelli P, Contin M, Lugaresi A, et al. Severe in patients with acute blood pressure elevations dysautonomic onset of Guillain–Barre syn- in the setting of many clinical scenarios. A later drome with good recovery. A clinical and chapter will be dedicated to hypertensive ence- autonomic follow-up study. ItalJNeurolSci phalopathy, however, to initiate the discussion 1990; 11: 159–162. on blood pressure management, it should be Durocher A, Servais B, Caridroix M, et al. Auto- understood that the parietal-occipital lobes are nomic dysfunction in the Guillain–Barre syn- preferably involved due to the lack of sympathet- drome. Hemodynamic and neurobiochemical ic innervation in the posterior circulataion. studies. Intens Care Med 1980; 6: 3–6. Acute blood pressure elevations lead to hyper- Haas AR, Marik PE. Current diagnosis and man- perfusion and blood–brain barrier dysfunction, agement of hypertensive emergency. Semin with protein and fluid extravasation leading to Dial 2006; 19: 502–512. vasogenic edema and, sometimes, intracerebral Hund EF, Borel CO, Cornblath DR, Hanley DF, hemorrhage. McKhann GM. Intensive management and The clinical effects of hypertensive encepha- treatment of severe Guillain–Barre syndrome. lopathy include, but are not limited to, headache, Crit Care Med 1993; 21: 433–446. altered mental status, visual changes, seizures, Kazui S, Minematsu K, Yamamoto H, et al. Predis- and coma. posing factors to enlargement of spontaneous Blood pressure management needs careful intracerebral hemorrhage. Stroke 1997; 28: attention, with acute lowering of the MAP by 2370–2375. 25% of admission MAP or diastolic less than Lee KH, Lukovits T, Friedman JA. “Triple-H” 100 mmHg within 1 hour, to prevent seizures therapy for cerebral vasospasm following sub- and intracranial hemorrhage. Short-acting arachnoid hemorrhage. Neurocrit Care 2006; 4: agents are a better choice for tighter blood pres- 68–76. sure control. 1 Hypertensive Emergency . 11

Mocco J, Rose JC, Komotar RJ, Mayer SA. Blood Qureshi AI, Palesch YY, Martin R, et al. Effect pressure management in patients with intrace- of systolic blood pressure reduction on rebral and subarachnoid hemorrhage. Neuro- hematoma expansion, perihematomal edema, surg Clin N Am 2006; 17 (Suppl 1): 25–40. and 3-month outcome among patients with Morgenstern LB, Hemphill JC, 3rd, Anderson C, intracerebral hemorrhage: results from the et al. Guidelines for the management of spon- Antihypertensive Treatment of Acute Cerebral taneous intracerebral hemorrhage: A guideline Hemorrhage study. Arch Neurol 2010; 67: for healthcare professionals from the American 570–576. Heart Association/American Stroke Associa- Rincon F, Mayer SA. Clinical review: critical care tion. Stroke 2010; 41: 2108–2129. management of spontaneous intracerebral Narotam PK, Puri V, Roberts JM, et al. Manage- hemorrhage. Crit Care 2008; 12: 237. ment of hypertensive emergencies in acute Rose JC, Mayer SA. Optimizing blood pressure brain disease: evaluation of the treatment in neurological emergencies. Neurocrit Care effects of intravenous nicardipine on cerebral 2004; 1: 287–299. oxygenation. J Neurosurg 2008; 109: 1065–1074. Ruland S, Aiyagari V. Cerebral autoregulation and Ntaios G, Bath P, Michel P. Blood pressure treat- blood pressure lowering. Hypertension 2007; ment in acute ischemic stroke: a review of 49: 977–978. studies and recommendations. Curr Opin Talbert RL. The challenge of blood pressure man- Neurol 2010; 23: 46–52. agement in neurologic emergencies. Pharma- Powers WJ, Zazulia AR, Videen TO, et al. Auto- cotherapy 2006; 26: 123S–130S. regulation of cerebral blood flow surrounding Vemmos KN, Tsivgoulis G, Spengos K, Zakopou- acute (6 to 22 hours) intracerebral hemorrhage. los N, Synetos A, Manios E, Konstantopoulou Neurology 2001; 57: 18–24. P, Mavrikakis M. U-shaped relationship be- Qureshi AI. Antihypertensive Treatment of Acute tween mortality and admission blood pressure Cerebral Hemorrhage (ATACH): rationale and in patients with acute stroke. J Internal Medi- design. Neurocrit Care 2007; 6: 56–66. cine 2004; 255(2): 257–265. 2 Airway Management in the Neurological and Neurosurgical Patient Michael J. Souter

Department of Anesthesiology & Pain Medicine, and Department of Neurological Surgery, University of Washington, Department of Anesthesiology, Harborview Medical Center, Seattle, WA, USA

Introduction receptors in the upper airways, as well as The term “airway” is an oversimplification of an neurohumoral and chemoreceptor activation. anatomical canal that serves many functions. This anatomical and functional distribution of the oropharynx, nasopharynx, and larynx allow Airway difficulties are often encountered after for communication, mastication, swallowing, traumatic brain injury with over 50–70% of head and continuous respiration. injuries experiencing associated facial injury. Air- A set of complex interconnections and reflex way compromise can arise from associated soft arcs, located diffusely throughout the brain, con- tissue swelling (often with frightening speed of trol the musculature of the pharynx and larynx. onset), hemorrhage and secretions, and fractured The diffuse distribution of these control centers teeth. Maxillary fractures are associated with fa- and the complexity of the integration needed to cial edema and pharyngeal blood, but may also coordinate these centers provide insight into the disrupt the skeletal support of the oropharyngeal ease with which the airway can be compromised. musculature leading to reduced pharyngeal dimensions, and increased susceptibility to obstruction. SCIENCE REVISITED Focal neurological insults to the midbrain, cerebellum, or brain stem (injury, stroke, demy- A masticatory center is located in the elination) can adversely affect airway control dorsolateral and anterolateral frontal cortex. centers. More diffuse disease (injury, infection, Reflex swallowing is mediated by the lateral inflammation, ischemia) can threaten conscious- precentral gyri, postcentral gyri, ness with the consequent impairment of cough supplementary motor area, insular cortex, and and swallow. basal ganglia. These areas modulate the A decreased level of consciousness can lead activity of the cranial nerve nuclei in the pons to a reduction in airway muscle tone which and brain stem. The control of respiration may lead to airway obstruction. Obstruction of itself is dynamically affected by mechanical the airway results in hypoxia, hypercarbia, and

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

12 2 Airway Management in the Neurological and Neurosurgical Patient . 13 further diminishes airway control. Subsequent Table 2.1. Indications for intubation increase in respiratory effort will generate nega- In the field and in hospital tive intrathoracic pressure and further collapse . Immediate (life-threatening hypoxia likely) airways. T persistent airway obstruction despite airway insertion CAUTION T inability to bag/mask ventilate . Urgent Care must be taken when attempting to T < 8 alleviate an obstructed airway. Intervention T protection of the lower respiratory tract itself can create the possibility of iatrogenic from aspiration injury to the airway. Lip laceration, bleeding, T anticipated occlusion by: dental damage, and tongue edema can all . edema (burns, angioedema) result from the use of poor technique in . hematoma airway instrumentation, while repeated . displacement of a laryngotracheal unsuccessful attempts at intubation may fracture induce edema of the pharynx, epiglottis, and In-hospital cords. . control of intracranial pressure by

controlling pCO2 . therapeutic ventilation for Assessment hypoxemia/hypercarbia in: T pulmonary contusion/edema/infection The urgency of intubation should consider the T flail chest neurological condition of the patient and the . therapeutic and diagnostic procedures in potential effects of hypercarbia and/or hypoxia. combative or uncooperative patients Either will lead to cerebral vasodilation with . high metabolic demand from work of subsequent increases in cerebral blood volume breathing and intracranial pressure. The need for intubation requires clinical judg- however, do allow for easier suctioning and/or ment. Some indications for intubation are listed bronchoscopy if needed. in Table 2.1. They can often coexist to amplify the Removingthegastriccontentpriortointubation urgency. Once the decision has been made to is desirable since most patients will not have been intubate the patient, a number of questions will fasting in an emergency situation. Existing gastric need to be addressed. tubes should be drained, but insertion at this point isnotrecommended.Theoperatorshouldidentify . What precautions are required? and assign assistants to pass equipment, to moni- . How easy is it to maintain a patent airway? tor vital signs and oxygenation, to immobilize the . How easy is it to intubate the airway? head in case of cervical spine injury (see below), or to apply cricoid pressure. This maneuver presses on the only competent cartilage ring in the trachea Preparation to compress and close the esophagus. Its utility is In ideal circumstances endotracheal intubation controversial with some arguing that it increases should be a structured and orderly process. This the difficulty of intubation without adding addi- requires a thorough preprocedural preparation tional protection. that should include optimization of the environ- If cricoid pressure is to be utilized, the clinician ment, with suction equipment connected, tested, should carefully inform the assistants (a) on ex- and immediately at hand. Oxygen, tubing, and actly how and when to apply this pressure, and (b) an inflatable bag are essential, and a broad range to stop only when instructed. A rapid sequence of endotracheal tubes should also be available. induction should be the norm in most urgent or A 7 mm tube will fit most adults and induce emergent cases, with good quality of sedation, minimal flow restrictions. Larger tubes (8 mm), facilitated by adequate muscle relaxation. 14 . Acute Management of Neurological Emergencies

Induction drugs comprise hypnotics, analge- sics, and paralytics. Their use should consider the desired speed of action, hemodynamic con- sequences, and side effects. For hypnotics, there is little to choose between thiopental (3–5 mg/kg) and propofol (2–3 mg/kg), as both cause similar degree of reduction in cardiac output. Etomidate (0.3 mg/kg) has the least hemodynamic effect while ketamine (1–2 mg/kg) will maintain or even increase blood pressure with attendant tachycardia. There is controversy regarding the effect of etomidate upon adrenal suppression, which tempers its use. Midazolam (0.3–0.4 mg/ kg) may be used for induction, causing slight hypotension but less than propofol or thiopental. All agents will produce transient apnea but ketamine has the least effect, followed by etomi- date. Fentanyl (1–2 mg/kg) can synergistically reduce hypnotic doses at induction and serves to decrease subsequent coughing, as well as respiration. It has the most favorable hemody- namic profile of the opiates, and is consequently the most useful at induction. Paralytic drugs provide the highest quality relaxation for intuba- tion, but at the risk of significant apnea and hypoxia if the airway can be neither intubated nor ventilated. However, coughing or moving on intubation does have consequences and the risk/benefit must be carefully considered for each patient. The shortest duration of effect is 3–5 minutes for succinyl choline (1–1.5 mg/kg). This well established agent has the fastest overall onset (45 s) but does have limitations due to hyperkalemia seen in burns and the recently Figure 2.1. (A) Airway with oropharyngeal and tracheal axes, prior to positioning. Note the effect of immobilized (more than 72 hours since burn/ gravity on the tongue. Axes will rotate around the immobility). Vecuronium, rocuronium or cistra- lower cervical spine and atlanto-occipital joint curium are acceptable alternatives, with rocur- (marked with circles). (B) Airway with orotracheal axis, onium (1 mg/kg) swiftly working at 60 seconds after positioning. post injection, but the effect lasting longest to 60 minutes. Cisatracurium (0.15 mg/kg) and vecuronium (0.1 mg/kg) take 2–3 minutes re- spectively to work, but effects last for 30–40 minutes. There is no evidence of any protective sary resources and personnel to safely secure the effect of any of the above agents upon the brain. airway. Competence requires frequent practice. An examination of Figure 2.1(A) illustrates that, in Support of the Airway the supine position, there is a tendency for both Supporting the airway with bag mask ventilation the mandible and tongue to fall back against the is a greatly undervalued skill which is intrinsic to posterior pharyngeal wall obstructing the airway. intubation, and is lifesaving when done correctly. The application of jaw lift is achieved by applying Its application allows for the collection of neces- upward pressure at the angle of the mandible, 2 Airway Management in the Neurological and Neurosurgical Patient . 15 without moving the neck (crucial in circum- advanced. This helps to negotiate the tongue, stances of trauma without cervical spine clear- which might otherwise obstruct the ance), or pushing the tongue into the pharynx. insertion. The insertion of an oropharyngeal airway will help to position the tongue anteriorly, particu- larly in the edentulous. An inexperienced provid- Nasal airways can be used with caution, having er can support the jaw with the fourth and fifth a higher frequency of bleeding on insertion. They fingers of each hand, sealing the mask to the face are relatively contraindicated in facial injuries or with the thumb and first finger, while an assistant basal skull fractures. squeezes the bag. There are various bags avail- In circumstances of difficulty in bag/mask ven- able, but the easiest to use are the self-inflating tilation, there are now a large variety of supra- types, e.g. Laerdal or Ambu. glottal airways, which all offer the ability to bring the airway closer to the epiglottis, and stay se- Difficult Mask Ventilation curely seated in the pharynx. These devices can Difficult mask ventilation (DMV) can be defined be used for emergent support and ventilation, but as an unassisted provider being unable to keep should rarely be a first-line treatment. They do the arterial saturations above not protect the lungs from aspiration, and indeed 92%, or to avoid and correct for signs of inade- may obscure the presence of vomitus in the quate ventilation during positive-pressure mask pharynx. ventilation. Identifying a potential DMV patient is an important step in addressing the adequacy Difficult Airway Intubation of available resources and alternate strategies Difficult intubation has a similar prevalence prior to any procedure. (1–8%) to that of difficult mask ventilation A useful mnemonic to identify a possible (3–8%). It has been defined by a need for more DMV patient is O-B-E-S-E, where O ¼ Obese pa- than three attempts at intubation or attempts tient (BMI > 26), B ¼ Bearded patient, E ¼ Elderly that last longer than 10 minutes. This latter patient (age > 55), S ¼ Snoring history of patient, metric is more applicable to the elective pre- and E ¼ Edentulous patient. These factors have oxygenated patient in the operating room, as all been independently associated with DMV and opposed to the emergent patient in the field, ER, may alert the clinician to possible difficulty. This or ICU. can ensure the availability of adjunct devices or Difficult intubation is usually associated with personnel prior to starting nonemergent intuba- limited exposure of the glottis on direct laryn- tion or before extubating patients with existing goscopy. In examining Figure 2.1(A and B), it can endotracheal tubes. Alternatively, it may indi- be seen that the degree of exposure correlates to cate that difficult airway devices should be kept the ability to align the pharyngeal, laryngeal, and by the bedside if a need for airway support is oral axes. anticipated later. The alignment involves a series of maneuvers, with the laryngeal axis moved “forward” by flexing the lower cervical spine, and the oral CAUTION and pharyngeal axes moved “backward” by opening the mouth with an extension of the Care should be taken with the insertion of any atlanto-occipital joint. Soft tissues can be man- airway device since a rough technique can aged by inserting a laryngoscope to displace lacerate gums, tongue, and palate and cause the tongue to the left and, simultaneously, bleeding which will exacerbate difficulty in compressing the tongue into the submandibular any situation. Most oropharyngeal airways space. The mandible is then lifted forward in should be inserted with the end curving up, the direction of the arrow. The final step is until the arch of the curve just enters the either (a) placement of the laryngoscope blade mouth, then rotated 180 degrees and (Macintosh type) anterior to the epiglottis in 16 . Acute Management of Neurological Emergencies

Table 2.2. Mallampati grading the sensitivities and specificities for all these parameters vary widely. Class I visualization of the soft palate, fauces, uvula, and both anterior and posterior pillars TIPS & TRICKS Class II visualization of the soft Finger width is not consistent! While 3 palate, fauces, and uvula fingerbreadths has been a traditionally Class III visualization of the soft employed measure to define a “normal” palate and the base of thyromental distance, the variation in the uvula clinician finger size is considerable, and a better measure is to define a 6.5 cm distance Class IV the soft palate is not as the threshold for normality. Some even (difficult) visible at all suggest a height/TMD ratio (greater than 23.5) to offset size bias. This may also help the vallecula, which will exert pressure on the with race and gender. hyoepiglottic ligament lifting the epiglottis to expose the cords (in a manner akin to a stepping on a pedal bin to lift the lid), or (b) lifting the TIPS & TRICKS epiglottis with the laryngoscope blade itself (Miller type), to expose the cords directly. In The Upper Lip Bite Test (ULBT) classes are this maneuver, the blade should never be used defined as: to lever the lower airways on the fulcrum of the upper jaw as this may induce trauma and does Class I: Lower incisors can bite the upper not improve the view. lip above the vermilion line A variety of clinical scoring assessments to Class II: Lower incisors can bite the upper predict the success of direct laryngoscopy have lip below the vermilion line been described. The best known is the Mallam- Class III: Lower incisors cannot bite the pati score introduced in 1985. This requires pa- upper lip; this correlates with tient cooperation, which limits its utility in the difficult intubation. ICU, but may be available from a previous as- sessment. Classification from grade I to IV is associated with an increasing difficulty of intu- Given the limitations of any single parameter, bation (and also of mask ventilation). Table 2.2 several authors have attempted to define com- shows the scores obtained on examining the soft posite scores based on an amalgam of physical tissues of the pharynx in a seated patient with his and historical characteristics. mouth open and silent extension of the tongue. The LEMON score summates a variety of an- Specificity and sensitivity for this scale range thropometric features along with somatypic widely in the literature, from 40 to 60% and 70 to characteristics and neck mobility. It uses four 95% respectively. “look” criteria, three “evaluate” criteria, the pres- A number of other attributes have been identi- ence of airway obstruction, and neck mobility fied to assess the patient for difficult intubation. (Table 2.3). It has been evaluated in an emer- These include decreased the thyromental dis- gency department setting. tance (TMD), limited neck extension, the mento- If a test cannot be performed the patient recei- hyoid distance, the sternomental distance, the ves a score of zero for that criterion. distance between incisors, and the inability to The maximum airway assessment score possi- protrude lower incisors forward beyond the up- ble is 10 and the minimum 0. In prospective per incisors (upper lip bite test). While this latter studies, the “evaluate” criteria could be fully test has the highest sensitivity in recent studies, assessed in 90% of the emergency department 2 Airway Management in the Neurological and Neurosurgical Patient . 17

Table 2.3. LEMON score grading Observation Trigger Point score

(L)ook externally . facial trauma 0–4 points . large incisors . a beard or moustache . large tongue (E)valuate the 3-3-2 rule . Interincisor distance in fingers 0–3 points no less than three finger breadths (3) . Hyoid-mental distance no less than three finger breadths (3) . Thyroid notch to floor of mouth no less than two finger breadths (2) (M)allampati score Greater than 2 0–1 point (O)bstruction? e.g. epiglottis, peritonsillar 0–1 point abscesses, traumatic swelling (N)eck mobility Limited neck flexion or extension 0–1 point (includes cervical collar) population and “Mallampati” was assessable in TIPS & TRICKS 57% of patients. Due to this limited utility a modification has been suggested to drop the SUGGESTIONS FOR A DIFFICULT INTUBATION KIT Mallampati element and use a 9-point maxi- Spare laryngoscope Handles (x 2) mum. The designers of the LEMON score accept Macintosh & Miller blades: sizes ranging the inherent subjectivity of observations but through 2, 3, and 4 stress the speed and sensitivity of the composite score. Eschmann “bougie”catheter or Cook The adequacy of any view itself should be Exchange catheter (not a ventilation device) recorded for future information. This can be ex- Laryngeal mask device: sizes ranging pressed on the Cormack–Lehane scale – from 1 to through 3, 4, and 5 4 depending on the decreasing visualization of McGill Forceps: for guiding tubes through vocal cords past epiglottis or tongue (Figure 2.2). the cords and/or removing obstructing Intubation itself should occur in an environ- foreign bodies ment that has been as prepared as possible. Spare CO detector There are a number of accessory devices that 2 should be considered for inclusion in a “difficult airway kit” and it is the practice in many The simple bougie is a straight catheter that institutions to have one of these available in can be used in circumstances where there is a each unit or floor. restricted view of the glottis. The smaller size of

Figure 2.2. Cormack & Lehane classification of glottal view at intubation. 18 . Acute Management of Neurological Emergencies the Eschmann bougie allows placement through this reason, after three unsuccessful attempts to the glottis under direct vision, and an endotra- intubate, the ASA task force recommends pro- cheal tube can then be passed over the bougie. ceeding through their difficult airway algorithm The Cook exchange catheter serves the same (irrespective of the experience of the provider). purpose but allows for a modest flow of oxygen. A failure of intubation does not necessarily mean This flow is insufficient to allow ventilation but a failure to ventilate. A return to bag/mask ventila- can maintain oxygenation in some circum- tion may allow time for oxygenation to recover and stances. A malleable stylet inside the endotrache- accessory resources to be gathered. The intubator al tube can be molded to curve toward a larynx must acknowledge that repeated attempts will aligned anteriorly to the axis of view. make airway edema, secretions, or bleeding more Other aids to difficult intubation range from likely and could thus render ventilation difficult. articulated laryngoscope blades (McCoy) with the While an experienced clinician may have more ability to exert more lift at the epiglottis, to video success at intubation than a novice, this advantage assisted laryngoscopes. The intubating laryngeal is eroded by increasing the number of attempts. mask (ILMA) is a specially adapted supraglottic For this reason, the intubator must give careful airway. When positioned above the glottis, an thought to stopping attempts while the situation accompanying endotracheal tube can be inserted is still under control. The intubator may want through the ILMA into the trachea. The ILMA can to seek assistance, while determining whether (a) then be removed or remain in place. changes in the patient’s position may improve Fiberoptic intubation is commonplace in the the intubating conditions; (b) the insertion of a operatingroomandcantransforman“impossible” supraglottic airway is appropriate; or (c) a crico- intubation into a practical procedure. There are thyroidotomy is required. somecaveats.Thereisa clear learning curve, which A modified difficult airway algorithm (adapted must be practiced in elective situations. Fiberoptic from the ASA version) is presented in Figure 2.3. procedures require an anesthetized airway, by ei- Its utility outside of the operating room is to lead ther local or general anesthesia, as their use in a the clinician through a series of rescue maneu- poorlyanesthetizedairway can provokesecretions, vers, with a clear indication for a surgical airway bleeding, laryngospasm, coughing, and hypoxia. when required. Fiberoptic visualization can also be compromised If the situation is uncontrolled (i.e. the patient’s by the presence of secretions and/or bleeding. In condition is deteriorating), there should be a low thesecircumstancesa“macroscopic”viewofdirect threshold to proceed straight to cricothyroidot- laryngoscopy is probably superior. omy. Since most providers are inexperienced in Once the endotracheal tube has been placed the surgical placement of cricothyroidotomy, an through the glottis, markers on some makes of inexperienced provider should practice assem- tube signify an appropriate depth of insertion bling the materials for this life-saving maneuver, when positioned at the level of the vocal cords. and rehearse the practical steps below.

The gold standard for tracheal placement is CO2 detection. Portable devices are available that re- 1. A 14 g intravenous cannula can be placed

flect either color change or display measured CO2 through the cricothyroid membrane into the concentrations as a waveform and/or numerical trachea, the needle withdrawn and the cathe- value. Relying on chest movement and breath ter connected to the empty barrel of a 5 mL sounds are inadequate and have fooled many syringe with the plunger removed. experienced providers. 2. This syringe barrel will serendipitously con- nect to a 7 mm or 7.5 mm ET tube connector. “When to Stop?” This allows connection to a standard oxygen This is an important question to ask during any source for small-volume ventilation. difficult intubation. There are many case reports 3. It is important to understand that this is a of experienced practitioners losing awareness of life-saving maneuver and will buy time in an hypoventilation and hypoxia in the patient, in extreme situation until a definitive surgical their desire to place an endotracheal tube. For airway is secured. 2 Airway Management in the Neurological and Neurosurgical Patient . 19

Initial intubation attempts UNSUCCESSFUL Successful intubation*

FROM THIS POINT ONWARDS CONSIDER: NON-EMERGENCY PATHWAY Alternative approaches FACE MASK VENTILATION ADEQUATE Ventilation to intubation (1) 1. Calling for help adequate,intubation 2. Returning to spontaneous ventilation 3. Awakening the patient

FAIL after multiple attempts FACE MASK VENTILATION NOT ADEQUATE IF BOTH FACE MASK AND LMA CONSIDER/ATTEMPT LMA LMA ADEQUATE* VENTILATION BECOME INADEQUATE

LMA NOT ADEQUATE OR NOT FEASIBLE Invasive airway access *(2)

EMERGENCY PATHWAY Ventilation not adequate, Consider feasibility of intubation unsuccessful other options (4)

Successful ventilation* Awaken patient Call for help

Emergency non-invasive

airway ventilation * Confirm ventilation, tracheal intubation or LMA placement with exhaled CO2

(1) Includes (but not limited to) –use of different laryngoscope blades; LMA as an intubation FAIL conduit (+/– fiberoptic guidance), fiberoptic intubation, intubating stylet or tube changer (2) Includes surgical or percutaneous tracheostomy or cricothyrotomy (3) Includes (but not limited to) – rigid bronchoscopy, combitube, or transtracheal ventilation Emergency invasive (4) Includes (but not limited to) – LMA (if mask ventilation okay), awake intubation airway access*(2)

Figure 2.3. Modified difficult airway algorithm – reflecting urgent/emergent practice. (Modified from an report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway, 2003, with permission from Lippincott Williams & Wilkins.)

4. There are two important limitations to note: ing the head between outstretched hands (a) This method will oxygenate but not with the fingers stabilized on the patient’s ventilate; shoulders; or (b) To avoid the risk of barotrauma, insuf- (b) stabilizing from “below” with the fingers on flated gas must be allowed to escape from the mastoid processes and the thumbs on the lungs through the trachea and mouth. zygomas with wrist and forearms bracing the patient’s neck on the shoulders.

Suspected Cervical Spine Injury Once the neck is supported, the front of the collar is removed to allow mandibular move- and Intubation ment. There should be no flexion or extension Trauma patients should always be considered to of the neck, as this has been associated with have a cervical spine injury until otherwise iatrogenic spinal cord damage. The back of the cleared. This requires immobilization of the neck collar may be left on. The head is left in a neutral during intubation by an assistant in either of two position for laryngoscopy. Although this signifi- positions: cantly adds to the difficulty of the procedure and increases the chances of failure, it is a necessary (a) stabilizing the head from “above” by crouch- precaution against injury. Once the ET tube is ing to the side of the intubator and support- placed, the collar is reassembled. 20 . Acute Management of Neurological Emergencies

Extubation Khemani RG, Randolph A, Markovitz B. Corticos- We must briefly consider the appropriate circum- teroids for the prevention and treatment of stances for extubation. As most neurological pa- post-extubation stridor in neonates, children tients will fail extubation due to airway issues, and adults. Cochrane Database Syst Rev careful attention should be paid to the compe- 2009 Jul 8;(3): CD001000. tency of the airway before extubating. Langeron O, Masso E, Huraux C, et al. Prediction The possibility of swelling should be consid- of difficult mask ventilation. Anesthesiology ered along with an assessment of the ability of 2000; 92: 1229–1236. cough and gag reflexes to protect the airway. This Levitan RM, Kinkle WC, Levin WJ, et al. Laryn- must be performed in the context of the overall geal view during laryngoscopy: a randomized neurological state of the patient. Swelling of the trial comparing cricoid pressure, backward- airway and cords is a noted problem that leads to upward-rightward pressure, and bimanual secondary reintubation. A recent randomized laryngoscopy. Ann Emerg Med 2006; 47: trial demonstrated that steroids administered 548–555. after an unsuccessful extubation, were clinically Neilipovitz DT, Crosby ET. No evidence for effective in facilitating subsequent extubation. decreased incidence of aspiration after rapid The question of how much reflex protection is sequence induction. Can J Anaesthesiol 2007; required for the avoidance of aspiration is con- 54: 748–764. troversial. Giving a trial of extubation is impor- Practice guidelines for management of the diffi- tant with appropriate warning to staff, patient, cult airway: An updated report by the American and family that reintubation may be required. Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthe- Conclusion siology 2003; 98: 1269–1277. The ABCs must never be forgotten when support- Ramachandran K, Kannan S. Laryngeal mask ing neurological function. The dependence on airway and the difficult airway. Curr Opin artificial airways and the potential complications Anaesthesiol 2004; 17: 491–493. demand significant expertise. The practitioner Reed MJ, Dunn MJ, McKeown DW. Can an airway must take every opportunity to practice in elec- assessment score predict difficulty at intuba- tive circumstances, in order to be able to avoid tion in the emergency department? Emerg Med insult and/or save lives in situations of urgency J 2005; 22: 99–102. and stress. Scrase I, Woollard M. Needle vs surgical cri- cothyroidotomy: a short cut to effective venti- References lation. Anaesthesia 2006; 61: 921–923. Coplin WM, Pierson DJ, Cooley KD, et al. Implica- Yentis SM. Predicting difficult intubation – tions of extubation delay in brain-injured pa- worthwhile exercise or pointless ritual? tients meeting standard weaning criteria. Am J Anaesthesia 2002; 57: 105–109. Respir Crit Care Med 2000; 161: 1530–1536. Yildiz TS, Solak M, Toker K. The incidence Cormac RS, Lehane J, Difficult tracheal intubation and risk factors of difficult mask ventilation. in . Anaesthesia 1984; 39: 1105–1111. J Anesth 2005; 19: 7–11. 3 Traumatic Brain Injury and Intracranial Hypertension Iain J. McCullagh1 and Peter J.D. Andrews2

1Department of Anaesthesia, Critical Care and , University of Edinburgh, Edinburgh, UK 2Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

Introduction The global extent of TBI is unknown, but the Epidemiology and Economic Assessment incidence of TBI that is severe enough to war- rant medical attention or result in death is The epidemiology of traumatic brain injury estimatedtobemorethan9.5million(1990). (TBI) is difficult to describe accurately due to Population-based studies from South Africa, inconsistencies in the definition and classifica- India, and Taiwan suggest higher rates in de- tion of the condition. It is estimated (2010) that veloping countries, predominantly attributed there are more than 1.1 million new hospitalized to traffic injuries. cases of TBI per annum in the USA, Japan, The consequences of TBI for patients, their France, Germany, Italy, Spain, and the UK. Cau- families, and caregivers are financial, emotional, tious estimates show the incidence of hospital- and psychological. Traumatic brain injury carries ized cases of TBI to be higher than the annual a high economic impact due to neurological incidence of some cancers, epilepsy, HIV/AIDS, deficit(s), including loss of memory and executive , and spinal cord injury. Im- function, and behavioral disturbances that result portantly, there remains no treatment that is able to prevent the cascade of physiological in dependency and chronic disability necessitat- events (known as the secondary injury process) ing lifelong care. It is estimated that 43.3% of TBI that leads to neuronal cell death and is believed victims in the USA have residual disability one to result in poorer functional recovery. The year after injury and recent estimates of the overall annual incidence of TBI in the USA is prevalence of US civilian residents living with 506.4 per 100,000, and each year approximately disability following hospitalization with TBI is 50,000 patients die after TBI. 3.2 million. The global burden of TBI approxi- The major risk factors for TBI in the USA are age, mates the combination of both cerebrovascular gender, and low socioeconomic status. Persons at and depressive illness disorders. Though progress the extremes of age have the highest incidence has been made to reduce the healthcare burden rates, 900 and 659 per 100,000 for those younger of TBI, including significant reductions in mor- than 10 and older than 74 years, respectively. The tality over the last 20 years, it remains a major rate among men is nearly twice that of women. issue worldwide. For this reason

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

21 22 . Acute Management of Neurological Emergencies there has been a significant campaign to improve Development of Treatment the outcomes of TBI patients, using evidence- Strategies based guideline management strategies devel- The goals of prehospital care for TBI are to stabi- oped by international panels of multidisciplinary lize patients for transport, to triage those with experts. It is hoped that a review of the current mass lesions and impending cerebral herniation, evidence will focus research on those areas of TBI and to prevent secondary insults and injury. management that lack evidence-based guide- Increased intracranial pressure (ICP), cerebral lines. The primary responsibility of critical care edema, loss of cerebral autoregulation, and physicians managing TBI patients is to minimize alterations in brain metabolism are inherent se- secondary brain injury. In this chapter we will quelae of the primary brain injury. External and/ explore the practical ways this may be achieved or iatrogenic events may exacerbate secondary during the patient’s journey from the prehospital injury processes. Patients with multiple trauma arena, to recovery in a critical care unit. frequently incur injuries that compromise car- diopulmonary status, and they are therefore Classification of Traumatic Brain particularly vulnerable to secondary injury. Injury These insults are common and are independent The heterogeneity of TBI is considered to be predictors of poor outcome in patients with TBI. one of the principal barriers to finding effective Well-organized trauma systems with robust therapeutic interventions. In October 2007, the protocols for field resuscitation, transport, and National Institute of Neurological Disorders trauma facility destination ensure reproducible and Stroke, with support from the Brain Injury high-quality prehospital care. Advances in Association of America, the Defense and Veter- prehospital practice are a key target for further ans Brain Injury Center, and the National improvements in long-term functional outcomes Institute of Disability and Rehabilitation Re- following TBI, not least because of the proximity search, convened a workshop to outline the to the time of impact. steps needed to develop a reliable, efficient, Several guidelines for the treatment of TBI and convincing classification system for TBI exist. The most frequently cited are those pro- that could be used to link specific patterns of duced by a joint project of the Brain Trauma brain and neurovascular injury to appropriate Foundation (BTF), the American Association of therapeutic interventions. Neurological Surgeons and the Congress of Neu- Currently, the Glasgow Coma Scale (GCS) is the rological Surgeons (AANS/CNS joint section on primary criterion for classification of TBI. While Neurotrauma and Critical Care). These evidence- the GCS is extremely useful in the clinical man- based guidelines were first published in 1995 with agement and prognosis of TBI, it does not provide the latest iteration published in 2007. The major- specific information about the pathophysiological ity of the clinical trials reviewed were small and mechanisms that are responsible for neurological methodologically poor and therefore most guide- deficits and are targeted by interventions. Due to lines are based on class II or III evidence with no the limitations of the GCS, it has been proposed positive level I recommendations. Despite these that a new, multidimensional classification sys- limitations, many experts regard them as a stan- tem should be developed for TBI clinical trials. dard of care. It is hoped that adherence to a In clinical practice, classification has generally guideline-based approach for TBI care will im- been based on clinical indices of injury severity at prove outcomes through standardization; and presentation. The 15-point GCS (Teasdale et al., this approach may also facilitate large-scale in- 1974) is the most commonly used neurological tervention trials in the future. injury severity scale for adults, because of its high These guidelines support the monitoring and inter-observer reliability and generally good management of raised ICP in the intensive clinimetric and prognostic capabilities (Narayan care unit. The influence of these guidelines is et al., 2002). Mild injury is defined as GCS 15–13, evidenced by the fact that between 1995 and moderate by GCS 12–9, and severe by GCS <9. 2005 the use of ICP monitoring has increased 3 Traumatic Brain Injury and Intracranial Hypertension . 23 from 32 to 78%. This approach makes it possible to calculate, and subsequently manage, the cerebral perfusion pressure (CPP) which is an essential parameter in preventing secondary brain injury.

Intracranial Pressure and Cerebral Blood Flow The understanding of a raised ICP originated from Scotland and is summarized in the princi- ples credited to Edinburgh Professors Monro (1783) and Kellie (1824), which state that, once the fontanelles and sutures are closed:

Figure 3.1. Intracranial compliance is the change in 1. the brain is enclosed in an inflexible case of volume (dV) per unit change in pressure (dP). bone of a fixed volume; Compliance is the inverse of elastance (dP/dV) 2. the brain parenchyma is nearly incompress- sometimes known as the volume-pressure response ible (80% of cranial contents are brain paren- (VPR). Compliance (C ¼ dV/dP) ¼ 1/Elastance ¼ 1/VPR. chyma, by volume approximately 1500 mL); [a ¼ normal intracranial compliance; b ¼ reduced 3. the volume of the fluid in the cranial cavity is intracranial compliance; and c ¼ exhaustion of therefore nearly constant (10% blood and 10% volumetric compensatory mechanisms and critical cerebrospinal fluid (CSF)); and reductionincompliance.](ModifiedfromLangfitt, 4. a continuous outflow of venous blood from 1964.) the cranial cavity is required to make room for the continuous incoming arterial blood, keep- ing the overall cerebral blood volume (CBV) near constant.

The importance of these observations is that the skull cannot accommodate any additional vol- ume and, therefore, when the system is chal- lenged by additional volume, the displaceable contents (i.e. venous blood and CSF) are initially moved outside the skull by a process called com- pression elimination. When these physiological volumetric compensatory mechanisms become exhausted, the ability to accommodate any fur- ther new volume is impaired and intracranial compliance is reduced. The final effect is a raised ICP. The cranium can tolerate only a 25 mL rise in total volume acutely before the ICP rises sharply (Figure 3.1) but if the rise in volume is slow, it can tolerate up to 150 mL. The effect of any mass Figure 3.2. Transtentorial herniation (A) and uncal lesion is also strongly dependent on its site, with herniation (B) is produced by expanding supratentorial posterior fossa lesions causing obstruction of lesions (M1), as opposed to posterior fossa lesions (M2) CSF flow and hydrocephalus, and subsequent which lead to both hydrocephalus via obstruction of brainstem compression with supratentorial le- CSF flow and tonsillar herniation (C) which will sions causing transtentorial herniation and uncal ultimately progress to brainstem death if no herniation (Figure 3.2). intervention occurs. 24 . Acute Management of Neurological Emergencies

The relationship between intracranial pressure to secondary injury. However, it is important to and volume is termed “compliance.” Compliance control both ICP and mean arterial pressure varies with age, being higher in older patients carefully within a balanced approach to CPP due, in part, to a smaller volume of brain paren- management. chyma. This may result in increased tolerance to space-occupying lesions, at least for a short peri- Initial Management of TBI od of time. All TBI patients are “trauma patients,” including those thought to have an isolated brain injury. All Cerebral Blood Flow should be assessed from head to toe, front and In healthly patients cerebral blood flow (CBF) is back, as a significant proportion of TBI patients autoregulated and remains approximately will have multiple injuries that benefit from 40–50 mL/kg/min between a mean arterial pres- management in a systematic and appropriately sure (MAP) of 50–120 mmHg. Within this global triaged manner. This requires a team approach, measure, the metabolic demands of subregions of with a team leader to coordinate their actions and thebraincreatedifferentialflowbyseveraldifferent prevent errors in prioritization. Most often this mechanisms, generally termed “autoregulation.” will involve a “trauma team” approach with ap- These mechanisms include metabolic feedback, propriate early involvement of neurosurgery. The with areas of high demand producing metabolites American College of Surgeons has developed a that increase the local blood supply. Neurogenic training program that guides therapy in this situ- mechanismsprobablyplayonlyasmallrole,viathe ation; the “Advanced Trauma Life Support” autonomic nervous system, but autoregulation is (ATLS) approach is now an international stan- not yet fully elucidated. dard. The most life-threatening injuries are given There is a near linear relationship between an order of priority: airway, breathing, circula- PaCO2 and CBF within the physiological range. tion, disability, and exposure. A detailed descrip- In TBI patients with raised ICP, an elevated tion is beyond the scope of this text but several PaCO2 will result in an increase in CBF and CBV important points should be made: and a further rise in ICP. Loss of vasoreactivity to . PaCO2 is a poor prognostic sign. The relationship All patients with a GCS score less than or equal to with oxygen tension is such that CBF is unaltered 8 (after resuscitation) should be intubated and until a low PaO2 threshold of approximately mechanically ventilated (i.e. all severe TBI pa- 50 mmHg is reached and arterial oxyhemoglobin tients); many practitioners would recommend desaturation occurs, thereafter vasodilation oc- intubating all patients not obeying commands. curs to preserve the cerebral oxygen supply, po- . Avoidance of hypoxemia and hypoventilation tentially increasing CBV and ICP. is vital if secondary brain injury is to be avoided. In the severely injured brain these autoregulation . A primary survey (exposure) is undertaken ear- mechanisms function less efficiently and this has ly, identifying visible injuries and assessing led to the modern practice of targeting a surrogate carefully for concealed injuries in order to plan of global cerebral perfusion in an attempt to ensure potential surgical management. an adequate cerebral oxygen supply. Cerebral perfusion pressure (CPP) is equal to Management of the airway is inextricably linked to MAP minus ICP, and is a determinant of cerebral management of the cervical spine. In head-injured perfusion. Therefore, as ICP increases in the patients it should be assumed that the cervical injured brain, MAP must also increase in order spine is unstable until proven otherwise. This to maintain CPP. This relationship is fundamen- makes airway management in these patients po- tal principle of modern management of the in- tentially dangerous as movement of the cervical jured brain. CPP is targeted in order to maintain spine may result in catastrophic injury. Rapid se- the oxygen supply to the injured areas of the quence intubation with manual inline stabilization brain that have the potential to recover, and to of the cervical spine is the recommended ap- prevent further damage. Areas of brain tissue proach. This should be undertaken by experienced adjacent to focal injury are especially vulnerable personnel with difficult airway equipment imme- 3 Traumatic Brain Injury and Intracranial Hypertension . 25 diately available. An appropriately fitted cervical required to maintain the systolic blood pressure collar should be worn afterward and the patient (SBP) above 90 mmHg, especially if sedative “log rolled” until the cervical spine is “cleared.” agents are being infused. This is a minimum SBP Direct laryngoscopy is likely to cause a significant target in the initial phase even though it is likely and sudden elevation in blood pressure and heart that it will be associated with a MAP of less than rate, which leads to a rapid rise in ICP (as auto- 60 mmHg. Currently, there are no data to support regulation is impaired). If ICP is already elevated or a higher target, though many experienced clin- unknown, then uncal herniation (coning) is a seri- icians will target a CPP of 60 mmHg (see below). ous risk. Intravenous opiates (fentanyl/sufentanil/ Therapy may require some individualization alfentanil) or lidocaine should be given prior to the when multiple trauma is evident and hemorrhage anaesthetic induction agents as these can obtund is not yet controlled. this response. Induction agents should be chosen for hemodynamic stability and familiarity. After intubation, prolonged hyperventilation CAUTION may be harmful. It reduces CBF, by a combina- tion of reduced venous return and cardiac out- Evidence has clearly correlated that even put, and cerebral vasoconstriction. It is therefore short periods of hypotension worsen important to use an end tidal carbon dioxide outcome. It is crucial that meticulous care be monitor both during and after the insertion of taken to avoid these episodes during all an endotracheal tube, and assess frequent arteri- phases of resuscitation and subsequent al blood gas measurements. The BTF guidelines management. include a recommendation to administer two doses of broad spectrum antibiotics around the time of intubation to reduce pneumonia rates, Indices of coagulation should be checked and but this is based on one small, single centre and actively treated, keeping the INR less than 1.4 and unblinded study and many clinics do not perform the platelets greater than 75 103/mm3. The he- this intervention. Physiological Targets During and moglobin should also be maintained at a level greater than 8 gm/dL to ensure an adequate oxy- After Resuscitation gen-carrying capacity. This is a controversial It is vital to maintain an adequate CPP and topic and many experts will target a higher he- arterial oxygenation during resuscitation in order moglobin level, particularly if monitors of cere- to ensure adequate cerebral oxygenation. PaO2 bral oxygenation suggest an inadequate oxygen greater than 100 mmHg or SpO2 > 90% should be supply. targeted. This SpO2 target is included in the BTF Finally, plasma glucose levels should be fre- guidelines but is based upon data from retrospec- quently checked to avoid even short periods of tive studies and the level of SpO2 that harms the hypoglycemia (ABC ...Don’t Ever Forget Glucose!). brain is unclear. Decisions regarding non-neurosurgical surgi- Volume resuscitation with 0.9% saline should cal intervention should be made rapidly with the occur concurrently with the initial assessment. aim of terminating hemorrhage and managing The goal is to maintain a state of euvolemia. any perforated viscus. Definitive surgery should Assessment of volume status may be assisted by be delayed until hemodynamic stability is the insertion of a central venous catheter (CVC) present. but only a dynamic assessment of volume re- The surgical management of intracranial mass sponsiveness is useful, e.g. after a fluid challenge. lesions depends on the nature of the lesion as However, a CVC is also useful to deliver vasopres- defined by the initial CT scan, but does not sor agents such as norepinephrine (levophed), generally take place until other hemorrhage has neosynephrine (phenylephrine), epinephrine, or been controlled. Thereafter, the neurosurgical vasopressin, though boluses of phenylephrine intervention will depend upon site, size, and can be given peripherally. These agents may be mass effect of the lesion, and often includes 26 . Acute Management of Neurological Emergencies placement of a ventriculostomy. Further guid- basal metabolic requirements. Skin, bowel, and ance can be found in standard neurosurgical oral care should be meticulously managed, with texts. Referral to neurosurgery should not oral care usually including antiseptic gel to re- be delayed longer than 2 hours from presenta- duce bacterial colonization. CVCs should be tion. This is mandatory if the initial CT is abnor- managed within strict local protocols to mini- mal or if an indication for ICP monitoring is mize infection. present. Prophylaxis against deep venous thrombosis is important but minimal data are available to General ICU Care of TBI Patients guide its use. The administration of subcutane- The intensive care management of TBI is a mul- ous heparin is delayed for at least 72 hours or tidisciplinary process and high-quality nursing more when intracranial hemorrhage is present, care is the cornerstone of this endeavor. Short with some authors recommending a much periods of hypotension or hypoglycemia can be greater delay of up to 14 days. Heparin is not disastrous and can only be managed effectively normally used when an ICP monitor is in situ. by experienced and appropriately trained staff. Pneumatic sequential compression devices and The whole process is aimed at the prevention of TED stockings should be used in all patients secondary brain injury. It is vital that patients unless contraindicated. Prophylaxis against have the head of their beds elevated at least 30 stress ulceration is usually provided with ranit- degrees at all times and that a patient’s head and idine until patients are fully established on en- neck are kept in a neutral position. Obstruction of teral nutrition. jugular venous flow, including endotracheal tube Virtually all mechanically ventilated patients ties, must be avoided (though internal jugular receive sedative and/or analgesic medications at CVCs are acceptable) as this will lead to an in- some stage. Regimens for TBI patients generally crease in CBV and subsequent increases in ICP. include short-acting agents such as propofol in a Poorly fitted cervical collars can also cause this dose of 2–5 mg/kg/h combined with an opiate problem; the sizing and fitting of these should be such as fentanyl, alfentanil, or remifentanil. meticulous, and their removal a priority if Shorter acting agents may reduce time to libera- appropriate. tion from ventilation when elevated ICP has re- solved. Most patients should have sedative infu- sions reduced or stopped at least daily to mini- TIPS & TRICKS mize drug accumulation and incidence of oversedation. Family members of TBI patients come under unimaginable strain during the care of their close relative. Initial contact with TIPS & TRICKS medical staff should include a realistic and consistent assessment of potential Propranolol reduces agitation in the positive or negative outcomes. One must post-sedation phase of care in the hyper- not underestimate how long these adrenergic patient. It is the only intervention conversations will be remembered by those to reduce assaults on staff. who experience them. Above all remember to LISTEN attentively, and not simply pass on information. Early post traumatic seizures (PTSs) have not been definitively associated with worse out- comes, however TBI patients do have a relatively Adequate nutrition should be provided, with high incidence of PTSs. Consequently, the BTF nonpharmacologically paralyzed patients requir- guidelines recommend either phenytoin or ing around 140% of basal metabolic require- valproate for at least 7 days. Regular monitoring ments (Harris Benedict Equation). Those who of plasma levels is required to ensure therapeutic have received a muscle relaxant require 100% of levels. 3 Traumatic Brain Injury and Intracranial Hypertension . 27

Monitoring of ICP Brain Distortion. There are several factors that ICP Waveform. Brain tissue pressure and ICP have to be taken into consideration when a mass increase with each cardiac cycle resembling an lesion within the cranial cavity starts to expand. arterial pressure wave. The ICP pressure wave- One is distortion of the brain. Because of the form has three distinct components that are viscoelastic properties of the brain, the tissues related to physiological parameters (Figure 3.3). adjacent to the lesion will tend to flow away from The first peak (P1) is the “percussive” wave and is it, with axial movement of the brain leading to due to arterial pressure being transmitted from brain displacement. Although the local proper- the choroids plexus to the ventricle. It is sharply ties of the brain are important, the major factor peaked and consistent in amplitude. The second responsible for spatial compensation is a reduc- wave (P2), called the “tidal” wave, is thought to be tion in the volume of intracranial CSF. The due to brain tissue compliance. It is variable, progression is, therefore, local deformity with indicates cerebral compliance, and generally in- displacement of CSF, shift and distortion of the creases in amplitude as compliance decreases; if brain and, eventually, in the intact cranium, the it elevates or exceeds the level of the P1 waveform appearance of internal herniation (Figure 3.2). there is a marked decrease in cerebral compli- This represents the displacement of brain tissue ance. P3 is due to the closure of the aortic valve from one intracranial compartment to another or and therefore represents the dichrotic notch. into the spinal canal. This herniation occurs due to the development of compartmentalized acute pressure gradients. The BTF guidelines suggest that it is desirable to monitor ICP in the following patients: all patients with a GCS score of less than 8 and an abnormal CT scan (level II recommendation); patients with severe TBI and a normal CT who, (A) if they are over 40, have (or have had) a blood pressure less than 90 mmHg systolic, or have P2 P1 unilateral or bilateral motor posturing (level III P3 recommendation). These recommendations cannot be proscriptive to cover every clinical scenario. It is important to remember that a persistently raised ICP greater than 20 mmHg is associated with poor outcome, and this will not be detectable without ICP monitoring. (B) P2

P1 P3 TIPS & TRICKS

Never make assumptions about the quality of survival in the acute phase of care. Unless the injury is obviously unsurvivable (penetrating injury, etc.) Figure 3.3. P1 is the “percussive” wave, due to arterial pressure transmitted from the choroids plexus to the ventricle. It is sharply peaked and consistent in amplitude. P2 is called the “tidal” wave, due to brain ICP Monitoring Device Technology tissue compliance and generally increases in amplitude as compliance decreases; if it elevates or exceeds the The ventricular fluid catheter attached to an level of the P1 waveform there is a marked decrease in external strain gauge is considered the gold stan- cerebral compliance. P3 is due to the closure of the dard. These devices can be re-zeroed at any time aortic valve. and can also be used to drain CSF, thus reducing 28 . Acute Management of Neurological Emergencies raised ICP. These devices can be inserted at pupillary changes are known to occur at levels as the time of surgery or in a separate procedure. low as 18mmHg. The BTF guidelines suggest, in a They are accurate but carry an increased risk of level II recommendation, that an ICP of 20 mmHg infection. The zero reference for arterial and ICP should be the treatment threshold. transducers is the external auditory meatus, facilitating CPP measurement. Intraparenchymal monitors, using micro strain CAUTION gauge transducers or fibre optic technology, are commonly used and can be inserted at the In a patient with raised intracranial pressure, bedside via an intracranial bolt. Several manu- posture is all important. Never forget a facturers produce them, and most manifest neg- neutral head position and head-up tilt, ligible drift which is independent of the duration exaggeration of this tilt will often bring about of monitoring. This is important as they cannot rapid resolution of raised intracranial be re-zeroed once inserted. There are several pressure. This position should be used in the other invasive and noninvasive methods of mea- patient that is considered euvolemic. If this suring ICP available, and more information can position is used in the hypovolemic patient, be found in the Bibliography at the end of this cerebral vasodilation may occur in response chapter. However, the overall safety of ICP mon- to a drop in cerebral perfusion pressure. The itoring devices is excellent, with clinically signifi- supine position, e.g. for CVC insertion, may cant complications (e.g. infection and hemato- be hazardous especially if an intracranial ma) occurring infrequently. pressure monitor is not in situ. Brain Oxygenation Monitors It is possible to measure focal brain tissue PO , 2 Cerebral Perfusion Pressure and have this measure guide care. The physio- logical concept behind cerebral oxygen moni- The BTF guidelines recommend the avoidance of toring is that the PbrO2 value accurately repre- a CPP less than 50 mmHg, even for a brief dura- sents the balance between oxygen delivery and tion. The sole RCT found no difference in out- oxygen consumption, and that changes in PbrO2 comes in 189 adults with severe TBI treated will therefore reflect pathophysiological altera- according to either a CPP-based or an ICP-based tions. Five observational studies have reported algorithm. It should be noted that this study was that low PbrO2 values in patients with TBI pre- neither blinded nor properly randomized and the dict a poor outcome when an initial PbrO2 < groups were also managed differently in respect

10 mmHg for 30 min, and in those with PbrO2 of PaCO2. There was a significant increase in < 15 mmHg lasting 4 h. In addition, both the incidence of acute respiratory distress syndrome level and duration of low PbrO2 correlated with in the CPP > 70 mmHg group, partly due to mortality. The question whether these measure- excessive fluid administration, and this condition ments can be used to improve outcome has not is associated with greater difficulty in arterial been well studied. When arterial oxygen tension oxygenation and control of CO2. This observation is about 100 mmHg and the hemoglobin con- has led to concerns with targeting a higher CPP. centration is stable, these monitors provide data The generally accepted CPP target is 60 mmHg on cerebral perfusion (oxygen tension being the and is pragmatically based on a 10 mmHg in- marker of perfusion). Manipulation of PaCO2, crease above a level thought to be harmful. CPP and hemoglobin can then be targeted to Treatment of Raised ICP maintain an established perfusion or oxygen- ation goal. AllpatientswithICPmonitoringandmanagement following TBI will be mechanically ventilated and ICP Monitoring and Management should receive comprehensive “Stage 1” interven- There are no randomized-controlled trials com- tions before considering any escalation of thera- paring ICP treatment thresholds. Herniation and peutic intensity (Figure 3.4). Escalation to “Stages 3 Traumatic Brain Injury and Intracranial Hypertension . 29

STAGE 1 STAGE 2 STAGE 3 Admission to the Intensive Mannitol (maintan serum) Care Unit (ICU) osmolarity <315m osmoles) ≥ Ventilation PaO2 11kpa PaCO2 4.5-5.0kpa Hypertonic Saline (avoid in Sedation hyponatracmic patients, Analgesia ±paralysis caution in patients with Barbiturate therapy 30º head of bed elevation cardiac or pulmonary Intravenous fluids ± problems) inotropes to maintain mean arterial pressure (MAP) Inotropes to maintain Decompressive ≥80mmHg cerebral perfusinon pressure Craniectomy (CPP) >60mmHg Ventriculostomy±CSF drainage Monitor blood Magnesium Surgical removal of space levels and replace as occupying lesions required ± prophylactic anticonvulsants Barbiturates not permitted ± therapeutic hypothermia

Figure 3.4. Summary of tiered to be used in control of raised ICP, as used in the Eurotherm3235 trial (ISRCTN 34555414). Tier one therapies must be provided meticulously until raised ICP is no longer a concern.

2 and 3” therapy is required in 10–15% of ICP- below 320 mOsm/L. Volume status must also be monitoredpatientsafterTBI(Eurotherm3235Trial carefully assessed. data). There are very few data to support any of Hypertonic sodium chloride is widely used, but the interventions listed, but evidence based med- currently the BTF guidelines do not give any icine supports their utility for ICP reduction. A recommendations for this therapy due to a pau- large RCT, www.Eurotherm3235Trial.eu, is exam- city of trial data. The dose is 250 mL of 3% saline ining titrated hypothermia in patients with TBI over 30 minutes. Other centers have used varying and raised ICP. concentrations of hypertonic solutions. Serum sodium should be kept below 160 mmol/L during Hyperosmolar Therapy therapy and it should not usually be used in The two commonly used agents are mannitol and patients who are hyponatremic. hypertonic sodium chloride. Mannitol is a sugar alcohol molecule which is given in a dose of 0.25– Hyperventilation 1.0 g/kg intravenously over 15 minutes. It is be- Previously hyperventilation was seen as benefi- lieved to exert two separate effects. Firstly, it cial to TBI patients, but this is no longer accepted. reduces blood viscosity and improves CBF (this The PaCO2 should never be below 25 mmHg. effect is rapid). Secondly, there is an effect on This is a level II recommendation in the BTF cerebral water volume, reducing the water con- guidelines, based on a single RCT that was un- tent of structurally normal brain and ICP. The derpowered and not blinded. Most consider that evidence base for this therapy has been weak- normocapnia is the accepted target (i.e. a PaCO2 ened by the recent withdrawal of a Cochrane between 35 and 45 mmHg), especially in the early systematic review due to concerns with trial data. stages of injury, when CBF may already be sub- Current recommendations remain that mannitol stantially reduced. Hyperventilation should only is an effective therapy to reduce ICP but the effect be instituted in patients without ICP monitoring of long-term or high-dose therapy is not clear. If if signs of a critically raised ICP are seen, such as a using this therapy, serum osmolality must be dilating pupil or a Cushing response (sudden regularly measured (up to 4 times daily) and kept bradycardia or tachycardia and hypertension). In 30 . Acute Management of Neurological Emergencies

ICP-monitored patients, hyperventilation may be age by a variety of mechanisms. Adequate used briefly for acute control of ICP where it is volume status and careful monitoring of MAP is usually effective. However cerebral oxygen moni- vital if this therapy is to be used and titration to tors such as brain tissue oxygen tension should EEG mandatory. be used if hyperventilation is considered for more prolonged periods. Neuromuscular Blocking Agents These drugs can be used in patients with diffi- Induced Hypothermia cult to control ICP, and adequate levels of se- Hypothermia is thought to be of benefit in reduc- dation must be assured prior to use. All will ing brain water content, modulation of cerebral reduce muscle tone, prevent coughing, and re- repair mechanisms, and alterations in brain free- spiratory efforts. This usually reduces ICP at radical concentrations after injury. It also reduces least initially, but these agents also increase the global cerebral energy demands and may limit risk of critical illness polyneuropathy which the production of excitatory . may have an effect on the long-term functional The evidence in this area comes from six system- status. When used, a train of four monitor that atic reviews, two of which were positive (n ¼ 2096 assess muscle response to a standard stimulus in total) and demonstrated a reduction in ICP should be used, and two twitches out of four during cooling. should be seen.

Steroids CAUTION Steroid administration is controversial in many areas of critical care. Current evidence, based While hypothermia appears to be very mainly on the 2004 Corticosteroid randomization effective in lowering ICP, the largest study to after severe head injury (CRASH) trial is against date did not demonstrate any benefit from therapy with steroids in TBI. This trial, which was hypothermia in a head trauma population. stopped early (but still recruited >10,000 pa- Clinical trials have not been able to tients) demonstrated a mortality increase in the demonstrate a benefit of hypothermia after steroid-treated group (21% vs. 18%), but included head trauma even when hypothermia is moderate and even mild TBI. applied soon after head trauma. However, subgroup analysis has raised the possibility Decompressive Craniectomy that patients with hematomas removed Decompressive craniectomy is an option in treat- surgically may benefit from hypothermia. ing refractory intracranial hypertension. No clear More work with this subgroup will need to be evidence exists regarding its utility, and although performed. the procedure has been used for decades many questions have still to be answered. A most recent trial suggested that decompressive craniectomy was not useful for this population but has been Barbiturates criticized for its severe methodological limita- Patients in whom ICP is refractory to other ther- tions. Hopefully, ongoing randomized trials will apies can be treated with barbiturates. This is a help our understanding of the role and utility of level II recommendation in the BTF guidelines. this procedure in future. In the interim, when The long-term effect of these drugs is not clear faced with refractory intracranial hypertension and all the studies performed were in an era that is likely to produce a fatal outcome, clini- when prophylactic hyperventilation, fluid re- cians should consider surgical decompressive striction, and steroids were routine therapies. craniectomy. Prior to making this decision, clin- They may provoke, or worsen, cardiovascular icians must have used all the medical therapies instability and are immunosuppressive. Barbi- available against intracranial hypertension (in turates also reduce cerebral oxygen consump- patients considered appropriate for surgical tion significantly and may reduce cellular dam- intervention. 3 Traumatic Brain Injury and Intracranial Hypertension . 31

Conclusion CliftonGL,MillerER,ChoiSC,etal.Lackofeffectof It is to be hoped that, over the coming years, high- induction of hypothermia after acute brain in- quality clinical trials will be conducted which jury. New Engl J Med 2001 Feb; 344(8):556–563. clarify some of the contentious issues discussed Langfitt TW, Weinstein JD, Kassell NF, Simeone above. Until then, as with all modern intensive FA. Transmission of increased intracranial care, outcomes are maximized when routine pressure. I. Within the craniospinal axis. J Neu- matters are attended to in detail, and adverse rosurg 1964 Nov; 21:989–997. events are avoided. Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: past experience and Bibliography current developments. Neurotherapeutics 2010 Jan; 7(1):115–126. Andrews PJ, Citerio G, Longhi L, et al. Neuro- intensive care and . (NI- Narayan RK, Michel ME, Ansell B, et al. Clinical CEM consensus on neurological monitoring in trials in head injury. J Neurotrauma 2002 May; acute neurological disease. Section of the Eu- 19(5):503–557. ropean Society of .) Sahuquillo J, Arikan F. Decompressive craniect- Intens Care Med 2008 Aug; 34(8):1362–1370. omy for the treatment of refractory high intra- [Epub 2008 Apr 9.] cranial pressure in traumatic brain injury. Co- Andrews PJ, Citerio G. Intracranial pressure. Part chrane Database Syst Rev 2006 Jan; 25(1): one: historical overview and basic concepts. CD003983. Intens Care Med 2004 Sep; 30(9):1730–1733. Steiner LA, Andrews PJ. Monitoring the injured [Epub 2004 Jul 9.] brain: ICP and CBF. Br J Anaesthesiol 2006 Jul; Cairns CB, Maier RV, Adeoye O, et al. (Roundtable 97(1):26–38. [Epub 2006 May 12. Review.] External Participants and Roundtable Steering Teasdale G, Jennett B. Assessment of coma and Committee and Federal Participants). NIH impaired consciousness. A practical scale. Lan- Roundtable on Emergency Trauma Research. cet 1974 Jul; 2(7872):81–84. Ann Emerg Med 2010 Nov; 56(5):538–550. The Brain Trauma Foundation. The American Citerio G, Andrews PJ. Intracranial pressure. Part Association of Neurological Surgeons. The two: Clinical applications and technology. In- Joint Section on Neurotrauma and Critical tens Care Med 2004 Oct; 30(10):1882–1885. Care. Resuscitation of blood pressure and oxy- [Epub 2004 Jul 9. No abstract available. PMID: genation. J Neurotr 2000 Jun–Jul; 17(6–7):471– 15243685.] 478. Review. 4 Critical Care Management of Acute Spinal Cord Injury Edward M. Manno

Neurological Intensive Care Unit, Cleveland Clinic, Cleveland, OH, USA

Introduction/Background of secondary damage. It is estimated that up to 25% of the final neurological deficit can be Acute spinal cord injury (ASCI) is a devastating attributed to changes that occur after the initial injury with significant consequences. The most insult. recent statistics for the United States estimate an An initial assessment requires a thorough neu- incidence of 40 cases per million. Spinal cord rological examination and documentation of the injury mainly occurs in young men, who account level of injury. Several grading systems exist for for 81% of the presentations. The average age of defining the location and severity of neurological injury has been slowly increasing with the aging of injury after spinal cord injury. The most common the population, and is now 40.2 years. Motor vehi- classification system employed is the American cle accidents are responsible for approximately Spinal Injury Association (ASIA) grading scale. 50% of the injuries. Falls and diving accidents This classification of impairment is based on the contribute approximately 20% of injuries, while assessment of the neurological level that is in- sports-related accidents and violence (mostly volved and whether the injury is complete or gunshot wounds) account for the remainder. incomplete. An ASIA impairment classified as an ASCI can be divided into primary and second- A represents no motor or sensory function in the ary injury. Primary injury represents damage to sacral segments S4–5; B is an incomplete lesion the spinal cord directly from cord compression. that maintains normal sensation but no motor This occurs due to herniation from disks, bones, function below an identified level and includes or ligaments. Forces that distract, or tear, local the sacral S4–5 segments; C is an incomplete structures occur with flexion, extension, disloca- lesion with preserved motor function (identified tion, and other rotational injuries. Secondary as at least antigravity strength in more than half injuries represent changes that occur after the of the muscles) below an identified neurological primary process. These injuries are attributed to level of injury; D is a similar incomplete lesion secondary systemic and local vascular insults but has only half of the muscles below the lesion that lead to the development of focal edema and with preserved antigravity muscle strength; and E ischemia. The primary focus of acute care for represents normal muscle and sensory function. spinal cord injury patients is to limit the amount

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

32 4 Critical Care Management of Acute Spinal Cord Injury . 33

Initial Assessment, Stabilization, entire spine should be imaged. Magnetic reso- and Transport nance imaging (MRI) is performed in areas of the spine that are known to be, or are suspected of Spinal cord trauma is oftentimes accompanied being, injured. MRI is also used to identify liga- by head or multisystem trauma. In 20% of pa- mentous, disk, or bony injury in the obtunded or tients, spinal cord injury occurs over multiple and ventilated patient. In a patient with focal tender- often noncontiguous levels. This mandates that ness a fracture should be suspected and imaging immediate immobilization must happen at the should be focused on this area. Spinal clearance scene of the accident. Emergency personnel of the spine is left to the neurosurgeon or attend- should assess the need for immediate spine im- ing responsible for the acute trauma. In mobilization based on several potential risk fac- patients with potential or confirmed ASCI, a tors for cervical spinal injury in a trauma patient. comprehensive trauma survey should be per- These include patients with an altered mental formed. When screening for cerebrovascular in- status, evidence of intoxication, a suspected frac- jury in a patient with ASCI, the use of CT or MR ture or distracting injury, a focal neurological angiography should be considered. deficit, and spinal pain or tenderness. Immobilization is accomplished through the use of a cervical collar and support blocks to Acute Management prevent appendicular movements with restraints. Any trauma patient should have an immediate The patient must be placed on a rigid backboard trauma assessment and survey. Any trauma pa- for stabilization and all transportation on and off tient that needs endotracheal intubation should of this backboard must include inline stabiliza- be considered to have a cervical neck injury. tion and maintenance of spinal alignment. This is The level of injury will have a significant influ- accomplished through the technique of “log roll- ence on the respiratory pattern of the patient. ing” a patient, but as this maneuver places the Patients with high cervical spinal cord injury will patient at risk for pressure ulcers and aspiration, only be able to use their spinal accessory muscles care must be taken to monitor respiratory func- to initiate respiration. These patients will almost tion and skin breakdown. Measures should be always require emergent endotracheal intuba- initiated to prevent skin breakdown if prolonged tion. Patients with injury below cervical levels immobilization is anticipated. 3–5 will leave phrenic innervation to the Guidelines should be developed to triage pa- diaphragm variably affected, as this respiratory tients to centers with the most experience of pattern may be more stable. These patients may treating ASCI patients. A growing body of evi- have a particular respiratory pattern where the dence and opinion suggests that secondary com- abdominal contents move outward with inspira- plications due to ASCI are decreased in centers tion while the chest wall moves inward. This that are experienced in caring for these patients. unique respiratory pattern represents the normal Transfer to a level I trauma center (as defined by movement of the diaphragm; however, due to loss the American College of Surgeons) should be of thoracic intercostal muscle innervation, the strongly considered, particularly in patients with chest will move inward with inspiration. The multisystem trauma. resultant tidal volume that is generated will be In patients with documented ASCI, neuro-im- limited. Subsequently, these patients may require aging should be performed based on the re- endotracheal intubation. sources of the institution and the ability to per- form testing safely. Most institutions will start with a three-view cervical spine series. To in- TIPS & TRICKS crease the sensitivity for detecting subtle lesions or in areas difficult to visualize with plain imag- Body positioning of the patient may assist ing, many centers will include CT imaging of the respiration, depending upon the level of spine. Spiral or helical CT is commonly used in cervical spine injury. Patients with high the setting. If a cervical fracture is identified the cervical spine injuries should be sitting up 34 . Acute Management of Neurological Emergencies

(once the neck is stabilized). In this position sepsis, etc. Evaluation may prove difficult since the accessory muscles are best positioned to the ACSI patient may not be able to localize or generate whatever small tidal volumes are identify the pain. Most patients will require im- possible. aging of the chest, abdomen, and pelvis to evalu- Patients with lower cervical spinal cord ate for these possibilities. damage and intact diaphragmatic movement A significant number of ASCI patients will de- will breathe easier when supine. This allows velop hypotension secondary to neurogenic the abdominal contents to compress the shock. Sympathetic denervation to the vascula- dome of the diaphragm upward, which can ture is the responsible mechanism for neurogenic increase air exchange. Patients that are awake shock after ASCI. It is common in quadraparesis/ and alert can often vocalize the position that plegia or in high-level paraparesis/plegia. Loss of is best for them. sympathetic innervation to the peripheral circu- lation leads to arteriolar vasodilation and venous pooling of blood. In addition loss of cardiac sympathetic innervation (T1–4), results in unop- The endotracheal intubation of patients with posed parasympathetic-induced bradycardia cervicalneckinjuryrequiresconsiderableskilland and decreased systemic vascular resistance. expertise.Caremustbetakentolimitmovementof Higher cord levels involved after ASCI appear to the cervical spine. Awake, fiberoptic intubation is be related to worse hypotension. the preferred method if time and facilities allow. If Experimental data strongly suggests that hypo- fiberoptic equipment is not available, intubation tension is deleterious to spinal cord perfusion and should occur with rapid sequence induction and worsens outcomes, therefore the aggressive treat- manual inline stabilization. ment of hypotension after ACSI is warranted. The Careful consideration must be given to both initial treatment for ASCI is fluid resuscitation. the induction agent and the neuromuscular Vasodilation, which is common after ASCI, will blocking agent. Propofol is commonly used for require fluid resuscitation to maintain intravascu- induction, however this may aggravate hypoten- lar volume. Care must be taken to avoid over- sion in the setting of ACSI. Etomidate, which has resuscitation since there are some concerns that less hemodynamic effects but suppresses cortisol this may aggravate spinal cord edema. Swan Ganz release, has been associated with acute adrenal intravascular monitoring may be helpful in select- crisis and some authors have suggested using ed circumstances. An initial base deficit or lactate supplemental corticosteroids with its use. Succi- level can also be uses to assess the initial degree of nylcholine is the preferred neuromuscular block- shock and response to fluid resuscitation. er if used within the first 48 hours of injury, but it Vasopressors will often be needed to maintain should be avoided if significant muscle damage is adequate blood pressure and spinal cord perfu- suspected due to the possibility of developing sion, and the choice of vasopressor agent will life-threatening hyperkalemia. Nondepolarizing depend upon the clinical situation. Phenyleph- neuromuscular blockers should be used in these rine is a pure alpha agonist and will lead to circumstances. It is important that a complete peripheral vasoconstriction. It is a good choice neurological assessment be performed prior to if vasodilation is the main source of hypotension using nondepolarizing neuromuscular blockade. as it will increase central venous pressures and If the patient does not require mechanical venti- increase venous return. Norepinephrine and lation, it is prudent to obtain baseline pulmonary dopamine possess both alpha and beta adrener- function tests that can be used for comparison gic qualities that will increase peripheral vascular during later studies. resistance and cardiac rate and contractility. Many patients after ASCI will develop hypoten- They are the preferred agents when symptomatic sion. There are multiple possible etiologies that bradycardia or cardiac involvement occurs must be initially evaluated, including acute he- post-ACSI. morrhages, aortic dissections, pneumothorax, The use of corticosteroids as a neuroprotective adrenal insufficiency, pericardial tamponade, agent post-ASCI have been controversial. There 4 Critical Care Management of Acute Spinal Cord Injury . 35 are three prospective randomized double-blind This is maintained for the first week post-ASCI. trials that have evaluated the use of high-dose Similarly, bradycardia may need to be treated methylprednisolone infusion after ASCI. Initially with atropine or glycopyrrolate. In recalcitrant there was great enthusiasm for the use of corti- cases a temporary and occasionally permanent costeroids since later trials seemed to suggest an pacemaker may be needed. improved one-year outcome. The initial enthusi- Patients with high cervical spine injury are asm waned, however, with closer scrutiny of the likely to need mechanical ventilation for an ex- data and statistical methods, and concerns over tended period of time. In these circumstances the medical complications with steroid use. Advo- initiation of early tracheostomy can facilitate cates against the use of steroids point out that the both pulmonary toilet and mobilization. Patients utility of steroids remains unproven and that the with lower cervical neck injuries may be able to risks of medical complications should negate come off mechanical ventilation over a period of their use. Advocates for the use of steroids sug- 1 to 2 weeks. Vital capacities will improve as gest that concerns over medical complications spasticity of the chest wall develops. A patient are overstated with close attention to medical with an intact diaphragmatic function may be detail, and that the current data, while not con- able to be successfully weaned from the ventila- clusive, continues to support its use. tor. Patients after spinal cord injury or surgery There are several other neuroprotective agents will need to lie flat initially. Protocols to prevent that have been studied in ASCI and include tir- aspiration pneumonia require raising the head of ilizad, naloxone, aspartate agonists, and the neu- the bed to at least 30 degrees, and in such a roganglioside GM-1. Unfortunately none to date situation reverse Trendelenburg may be used. has proven to be effective. Patients with neurogenic shock may develop The timing of surgical decompression is con- symptomatic bradycardia in response to either troversial and variable. A majority of spine sur- internal or external stimuli. Endotracheal suc- geons in one survey prefer to decompress ASCI tioning can commonly initiate this response. within the first 24 hours. Surgery may be enter- Early nutrition is important to avoiding protein tained earlier for patients with incomplete le- malnutrition. Many ASCI patients will develop a sions. Central cord syndromes are usually man- significant ileus early in their clinical course, aged nonoperatively initially. which may make enteral nutrition difficult. Placement of a nasogastric tube for both decom- Management in the Intensive pression and early nutritional support is impor- tant. Enternal nutrition is preferred over paren- Care Unit teral nutrition. If a nasogastric tube is used, the There are several critical care issues that need to head of the bed must be elevated and gastric be evaluated and followed in the patient after residuals followed. A feeding tube placed into ASCI. Most are related to the mechanism of the the duodenum may facilitate nutrition and is initial injury, loss of autonomic innervation, and preferred for long-term treatment. Stress ulcer care for the immobilized patient. Most patients prophylaxis, as well as a bowel regimen, should with cervical neck injury will need to be admitted be initiated in the intensive care unit as soon as to an intensive care unit. feedings are started. The swallowing function The first role in the intensive care unit is to prior to oral feeding should be evaluated in any maintain adequate oxygen delivery to the injured patient with cervical spine surgery, prolonged cord. Various modes of mechanical ventilation intubation, tracheostomy, or halo fixation. may be needed to provide adequate oxygenation An indwelling urinary catheter should be in the multisystem trauma patient. In addition, placed during the initial assessment. It should maintenance of adequate blood pressure is need- be maintained until the patient is hemodynami- ed to maintain appropriate spinal cord perfusion. cally stable and strict control of the patient’s fluid A series of noncontrolled studies have supported balance is no longer considered necessary. the use of vasopressors to maintain a mean arte- A number of complications can be anticipated rial blood pressure between 85 and 90 mmHg. in patients with prolonged immobilization. Skin 36 . Acute Management of Neurological Emergencies breakdown is common and must be evaluated while the intensive care unit management focus- frequently; patients should be placed on a pres- es on preventing secondary complications and sure reduction mattress as soon as is feasible. initiating early nutrition and mobilization. Prophylaxis to prevent deep venous thrombosis should similarly be started as soon as feasible. Mechanical compression devices can be started Acknowledgment early. Low molecular weight heparin or an un- The author would like to acknowledge Ed Benzel, fractionated heparin can be started once a con- MD, for his review of this chapter. cern for bleeding has abated. Early mobilization in a rotating bed may decrease the incidence of Bibliography deep venous thrombosis. Berlly M, Shem K. Respiratory management dur- ing the first five days after spinal cord injury. J Spinal Cord Med 2007; 30: 309–318. TIPS & TRICKS Cohen-Gadol A, Pichelman MJ, Manno EM. Man- A rotating bed can sometimes help with fluid agement of head and spinal cord trauma in mobilization. Patient with ASCI often adults. In: Neurological Therapeutics Principles receive large amounts of fluids - either during and Practice ( Noseworthy JH,ed. ) Martin initial resuscitation or when returning from Dunitz Ltd, London, UK 2002 (2nd Edition, surgery. Many will have significant peripheral 2005), pp. 1221–1237. edema. In some cases the use of a rotating Consortium for Spinal Cord Medicine. Early bed can mobilize fluid without the need acute management in adults with spinal cord for pharmacologic diuresis. injury: a clinical practice guideline for health- care professionals. J Spinal Cord Med 2008; 31: 403–479. Psychological support is important for the pa- Fehlings MG, Rabin D, Sears W, et al. Current tient with significant spinal cord injury, and fre- practice and timing of surgical intervention in quent evaluation and support groups may be spinal cord injury. Spine 2010; 215: S166–S173. helpful. Consider the use of antidepressants in Hurlbert RJ. Strategies of medical intervention in patients with early signs of depression. Similarly, the management of acute spinal cord injury. pain can be underestimated in the patient Spine 2006; 11 (Suppl): S16–S21. with spinal cord injury, and pain should be Miko I, Gould R, Wolf S, Afifi S. Acute spinal evaluated using a rating scale. Methods to im- cord injury. Internat Anesthesiol Clin 2009; prove a patient’s communication should also be 47: 37–54. initiated. Miller SM. Methylprednisolone in acute spinal Conclusions cord injury: a tarnished standard. J Neurosurg Anesthesiol 2008; 20: 140–142. Patients after ASCI present a challenge to the critical care system. Acute stabilization of the National spinal cord injury statistical center. injury and maintenance of adequate oxygen de- Spinal cord injury Stats and figures. Updated livery to the spinal cord are paramount to im- June 2009. http://www.fscip.org/facts.htm. proving long-term neurological function. An ini- Ploumis A, Yadlapalli N, Fehlings MG, et al. A tial assessment and stabilization are required systemic review of the evidence supporting a prior to a decision for surgery. The use of steroids role for vasopressor support in acute SCI. remains controversial and a growing number of Spinal Cord 2010; 48: 356–362. centers are not using this in routine practice. The Rozet I. Methylprednisolone in acute spinal cord optimization of spinal cord perfusion focuses on injury. Is there any other ethical choice? maintaining adequate mean arterial pressures, J Neurosurg Anesthesiol 2008; 20: 137–139. 5 Subarachnoid Hemorrhage Muhammad A. Taqi and Michel T. Torbey

Department of Neurology and Neurosurgery, The Ohio State University, Columbus, OH, USA

Introduction smoking, and a family history of cerebral aneu- rysm, should raise suspicion for the diagnosis of The occurrence of subarachnoid hemorrhage SAH. Table 5.1 reviews the clinical Hunt and Hess (SAH) is almosy 3% of all strokes and one-third grading of SAH. of hemorrhagic strokes. Aneurysm rupture is the most common cause of spontaneous SAH. Brain Imaging The most common locations for an aneurysm The initial step in the diagnosis of a suspected include the anterior communicating artery, pos- SAH includes a CT scan of the head. The sensitiv- terior communicating artery, bifurcation of the ity immediately after the bleed is 98% within 12 middle cerebral artery, tip of the basilar artery, hours and declines with time to 57% after day 6. and posterior inferior cerebellar artery origin. The With the advent of new proton density sequences incidence of SAH is between 6 and 8 per 100,000 like gradient echo (GRE), MRI use has been population, with a mortality ranging between 32 gaining popularity especially when the clinical and 67%. suspicion of SAH is high and a CT scan is negative. Fisher grades and modified Fisher grades (Fig- Presenting Symptoms and Signs ures 5.1 and 5.2) are used to describe the extent of The classic “worst headache of my life” presen- SAH on a CT scan (Table 5.2). The Fisher grade tation occurs in more than 80% of patients with helps to predict the risk of cerebral vasospasm. aneurysmal SAH (aSAH). It is important to men- The next step after confirming the diagnosis of tion that only 1% of all headaches that present SAH is to identify the etiology. Traumatic SAH is to the ED are SAH. Milder headaches associated mostly cortical with associated contusions, skull with a sentinel bleed can be easily missed. Other fractures and subdural/epidural hematomas. It common symptoms of SAH include nausea, vo- is often difficult to conclude that the causal rela- miting, neck stiffness, focal neurological deficits, tionship between the trauma is the result of SAH and/or brief loss of consciousness. Ocular or the cause of SAH, and concomitant injuries can hemorrhages (subhyloid, retinal, or vitreous) are therefore be deceiving. A diffuse SAH without present in up to one-fourth of the cases. The evidence of trauma and contusions is very presence of risk factors such as like hypertension, suggestive of an aneurysmal bleed.

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

37 38 . Acute Management of Neurological Emergencies

Table 5.1. Hunt and Hess grade Grade Description I Asymptomatic, or mild headache and slight nuchal rigidity II CN palsy, moderate to severe headache, nuchal rigidity III Mild focal deficits, lethargy or confusion IV Stupor, moderate to severe hemi- paresis, early decerebrate rigidity V Deep coma, decerebrate rigidity, moribund appearance Add one grade for severe systemic disease(HTN, DM, COPD or severe atherosclerotic disease) Figure 5.2. An associated Acomm aneurysm. The location of bleed can be helpful in localiz- ing the aneurysm. The following patterns corre- late well with specific aneurysm locations: . Prepontine or peduncular: Basilar tip, Pcomm, PICA, or SCA . Interhemispheric fissure or gyrus rectus: . Isolated or predominantly IVH: Depending on Acomm the ventricle could be PICA, vertebral artery, or . Predominantly in one sylvian fissure: MCA or basilar. Pcomm TIPS & TRICKS

. CT head can be negative in up to 2% of the acute bleed (within 12 hours) and up to 57% of subacute bleeds. . is most sensitive for ruling out acute SAH, and MRI is most sensitive for detecting subacute SAH.

Cerebrospinal Fluid Studies A negative CT scan does not exclude the diagno- sis of SAH. Cerebrospinal fluid (CSF) evaluation is the most sensitive test to exclude SAH. However, a traumatic spinal tap could create a diagnostic dilemma, and the following steps may help fur- ther in the differentiation between a traumatic and an aneurysmal SAH:

. Test RBC in all four tubes: A decremental trend in RBC suggests a traumatic tap. . Centrifuge immediately and observe the super- Figure 5.1. Fisher III or modified Fisher I aneu- natant fluid by eye exam: yellow is suggestive of rysmal SAH. hemorrhage. 5 Subarachnoid Hemorrhage . 39

Table 5.2. Fisher grades and specificity of CT angiogram hasbeen reported to be between 80 and 90%. In a recent paper by Grade Description Description per Zhangetal.(2010),thesensitivityandspecificityof per Modified original Fisher dual energy CT angiogram (CTA) was 95% and Fisher scale scale 100%, respectively for less than 6 mm. 0 No blood — Thesensitivity andspecificity ofan MRangiogram I Thin cisternal No blood (MRA), according to Wilcock et al. (1996), is 81% blood without and 100% respectively. In general, for aneurysms IVH of less than 5 mm, the sensitivity of both CTA and II Thin cisternal Diffuse or vertical MRA is suboptimal. blood with IVH layer < 1 mm thick III Thick cisternal Localized clot or Management of Early blood without vertical layer Complications IVH >1 mm The initial ABC management is crucial and IV Thick cisternal Intracerebral or should always be followed with any critically ill blood with IVH intraventricular patient (Figure 5.3). This chapter will focus only hemorrhage with on SAH-related management issues prior to sur- or without SAH gical or endovascular treatment. The early spe- cific complications of SAH are as follows, and warrant detailed discussion: . Spectrophotometry: The presence of only oxy- hemoglobin without bilirubin is suggestive of 1. Rebleeding traumatic tap; the presence of erythrophages 2. Seizures confirms nontraumatic hemorrhage. 3. Hydrocephalus 4. Neurocardiogenic shock (Takotsabu It takes around 6 hours for red blood cells to lyse cardio-myopathy) and release the product, therefore xanthochro- mia can be absent in the initial 6 hours post bleed. In some studies a visual inspection has Rebleeding been shown to provide a better assessment than The mortality associated with rebleeding is 70%. spectrophotometry. Visual inspection against a It is one of the most preventable causes of poor white background is more specific, while spec- outcome after aSAH. The risk of rebleeding is 4% trophotometry is more sensitive. on day 1 and 1–2% every day for 4 weeks. The risk of rebleeding decreases significantly after the first month to 3% per year. Recent studies have TIPS & TRICKS shown that ultra-early bleeds are more common in the first 2 hours. Factors associated with In all CT negative thunderclap headaches rebleeding are: with no other obvious etiology, lumbar puncture should be performed to rule out a . Elevated blood pressure. sentinel bleed. . Delay in securing an aneurysm.

Vascular Imaging Elevated Blood Pressure Once aneurysmal SAH (aSAH) is suspected the There are no randomized trials to demonstrate next step is to identify the aneurysm by vascular that elevated blood pressure can lead to aneu- studies. Available studies include CT angiogram, rysm re-rupture, but theoretically higher pres- MR angiogram, and digital subtraction angiogram sure can exert a pounding effect on the wall of (DSA), which is the gold standard. The sensitivity recently ruptured aneurysm and potentially 40 . Acute Management of Neurological Emergencies

History suggestive of SAH

CT head

Blood present No blood seen

Spinal tap

Confirm SAH Inconclusive Negative

CT angiogram CT angiogram or DS

Aneurysm Aneurysm Aneurysm Aneurysm + – + –

Consult Neurosurgery or Repeat angiogram in Discharge home Neuro-Intervention 1 week

Figure 5.3. A flow chart for the initial evaluation of a SAH.

disrupt the clot covering the dome of the aneu- Association guidelines recommend the control of rysm. Fujii et al. (1996) demonstrated a correla- blood pressure to avoid rebleeding and to main- tion between rebleed and elevated blood pres- tain optimal cerebral perfusion pressure. No sure and found that a cutoff of systolic blood specific target range is defined. pressure (SBP) >150 was associated with a higher risk of rupture. In another study, a cutoff of SBP >160 was identified. Few studies found no corre- TIPS & TRICKS lation between the two. In our center a SBP cutoff of >140 is used to treat elevated blood pressure Systolic blood pressure should be kept at (Figure 5.4). least below 150–160 mmHg. If an ICP Commonly intravenous nicardipine drip or in- monitor is available, cerebral perfusion termittent labetolol boluses are used to control pressure (CPP) should be above 60. blood pressure. Nitroprusside is avoided due to the potential effect of elevated ICP. Any proce- dure that can transiently elevate the blood pres- Antifibrinolytics. Multiple randomized clinical sure such as the placement of an arterial line, trials have been performed using either tranexe- central line, intubation, or external ventricular mic acid or aminocaproic acid with mixed drain (EVD) should be performed after optimal results. Adam et al. (1981) published a meta sedation and pain control. The American Stroke analysis of three such trials showing reduction 5 Subarachnoid Hemorrhage . 41

ABC’s TIPS & TRICKS (rapid sequence The use of antifibrinolytics may be helpful in intubation if needed) selected circumstances where treatment is delayed and there appears to be little risk for developing delayed vasospasm. It can also be used in a situation where securing an Consider prphylactic AED immediate aneurysm is not possible due to (phenytoin 18mg/kg then an unstable medical condition. 5-7mg/kg)

Delay in Securing an Aneurysm SBP <140 (IV nicardipine drip or . Lack of awareness: No major studies have been labetolol boluses) performed to evaluate the awareness of SAH in the general community, but from acute ische- mic stroke studies, it is well known that a lack of education regarding symptoms of acute EVD for ICP monitoring stroke can cause significant delays. Although (if CTH and clinical suspicion the symptoms of SAH are more robust and are of hydrocephalus) more comparable with acute coronary syn- drome, lack of awareness of the disease can result in significant delays in calling 911. . Delay in the emergency medical service (EMS): Although there is no way to definitely diagnose SAH without a brain-imaging study, a high sus- Secure aneurysm picion based on the history and examination (clip or coil) and subsequent triage to a comprehensive stroke center, helps significantly in achieving early intervention and proper management of an aSAH. The classic symptom “worst headache of life” along with complaints of neck stiffness, Post clipping/coiling ICU altered mental status, focal neurological deficits care and/or loss of consciousness, should alert the EMSpersonfor anaSAH.On siteandprehospital management include ABC’s, rapid sequence Figure 5.4. Management of aSAH intubation if required and close monitoring of the blood pressure during the transfer. . Delay in the emergency room (ER): According to one study, the average ER door to CT scanner in the rate of rebleeding in patients using anti- time is around 50 minutes. An early recognition fibrinolytics. Other studies have shown that the of the above symptoms and appropriate report overall outcome is not changed, or even worse, to the hospital in advance can expedite the which can be explained by the high risk of ische- process and confirm diagnosis. After confirm- mic strokes with the use of antifibrinolytics. In ing the diagnosis, consulting the neurosurgery particular, if the patient is to undergo endovas- or neurology service, managing ABCs, strict cular treatment of an aneurysm, the use of blood pressure control, and initiating antifibrinolytics can significantly increase the prophylaxis play an important role in avoiding risk of thromboembolic complications. rebleeding and other complications. 42 . Acute Management of Neurological Emergencies

. Early clipping or coiling: Multiple studies have vulsants is unknown. Mayer and colleagues shown the benefit of early treatment to secure (2005) showed the benefit of continuous EEG in an aneurysm by surgical or endovascular this population for the detection of both vaso- means. The mortality of aSAH has been re- spasm and seizure in a small number of patients. duced significantly in the past decade mainly Clinical judgment should be used; if there is no due to early securing of an aneurysm. evidence of significant hydrocephalus and the patient is a Hunt–Hess grade IV or V, an EEG to rule out subclinical status is not unreasonable. Seizures The incidence of seizures after SAH varies between TIPS & TRICKS 2 and 11%. No definite mechanism of seizure is known but theoretically it is related to the irritation The prophylactic use of anticonvulsants after of the cortex from the breakdown product of subarachnoid hemorrhage is controversial. blood. This would suggest that patients with more Traditionally, patients were loaded with cortical blood are at higher risk of seizures. None of phenytoin to prevent seizure activity which the studies has actually demonstrated the detri- could potentially lead to an increased rate of mental effects of seizures in SAH patients. Other rebleeding. Epidemiologic studies however than the potential neuronal damage from pro- have shown worse outcome in patients longed seizure, the other potential effects include: maintained on phenytoin. If anticonvulsant use is entertained then a loading dose of phenytoin . Sudden increase in the intracranial pressure 18 mg/kg should be considered in all suspected with seizures that could reduce the already aSAH patients. Therapy should be continued for compromised cerebral blood flow and cause at least 3 days. brain ischemia. Elevated ICP can also result in central brain herniation. . Increase cerebral blood flow related to hyper- Hydrocephalus active brain due to seizures can result in re- rupture of the aneurysm. The incidence of hydrocephalus after SAH has . Subclinical status can falsely present as a high- been reported using different definitions and er Hunt–Hess grade that might result in alter- ranges from 6 to 67%. The timing can vary from ation of the treatment options, as most Hunt– a few hours post-bleed to a few days. Hydroceph- Hess grade V patients are not taken to surgery alus plays a significant role in the morbidity and due to poor prognosis. mortality associated with SAH. Either a CT of the head or a MRI of the brain can be used to diagnose The recommended treatment of seizures in- hydrocephalus. Several methods are available but clude loading with antiepileptic, the most com- most commonly a bicaudate index criterion is monly used is phenytoin. A comparison between a used for radiological diagnosis. This calculates the long-term phenytoin treatment (until discharge) ratio of the frontal horns of lateral ventricles at the versus a 3-day course of phenytoin has shown that level of the caudate head to the distance between patients with a prolonged hospital course had the inner tables of the frontal bone from side to more side effects and no added benefit. Levicetra- side. The following cutoff values are used for cam has recently been studied for the prophylaxis different ages: < 36 years (0.16), 36–45 years in SAH and has shown promising results. Due to (0.17), 46–55 years (0.18), 56–65 years (0.19), 66– minimal drug interactions and less side effects, this 75 years (0.20), and 76–85 years (0.21). An index might become the drug of choice in future. Other more than or equal to these age-specific values options include depakote and phenobarbital. suggests hydrocephalus. Later monitoring for subclinical seizures in SAH patients is controversial. Studies have re- SCIENCE REVISITED ported an incidence of up to 28% in combined ICU populations, but the specific incidence of . Hydrocephalus after SAH occurs as a result subclinical seizures in SAH patients on anticon- of malabsorption of the CSF through the 5 Subarachnoid Hemorrhage . 43

arachnoid villi or impedance of flow shock. After other potential causes of shock through the cerebral aqueduct. (septic/hemodynamic) are ruled out, the patient . The amount of ventricular blood grade should be evaluated for causes of cardiogenic on presentation is a major predictor of shock. The diagnosis of stress-induced cardiomy- the development of hydrocephalus, although opathy is usually based on echocardiograph there are a number of other variables findings, which may include: that have been shown to be associated with hydrocephalus. . EKG findings: Multiple EKG abnormalities . Symptoms of hydrocephalus include have been reported with this kind of cardiomy- headache, diplopia, nausea, vomiting, opathy and include prolonged PR or QTc decreased level of consciousness and/or interval, focal or diffuse ST elevations, and bilateral sixth nerve palsy. pathological Q waves. . Cardiac enzymes: Most of the patients have mild elevation of troponins and normal CK-MB. . Echocardiogram: The classic echo findings of Hydrocephalus after SAH represents a problem Takotsubo cardiomyopathy are apical akinesia in either reabsorption of the CSF or impedance in with mid-ventricular dyskinesia and normokine- the flow of the CSF due to high protein and blood sia of the heart base. The name Takotsubo de- products. In the acute phase, the hydrocephalus rived from the word “octopus trap” which cor- may be noncommunicating and hence should be responds to the shape of the heart seen on the treated with an external ventricular drainage. echo. This is usually reversible after few days. In any patient with a Hunt–Hess grade greater than or equal to 3, and evidence of early hydro- SCIENCE REVISITED cephalus on CT, we recommend the placement of an EVD. The pathophysiology of a neurocardiogenic shock state is not very well understood. It is generally agreed that a strong sympathetic CAUTION stimulation leads to myocardial stunning, but the mechanics of this is not clear. There are Lumbar puncture in the setting of an acute three proposed mechanisms: noncommunicating hydrocephalus can lead to brain herniation and should be avoided. . Spasm of coronary arteries: This has been led down by the fact that cardiac angiography even during the period of active ST elevations Neurocardiogenic Shock (Takotsubo has been negative, except in one case series Cardiomyopathy) of Takotsubo cardiomyopathy. . Microvascular spasm: Bybee et al. (2004) has Also known as broken heart syndrome, apical demonstrated that the coronary flow can ballooning syndrome, Gebrochenes–Herz syn- be abnormal even with normal coronary drome or stress cardiomyopathy, this is a cardiac arteries in these patients. dysfunction due to a nonischemic cause. Patients with aSAH can develop this stress-induced car- . Direct myocyte injury: High levels of cate- diomyopathy and it is frequently a cause of car- cholamine can decrease the viability of myocyte diogenic shock. through stress and calcium overload. Con- Stress-induced cardiomyopathy has been de- traction band necrosis and inflammatory scribed with other acute neurological illnesses infiltrates have been described on the pathol- such as ischemic stroke and even psychological ogy of cardiac muscle in these patients. stress. It is more common in post-menopausal women. SAH patients presenting with hemody- namic instability require close cardiac monitor- Management ing. A Swan–Ganz catheter helps to diagnose and The first line of treatment is intravenous crystal- treat patients with hypotension and suspected loid or colloid fluids to maintain a CVP goal of 44 . Acute Management of Neurological Emergencies

8–10 mmHg. Persistence hypotension after arachnoid hemorrhage. Neurosurgery 2007 Jan; achieving optimal CVP requires cardiac output 60(1):99–102. augmentation. This can be achieved with any Frontera JA, Claassen J, Schmidt JM, Prediction of inotropic/chronotropic agent. Dopamine helps to symptomatic vasospasm after subarachnoid achieve this goal but has two potential disadvan- hemorrhage: the modified fisher scale. Neuro- tages: (1) it increases the after load and can make surgery 2006 Jul; 59(1):21–27. the cardiogenic shock worse, and (2) since this is a Fujii Y, Takeuchi S, Sasaki O, Ultra-early rebleed- hyper-adrenergic state, the addition of another ing in spontaneous subarachnoid hemorrhage. catecholamine can potentially deteriorate the car- J Neurosurg 1996; 84: 35–42. diacfunctionbypromotingthestunningphenom- Laidlaw JD, Kevin H, Siu KH. Ultra-early surgery enon. Milrinone is better in this regard and has an for aneurysmal subarachnoid hemorrhage: altered mechanism of action through the phos- outcomes for a consecutive series of 391 phodiesterase pathway. It can potentially aug- patients not selected by grade or age. J Neuro- ment the cardiac output without any further surg 2002; 97(2):250–258. increase in cardiac stress. Vasopressors, like nor- epinephrine or phenylephrine, should be avoided Lee VH, Connolly HM, Fulgham JR, Takotsubo due to the fact that increasing the after load can cardiomyopathy in aneurysmal subarachnoid actually worsen the cardiac output. Patients with hemorrhage: an underappreciated ventricular hemodynamic instability should be stabilized dysfunction. J Neurosurg 2006 Aug; 105(2):264– prior to surgery or endovascular intervention. 270. Mayer SA, Claassen J, Hirsch LJ, Continuous EEG monitoring in patients with subarachnoid TIPS & TRICKS hemorrhage. J Clin Neurophysiol 2005 Apr; 22(2): 92–8. In a nutshell, the aim of the acute Ohkuma H, Tsurutani H, Suzuki S. Incidence and management of subarachnoid hemorrhage is significance of early aneurysmal rebleeding to prevent rebleeding, to prevent global before neurosurgical or neurological manage- ischemia due to elevated intracranial ment. Stroke 2001 May; 32(5):1176–1180. pressure, and to manage the ABCs. Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded com- parative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Bibliography Neurocrit Care 2010 Apr; 12(2):165–172. Adams HP Jr, Nibbelink DW, Torner JC, Sahs Al, Van der Wee N, Rinkel GJ, Hasan D, van Gijn J. Antifibrinolytic therapy in patients with aneu- Detection of subarachnoid haemorrhage on rysmal subarachnoid hemorrhage. A report of early CT: is lumbar puncture still needed after the cooperative aneurysm study. Arch Neurol a negative scan? J Neurol Neurosurg Psychiat 1981 Jan; 38(1): 25–9. 1995; 58: 357–359. Buruma OJ, Janson HL, Den Bergh FA, Bots GT. Wilcock D, Jaspan T, Holland I, Cherryman G, Blood-stained cerebrospinal fluid: traumatic Worthington B, Comparison of magnetic res- puncture or haemorrhage? J Neurol Neurosurg onance angiography with conventional angi- Psychiat 1981; 44: 144–147. ography in thedetection of intracranial aneur- Bybee KA, Prasad A, Barsness GW, Lerman A, Jaffe ysms in patients presenting with subarach- AS, Murphy JG, Wright RS, Rihal CS, Clinical noidhaemorrhage. Clin Radiol 1996 May; 51 characteristics and thrombolysis in myocardi- (5): 330–4. al infarction frame counts in women with Zhang LJ, Wu SY, Niu JB, Dual-energy CT angi- transient left ventricular apical ballooning ography in the evaluation of intracranial an- syndrome. Am J Cardiol 2004 Aug 1; 94(3): eurysms: image quality, radiation dose, and 343–6. comparison with 3D rotational digital subtrac- Chumnanvej S, Dunn IF, Kim DH. Three-day tion angiography. Am J Roentgenol 2010 Jan; phenytoin prophylaxis is adequate after sub- 194(1):23–30. 6 Acute Management of Cerebral Ischemia Leonid Groysman and Gene Sung

Neurocritical Care and Stroke Division, University of Southern California, Los Angeles, CA, USA

Introduction The First Hour Stroke is the third leading cause of death and the The availability of revascularization treatment leading cause of disability in the United States. modalities changed the practice of neurology As with a lot of different nosological entities, the from “diagnose and adios” to “time is brain.” best treatment is primary prevention. But in case Once a patient arrives at the emergency depart- prophylaxis fails, the authors hope that this chap- ment (ED), the stopwatch is started. The ter will be of assistance in the acute management American Heart Association (AHA) guidelines pri- of cerebral ischemia. oritize the initial management before making de- There are two major categories of stroke: cisions regarding treatment. The suggested “door- ischemic (80%) and hemorrhagic (20%), to- needle” time should be less than 60 minutes. with further subdivision of the first one into In the first 15 minutes in the ED, the patient three main etiologic subtypes: large-artery should be screened by appropriately trained per- atherosclerotic, cardioembolic, and lacunar. sonnel and triaged accordingly. After initial However, at presentation, the main common cardiopulmonary stabilization (once again, re- treatment goal is reperfusion regardless of the member ABC for Airway, Breathing, Circulation), etiology of the ischemic stroke. As with any the neurological deficit can be safely addressed. emergency, ACLS goals (think ABC) should be In emergency settings, the most pertinent parts met before any further steps are undertaken. of the medical history include the history of Prehospital steps are outside the scope of this baseline impairments, new symptoms, time of chapter, but the important points of stroke symptom onset, history of previous trauma, sur- system activation require patients to call 911 geries, strokes, cardiovascular events, intracr- with the first symptoms of neurological com- anial hemorrhages, other comorbidities (notably promise. Expedited patient delivery to the hos- hypertension, diabetes, and bleeding disorders), pital by the EMS with advance warning to the medication list (use of hypoglycemic, anticoagu- destination emergency room (ER) is of para- lant, or antiplatelet agents), and drug abuse. mount importance in order to avoid unneces- One of the paramount questions in obtaining the sary delays and meet ER “door-to-needle” time history is the time of symptoms onset, defined as requirements of less than 60 minutes. “last seen normal.” The patient may not be the

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

45 46 . Acute Management of Neurological Emergencies best source of information, and interviewing wit- individual asking for assistance should err on the nesses and family as well as confirmation of an side of high sensitivity when deciding to activate estimated time of onset against verifiable time the stroke team. points, is essential. At this point an imaging study should be per- formed to help with the decision regarding eligi- bility for reperfusion. While there is significant TIPS & TRICKS data for use of MRI in this situation, the universal One way to help toidentify the exact time on availability of computed tomography (CT) scan- onset may include identifying the program ners and speed of performing CT makes this test the patient was viewing on the television. the first choice in the majority of institutions. Clues in the household may include whether Imaging must be completed before the meals were being prepared or the patient was 30-minute time point after arrival in the ED. making plans for bed. Availability of the creatinine/BUN level may as- sist in carrying out safely a contrast-based CT study (see the imaging section below). Anticipa- tory orders to the pharmacy to prepare a tissue Obtaining vital signs, drawing blood for labo- plasminogen activator (tPA) may also expedite ratory tests, and performing diagnostic tests may door-to-needle time. overlap with history-taking and examination. Blood pressure management is still a subject Physical and neurological exam may be limited of significant controversy. If the pressure is and directed toward acute management and above 185/110 mmHg and the patient is eligible stroke evaluation (see NIH Stroke Scale below). for tPA, lowering the pressure below the above General laboratory tests like Complete Blood level with labetalol boluses is mandatory to Counts, coagulation panel, glucose, chemistry decrease the possibility of hemorrhagic compli- panel, and pregnancy tests (when appropriate) cations. Failure to control the blood pressure should be sent to the laboratory at the highest with labetalol boluses, or the continuous infu- level of priority even before the arrival of the sion of nicardipine, is a contraindication for IV stroke team. Having a predefined stroke-related tPA. If the patient is not a candidate for IV tPA order sheet may help to significantly shorten the and does not have an intercerebral haemorrhage time to treatment. It is expected that assessment (ICH), we utilize permissive hypertension with for anemia, thrombocytopenia, coagulopathy, blood pressure goals below 220/120 mmHg un- electrolyte disorder, glucose level abnormality, less contraindicated. or cardiac ischemia/arrhythmia (troponin and In order for clinical, radiologic, and laboratory EKG) will be started immediately upon the pa- data to be available by the 45-minute time tient’s arrival in the emergency department. point, collaboration of different teams and pre- However, it is the ultimate responsibility of the emptive training of personnel are crucial. When managing physician to ensure the availability of the necessary diagnostic data is available, a brief this information at the time the decision for discussion among involved teams and the pa- revascularization is made. tient’s family should lead to a decision in support of or against tPA administration (see indications TIPS & TRICKS and contraindications in Table 6.1). Alteplase total dose is calculated as 0.9 mg/kg (maximal Symptoms associated with extremely high or dose 90 mg). The first 10% is given as a bolus over low blood glucose level are the most frequent 1 minute, and the remaining 90% is infused over stroke mimics and should be ruled out early 1 hour. in the evaluation. The First 24 Hours After the initial screening, a call to a neurologist If the patient is not eligible for IV tPA treatment should be started. It is advisable that the (for example, in case the time of symptom onset 6 Acute Management of Cerebral Ischemia . 47

Table 6.1. Indications/contraindications to IV tPA Indications 1. Age >18 years old 2. Clinical diagnosis of ischemic stroke with a measurable neurologic deficit 3. Exact time of onset established to be <180 minutes before treatment Contraindications 1. Evidence of intracranial hemorrhage on pretreatment HCT 2. Minor or rapidly improving symptoms 3. Presentation suggestive of SAH even with normal HCT 4. Seizure at onset of stroke (relative) 5. Platelet count <100,000 6. Received heparin within 48 hours and with elevated PTT 7. Known history of intracranial hemorrhage 8. Other stroke or serious head trauma within past 3 months 9. Major surgery within the last 14 days 10. Sustained systolic BP>185 mmHg 11. Sustained diastolic BP >110 mmHg 12. Aggressive treatment necessary to lower BP 13. Gastrointestinal or urinary tract hemorrhage within 21 days 14. Arterial puncture at noncompressible site within 7 days 15. Serum glucose <50 mg/dL or >400 mg/dL

is beyond 4.5-hour window) or has demonstrable Indications for Admission to the tissue at risk (so-called penumbra, see the imag- Neurocritical Care Unit (NCCU) ing section), further consultation with the inter- Patients with AIS may be admitted to the NCCU ventional team is recommended. Intra-arterial for neurologic or medical reasons (Table 6.2). (IA) tPA may be beneficial if the patient angio- Patients treated with IV tPA are at risk of intra- graphically demonstrates a middle cerebral ar- cranial hemorrhage and require close monitor- tery occlusion and no major early infarct signs on ing for at least 24 hours. Frequent neurology the baseline head CT scan within 6 hours of checks should be performed to assess for any symptom onset in selected cases. Emergency worsening in a clinical examination. The pres- angioplasty and stenting or mechanical extrac- ence of intracranial hemorrhage after thrombo- tion of an occlusive clot are also available options lytics requires the aggressive management of in centers with the appropriate neurologic and blood pressure (while maintaining proper cere- interventional expertise. Mechanical thrombect- bral perfusion) and the reversal of coagulopathy omy may be used up to 6–8 hours after symptom to prevent expansion of the hematoma. The onset. Mechanical thrombectomy is indicated for presence of a massive middle cerebral artery those patients where the IV tPA has not resolved a (MCA) infarct as determined by an NIHSS >18, visible clot or the neurological examination has and >50% of the MCA territory involved on CT not improved with a residual clot visible on im- imaging is an indication for close monitoring in aging and a diffusion–perfusion mismatch is the NCCU. These patients may develop malig- present on MR or CT perfusion studies. The nant cerebral edema in the first 3–5 days post- decision to try to remove a clot mechanically stroke. The development of malignant cerebral should be made on a patient-to-patient basis edema carries a high mortality rate and has a depending on the NIHSS score, underlying med- high frequency of cardiac and pulmonary ical history, age, imaging data, and risk-benefit complications. assessment. 48 . Acute Management of Neurological Emergencies

Table 6.2. Indications for admission to the NCCU after AIS Neurologic 1. Post-thrombolysis 2. Massive cerebral infarction 3. Intracranial bleeding 4. Crescendo transient ischemic attacks 5. Progressive worsening of neurologic symptoms 6. Arterial dissection 7. Post-endovascular treatment 8. Cerebral vasospasm after subarachnoid hemorrhage Non-neurologic 1. Respiratory failure 2. Mechanical ventilation for airway protection 3. Persistent hypotension 4. Intravenous drug management for hypertension 5. Aggressive pulmonary therapy 6. Cardiac infarction or arrhythmias 7. Severe systemic bleeding

The Brain Attack Coalition: tPA Stroke Study Group Guidelines. http://www.stroke-site.org/guidelines/tpa_guidelines.html

Other neurologic conditions that warrant systems, visual fields, speech, and inattention. admission to the NCCU or stroke unit include A high score (maximum possible is 42) indicates crescendo transient ischemic attacks (TIAs) or significant neurological impairment. It is impor- limb-shaking TIAs (has a high incidence of ische- tant to perform the NIHSS in the acute setting mic stroke if untreated), progressive worsening of because it helps to screen patients who are eligi- neurologic deficit (may benefit from the use of ble for aggressive medical management, facili- vasopressor agents to induce hypertension in- tates communication between different teams, creased perfusion to brain), arterial dissection and aids the assessment of the evolution of (requires hypervolemia and close blood pressure stroke symptoms. Interviewing the patient and control), and post-endovascular therapy (high establishing an NIHSS score should not delay risk for embolization and re-occlusion). laboratory and radiological evaluations that are Non-neurologic reasons for admission to the important for further interventions. NCCU are those with respiratory failure, me- chanical ventilation, vasopressor administration Stroke Imaging for hypotension, IV therapy for hypertension, Several imaging modalities are available for use cardiac abnormalities (i.e. infarction, ischemia, in the AIS patient. These include head CT, CT or arrythmias), severe systemic bleeding follow- angiography, CT perfusion, magnetic resonance ing thrombolytic therapy, and need for aggressive imaging (MRI), magnetic resonance angiography pulmonary therapy. (MRA), and transcranial doppler (TCD). Head CT is the fastest scan to obtain to differ- National Institute of Health Stroke Scale entiate acute ischemic strokes from hemorrhagic The most widely accepted method to evaluate a strokes, subarachnoid hemorrhages, subdural patient with acute neurological deficits consis- hematomas, hydrocephalus, and cerebral edema. tent with stroke is the National Institute of Health The presence of hypodense areas affecting more Stroke Scale (NIHSS). This scale evaluates differ- than one-third of the MCA territory within 3 hours ent aspects of the neurological examination, in- of symptom onset may be a contraindication for cluding consciousness, language, sensorimotor administering IV tPA due to the increased risk of 6 Acute Management of Cerebral Ischemia . 49 hemorrhagic conversion. Involvement of the en- Subsequent Management of Acute tire MCA territory 24–48 hours after stroke onset Ischemic Stroke (AIS) in the is highly predictive of poor outcome and death in Neuroscience ICU 80% of these patients. The visualization of a hyperdensity in one of the MCA lumens on a CT Blood Pressure (BP) Before and After scan may signify a clot. This has been labeled the IV/IA tPA “hyperdense MCA sign.” This sign, however, has The management of arterial hypertension re- low sensitivity and specificity and should not mains controversial. The goal of maintaining guide further management. A CT angiography of adequate cerebral perfusion must be balanced the head and neck can be administered and by minimizing the complications of hyperten- evaluated in a timely manner and can assess the sion. The blood pressure (BP) before administer- vasculature of the head and neck for an obstruc- ing IV tPA should be systolic BP <185 mmHg tion amenable to intervention. or diastolic DB <110 mmHg. The guidelines rec- MRI is another imaging modality that has ommend labetalol, nitropaste, or nicardipine revolutionized the evaluation process of patients infusions to help to lower the BP to less than with AIS. Such techniques include diffusion- 185/110 mmHg. The goal for blood pressure weighted imaging (DWI) and perfusion-weighted management post-IV/IA tPA or other acute re- imaging (PWI). DWI measures the diffusion of perfusion interventions should be systolic BP water molecules in the brain tissue which can be <180 and diastolic BP<105 for at least the first quantified by the calculation of the apparent 24 hours. Blood pressure should be measured diffusion coefficients (ADCs). DWI is more sen- every 15 minutes for the first 2 hours and subse- sitive than conventional MRI sequences to de- quently every 30 minutes for the next 6 hours, tect ischemic tissue within minutes after stroke then hourly until 24 hours after treatment. If, onset in both animal and human studies. Ab- during or after IV tPA, the systolic BP ranges from normal areas appear hyperintense compared to 180 to 230 mmHg, or the diastolic BP ranges from normal brain tissue. The addition of PWI gives a 105 to 120 mmHg, then labetalol should be given. better understanding of the hemodynamic If the systolic BP >230 mmHg, or the diastolic BP characteristics of the ischemic brain. A MRA of is between 121 and 140 mmHg, then labetalol the head and neck is also used to assess the or nicardipine IV drip may be used. If the BP vasculature, though it is less specific than a CT remains uncontrolled with the use of the afore- angiography in the evaluation of a vascular mentioned agents, then one may consider the use obstruction. of nitroprusside. As nitrates and nitroprusside Cerebral angiography is considered to be the can lead to cerebral vasodilation, and can in- “gold standard” radiological method of choice to crease intracranial pressures, they should be used detect cerebral vessel occlusion and delineate with caution. the vascular anatomy. The advantages of this Failure to meet the BP parameters after admin- technique are the possibility of intra-arterial ad- istration of tPA is associated with an increased ministration of medications (i.e. thrombolytic risk of symptomatic hemorrhagic transformation agents), and the performance of endovascular and poor neurological outcome. The lower limit treatments (i.e. angioplasty or stent placement of blood pressure should be adequate to keep the of stenosed arteries). cerebral perfusion pressure (CPP) >70 mmHg. Transcranial dopplers (TCDs) are useful in the CPP is a derived measure of cerebral blood flow evaluation of vessel stenosis or occlusion. They (CBF). It is a function of both systemic BP and may prove to be indispensible in the estimation intracranial pressure (ICP) and is estimated using of collateral circulation, the origination of micro- the following equation: emboli in the heart or proximal arteries, and be particularly useful as a safe bedside test when CPP ¼ MAP ICP following patients before and after treatment with thrombolytic agents to gauge recanalization No antiplatelets or antithrombotics should be success. given for 24 hours after receiving tPA. One should 50 . Acute Management of Neurological Emergencies also avoid placing nasogastric tubes, indwelling Glucose Control in the NCCU bladder catheters, or intra-arterial pressure ca- When being evaluated, all suspected acute stroke theters for 24 hours. Many patients have a spon- patients should get their blood glucose checked taneous decline in BP within the first hours of since hypoglycemia may mimic symptoms of stroke, even without treatment. This may be ischemic stroke and may also lead to brain injury. facilitated when, in a less stressful environment The glucose level at presentation predicts symp- (out of the ED, in a quiet room), the bladder is tomatic intracerebral hemorrhage as well as mor- emptied and pain is controlled. tality and functional outcomes on 12-month There is a need for large, well-designed trials to modified Rankin scales and NIHSS scores. Most clarify the management of arterial hypertension patients who present to the ED with stroke symp- after an acute stroke. Lowering the blood pres- toms usually have moderate elevations of glucose sure post-stroke may be beneficial in that lower- in their serum. This is most likely a reflection of ing pressures reduces the formation of brain the hyperadrenergic state encountered post- edema, lessens the risk of hemorrhagic transfor- stroke. The effect of high blood sugar in acute mation of infarction, prevents further vascular stroke patients is not completely understood but damage, and forestalls early recurrent strokes. may have to do with increasing tissue acidosis However, Castillo et al. (2004) noted that the from anaerobic glycolysis, lactic acidosis, and aggressive treatment of BP (>20 mmHg) may lead free radical production. It may affect the to worsening of the neurological examination, blood–brain barrier and the development of higher rates of poor outcomes or death, and brain edema. Baird et al. (2003) found that the larger infarct volumes by reducing the perfusion effects of hyperglycemia (blood glucose level pressures to infracted areas of the brain. A trial > 200 mg/dL) during the first 24 hours after stroke testing the utility of antihypertensive therapy in independently predicted the expansion of the the setting of stroke – Controlling Hypertension volume of ischemic stroke and poor neurological and Hypotension Immediately Post-Stroke outcomes. Also reported was a 25% symptomatic (CHHIPS) – showed that stroke patients who hemorrhage rate in ischemic stroke patients who were treated for hypertension had lower mortali- received tPA and whose serum glucose was ty after 3 months than patients who received >200 mg/dL. The desired level of blood glucose placebo. BP reduction was not associated with is in the range of 80–140 mg/dL. deterioration in neurological status at 72 hours In the NCCU, the serum glucose should be and treatment did not alter death or disability at monitored every 4 hours and a sliding scale of 2 weeks. The CHHIPS pilot data emphasizes insulin or insulin drips started if glucose is >140. the need for a full-scale trial to see if these In patients who received tPA, admission glucose encouraging preliminary results can be repro- levels of 140 mg/dL were associated with poor duced. Pending ongoing trials on whether the outcomes. Until more conclusive evidence is acute lowering of BP or keeping BP high in the found, avoiding both hypoglycemia and hyper- acute setting is better, the consensus is that glycemia in acute stroke patients should contin- emergency administration of antihypertensive ue. A serum glucose level >140 mg/dL will trigger agents should be withheld unless the diastolic the administration of an insulin drip at our insti- BP is >120 mmHg or the systolic BP >220 mmHg. tution, with close monitoring of the serum Lowering the BP should be done cautiously. glucose to avoid hypoglycemia. A reasonable goal would be to lower the BP by 15–25% within the first day (post-24 hours tPA). No data supports the administration of any spe- Temperature Management in the NCCU cific antihypertensive agent and the treating Fever in the setting of an acute ischemic stroke is physician should select medications for lowering associated with an increased risk of morbidity the BP in the acute stroke setting on a case-by- and mortality by increasing the metabolic de- case basis, based on any underlying medical mands of the brain (releasing neurotransmitters) conditions that would prohibit certain BP med- and the production of free radicals. When a ications (i.e. using beta blockers in asthmatics). patient becomes febrile, the source of fever 6 Acute Management of Cerebral Ischemia . 51 should be investigated by obtaining blood cul- rapidly in AIS patients. Induced moderate hypo- tures, urine cultures, chest radiograph, and as- thermia was feasible using an endovascular cool- sessing line status (i.e. when lines were placed ing device in most patients with AIS. Further stud- and whether that could be a nidus for infection). ies are still needed to determine if hypothermia Patients are placed on acetaminophen 650 mg improves neurological outcome in AIS patients. every 4–6 hours by mouth, per rectum, or by There are several methods of cooling down the nasogastric tube when the temperature is >38 C. body as well as the brain. Cooling blankets are If the temperature is > 38.5 C, a cooling blanket available but do not efficiently cool the body and ice packs may also be used on top of acet- down in a controlled manner, as is the case of aminophen to lower the temperature to less than other traditional methods such as ice water baths or equal to 37 C. There have been several studies and fans. Newer methodologies utilize comput- in the past with using either aspirin or acetamin- er-regulated cooling units that circulate cool wa- ophen to achieve normothermia. To date, there is ter through an endovascular device or supercon- no data demonstrating that lowering body tem- ductive gel pads that circulate to effectively cool perature among febrile or afebrile patients im- patients down to 33 or 34 C over a 24-hour proves neurological prognosis after a stroke. The period. The endovascular cooling devices have goal in the NCCU is to maintain normothermia in been used effectively to cool patients in a con- the AIS patient. trolled fashion but require the placement of a Hypothermia has been shown to be neuropro- large-bore catheter in the inferior vena cava via a tective in experimental and focal hypoxic brain femoral vein. The machine allows for the con- injury models. It is thought that cooling the brain trolled rewarming of a patient no greater than delays the depletion of energy stores, lessens 0.3 C/hour up to 36.5–37 C to prevent the risk of intracellular acidosis, slows the influx of calcium cerebral edema. The use of paralytics and seda- into ischemic cells, suppresses the production of tive agents are indicated to help to prevent shiv- oxygen free radicals, and lessens the impact of ering during the cooling process and prevent the excitatory amino acids. Hypothermia has been body from increasing its core temperature. The shown to reduce mortality and improve neuro- patient should be placed on a deep venous logical outcomes among patients with cardiac thrombosis (DVT) prophylaxis 12 hours after the arrest (ventricular fibrillation). Hypothermia on removal of the catheter. A lower extremity dopp- the central nervous system may decrease ICP by ler ultrasound may be obtained if a DVT is sus- cerebral vasoconstriction and an associated de- pected since the use of an intravascular device crease in blood volume. It may also act as an predisposes one to DVTs (because of the large anticonvulsant. size of catheter). Some of the side effects to thera- Studies using induced hypothermia in patients peutic hypothermia are hypotension, cardiac with malignant ischemic strokes in improving arrythmias, and infections. An intranasal cooling neurological outcome have been mixed. Reith device is under development that may effectively et al. (1996) prospectively enrolled 390 patients cool the brain and avoid some of the side effects, within 6 hours of stroke onset. They found that an and deliver a perfluorochemical spray via nasal association exists between body temperature and tongs within minutes. The nasal cavity is cooled initial stroke severity, infarct size, mortality, and down to 5 C, thus cooling the brain by con- outcome. Mortality rates and neurological out- duction.. Exciting devices are being developed come improved in the hypothermic group. For and hopefully larger well-designed trials will every 1 C increase in temperature, the risk of prove that hypothermia is safe and effective in the poor outcome doubled. Only randomized- treatment of acute ischemic strokes. controlled trials of hypothermia can prove whether this relation is causal. Fluid Status Management and Nutrition The COOL AID (Cooling for Acute Ischemic in AIS Brain Damage) trial tested whether endovascular The goal in the NCCU for AIS patients is to cooling combined with meperidine, buspirone, maintain euvolemia. Systemic dehydration may and surface warming could achieve hypothermia reduce cerebral edema but may worsen cerebral 52 . Acute Management of Neurological Emergencies perfusion. The average maintenance fluid is 1 ml/ reduction seen of asymptomatic DVTs in the en- kg/hour, which is approximately 2000–2500 mL/ oxaparin group but this was matched to an in- day for adults. Normal saline is the intravenous crease in major extracranial bleeding.. Low molec- fluid of choice in the NCCU. Hypotonic solutions ular weight heparins have been found to be equiv- can worsen cerebral edema and are avoided. alent to, or better than, UFH in preventing DVT. Dextrose-containing solutions are also avoided In patients with an acute intracerebral hemor- in that glucose is metabolized to lactic acid in the rhage or any contraindication to anticoagulants, ischemic tissue by anaerobic metabolism and intermittent pneumatic compression (IPC) de- worsens cerebral injury. An ongoing trial ALIAS vices or elastic stockings should be used initially. (albumin therapy for neuroprotection in AIS) is In stable patients with intracerebral hemorrhage, currently enrolling patients to determine if hu- the use of low-dose SC heparin can be started as man serum albumin at 2 g/kg given over 2 hours soon as the second day post-hemorrhage. This to ischemic stroke victims within 5 hours of recommendation is based on one study that stroke onset, results in improved outcome at 3 emphasizes the risk reduction of thromboembo- months. If the results are significant when the lism compared to minimizing the risk of cerebral trial is completed, it would be the first neuropro- rebleeding. tective agent to improve outcome in AIS patients. Nutrition considerations in the NCCU are Management of Intracranial important. Metabolic activity and nutritional de- Bleeding After Thrombolytic mands are increased post-stroke. Early institu- tion of nutrition is associated with improved Therapy outcomes. A formal swallow evaluation should The major risk of thrombolytic therapy is intra- be done to assess whether or not the patient has cranial hemorrhage. If bleeding occurs, infusions difficulty swallowing and is at risk for aspiration. of a thrombolytic should be stopped immediate- Patients who have a decreased level of conscious- ly. A head CT without contrast is ordered imme- ness or fail their swallow study should have a diately if intracranial hemorrhage is suspected. nasogastric tube placed, nutritional consultation, Hemorrhagic transformation (petechial hemor- and nutritional preparations started. A good rhage within an infarct) and parenchymal or bowel regimen should also be implemented since symptomatic hemorrhage should be differentiat- delayed gastric emptying is common in the ed. Poor compliance with national guidelines for NCCU. The use of narcotic agents for pain may the administration of thrombolytic therapy also delay bowel movements and laxatives should increases the incidence of intracranial bleeding. be started. A gastrointestinal prophylaxis should If bleeding is suspected, blood should be im- also be started in NCCU patients. mediately drawn to measure the patient’s he- matocrit, hemoglobin, partial thromboplastin DVT and PE Prophylaxis time (PTT), prothrombin time (PT), international Deep venous thrombosis (DVT) and pulmonary normalized ratio (INR), platelet count, and fi- embolism (PE) are frequent complications in brinogen. Blood should also be typed and cross- stroke patients. Stroke patients with restricted matched if transfusions are needed (at least 4 movement because of weakness, and are bed- units of packed red blood cells, 5–6 units of fresh ridden, should receive SC (subcutaneous) low- frozen plasma, or 6–8 units of cryoprecipitate doseheparinorSClowmolecularweightheparins. and 1 unit of donor platelets). These blood pro- PREVAIL (Prevention of Venous thrombo-embo- ducts should be available for emergent adminis- lism after AIS) was an open-label, randomized tration. Neurosurgery should also be consulted if comparison of either enoxaparin 40 mg SC once evacuation is a consideration. Surgical evacua- a day or unfractionated heparin (UFH) at 5000 tion of an intracerebral haemorrhage can be units SQ every 12 hours in patients with ischemic carried out once the coagulopathy is corrected, stroke. The risk of both symptomatic intracranial the size of hematoma is assessed, and the loca- bleeding and major extracranial bleeding was tion of the hematoma is determined. Cerebellar similar in both groups. There was, however, a hematomas that are > 3 cm, or larger (>60 cc) 6 Acute Management of Cerebral Ischemia . 53 lobar hematomas with mass effect, should be it is important to anticipate possible complica- evacuated emergently. tions from this therapy. These include: cardiac and blood pressure depression, diminished Management of Malignant interstitial peristalsis, sepsis, pneumonia, poiki- Hemispheric Ischemic Strokes lothermia, and coagulopathies. Maintaining nor- with Cerebral Edema and/or mothermia and euglycemia are also important in these patients. Decompressive hemicraniectomy Elevated Intracranial Pressures by neurosurgery can also be considered on a case Cerebral edema in acute ischemic infarcts usual- by case basis in those patients >50 years of age ly peaks in 48–72 hours and starts to resolve by that were otherwise healthy with large territory day 5. The treatment of cerebral edema is pri- infarcts that are unresponsive to maximal medi- marily medical and overlaps with that of elevated cal management. Patients age 50 or younger with intracranial pressure (ICP). First and foremost, a decreased level of consciousness and infarction one must assess the patient’s ability to protect involving >50% of MCA territory are at risk of hisairway if he starts to become less responsive. developing malignant edema. In those patients Endotracheal intubation should be initiated if the that desire aggressive therapy, decompressive patient appears to be in respiratory distress and if hemicraniectomy may be offered. his Glasgow Coma Scale (GCS) score is <8. Short- acting medications should be used for intubation Conclusion such as etomidate, thiopental, propofol, or lido- The close attention that a neurocritical care unit caine. Once controlled, hyperventilation to a provides for an AIS patient is important in the PaCO2 of <25 should be avoided because of long- term prognosis and recovery from this the possibility of cerebral vasoconstriction and devastating illness. The importance of BP con- ischemia. At the same time, MAP should be trol before and after IV tPA, maintaining eugly- maintained with intravenous isotonic fluids cemia, normothermia, euvolemia, and following and vasopressors if necessary to keep CPP cerebral edema can all be monitored in the >70 mmHg, and head of the bed elevated about NCCU. Exciting new therapies such as induced 30 degrees. The use of an intracranial pressure hypothermia in AIS and whether or not blood (ICP) monitoring device should be implemented, pressure lowering in AIS is beneficial will be especially when using osmotic agents to help determined in the near future. As time goes on, decrease ICP. Several devices are available for many new options will be available for treating ICP monitoring: intraventricular catheters (IVCs), AIS patients in the NCCU, which will get them subarachnoid bolts, and fiberoptic transducers. out of the acute phase and on the road to Osmotic agents such as mannitol are used to rehabilitation. reduce the cerebral water content. It also de- creases the viscosity of blood in the cerebral Bibliography arterioles and induces vasoconstriction leading to reduction in ICP. The initial dose is 0.5–2.0 Adams HP, Jr., Bendixen BH, Kappelle LJ, et al. g/kg and maintenance dose of 0.25 g/kg every 4–6 Classification of subtype of acute ischemic hours to keep serum osmolality between 310 and stroke. Definitions for use in a multicenter 320 mOsm/L. Serum sodium and osmolalities are clinical trial. TOAST. Trial of Org 10172 in Acute usually checked every 6 hours when mannitol Stroke Treatment. Stroke 1993; 24: 35–41. and/or hypertonic saline is used to help to keep Ahmed N, Wahlgren N, Brainin M, et al. Relation- ICP <20 mmHg. 3% hypertonic saline boluses ship of blood pressure, antihypertensive ther- may also be used to help to lower ICPs as well. apy, and outcome in ischemic stroke treated A bolus of 250 cc every 6 hours, needed to keep with intravenous thrombolysis: retrospective the serum osmolality in the 310–320 mOsm/L analysis from Safe Implementation of Throm- range, can be given while trying to maintain bolysis in Stroke–International Stroke Throm- euvolemia. Barbiturate coma can be instituted bolysis Register (SITS–ISTR). Stroke 2009; 40: once all other medical maneuvers have failed, but 2442–2449. 54 . Acute Management of Neurological Emergencies

Baird TA, Parsons MW, Phanh T, et al. Persistent ischemic stroke. New Engl J Med 2008; 359: poststroke hyperglycemia is independently 1317–1329. associated with infarct expansion and worse Latchaw RE, Alberts MJ, Lev MH, et al. Recom- clinical outcome. Stroke 2003; 34: 2208–2214. mendations for imaging of acute ischemic Castillo J, Leira R, Garcıa MM, et al. Blood stroke: a scientific statement from the American pressure decrease during the acute phase of Heart Association. Stroke 2009; 40: 3646–3678. ischemic stroke is associated with brain injury Lyden P, Brott T, Tilley B, et al. Improved reli- and poor stroke outcome. Stroke 2004; 35: ability of the NIH Stroke Scale using video 520–526. training. NINDS TPA Stroke Study Group. Flint AC, Duckwiler GR, Budzik RF, et al. Mechan- Stroke 1994; 25: 2220–2226. ical thrombectomy of intracranial internal ca- Reith J, Jørgensen HS, Pedersen PM, et al. Body rotid occlusion: pooled results of the MERCI temperature in acute stroke: relation to stroke and Multi MERCI, Part I Trials. Stroke 2007; 38: severity, infarct size, mortality, and outcome. 1274–1280. Lancet 1996; 347: 422–425. Gruber A. Interventional management of stroke. Sung GY. Emergency and Critical Care Manage- Stroke 2008; 39: 1663–1664. ment of Acute Ischemic Stroke. American Acad- Hacke W, Kaste M, Bluhmki E, et al. Thrombo- emy of Neurology, 2008. lysis with Alteplase 3 to 4.5 hours after acute 7 Neurocritical Care of Intracerebral Hemorrhage James M. Gebel Jr

Cerebrovascular Center, Cleveland Clinic, Cleveland, OH, USA

Introduction proactively address potential medical and Background neurological complications. Intracerebral hemorrhage (ICH) is the most com- mon form of hemorrhagic stroke in the United Pathophysiology States and is twice as common as subarachnoid The most common cause of spontaneous ICH is hemorrhage. Although ICH represents only 10– uncontrolled hypertension, which leads to the 15% of all strokes, it has a higher mortality, rupture of deep penetrating arteries and explains particularly in certain ethnic groups. For in- why hypertensive ICHs are most often located in stance, African American men ages 35 to 54 in the basal ganglia (putamen, thalamus, internal the United States have quadruple the stroke capsule, caudate), subcortical white matter, cer- mortality attributable to ICH than comparable ebellum, and brainstem. In fact, approximately age Caucasian men. ICH mortality rates range one quarter of all ICHs in hypertensive patients from 25 to 50% in most series, with only 25% would be eliminated if hypertension were recovering without death or permanent signifi- treated. Charcot–Bouchard micro-aneurysms are cant neurological disability. Thus, by definition, believed to be the direct pathophysiological most ICH patients are neurologically critically ill. substrate of these vessels rupturing, with lipo- Furthermore, a substantial proportion of hyper- hyalinosis preceding the formation and rupture acute ICH patients who, upon initial presenta- of these micro-aneurysms. Fisher, however, was tion, appear neurologically and medically stable able to identify these aneurysms in only about deteriorate within minutes or hours secondary to 10% of patients after ICH (Figure 7.1). rebleeding, intraventricular extension, acute ob- Cerebral amyloid angiopathy (CAA) is the sec- structive hydrocephalus, or airway compromise. ond most common cause of ICH and affects the Others suffer from delayed neurological deterio- lobar regions preferentially due to its underlying ration due to perihematomal edema. Therefore, pathological substrate of amyloid deposition pre- the best approach is to assume that any hyper- dominantly in small cortical arterioles in this acute or acute ICH patient is critically ill. This region (Plate 7.1). It mainly affects elderly indi- requires that the patient is triaged to an area in viduals and is also associated with Alzheimer the hospital that has the resources to monitor and dementia. A more recently described variant of

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

55 56 . Acute Management of Neurological Emergencies

Figure 7.1. Location and computed tomographic correlates of intracerebral hemorrhages attributed to chronic hypertension. Chronic hypertension leads to pathological changes in the perforating arteries of the large basal cerebral arteries leading to hemorrhages commonly found in the (A) deep white matter, (B) basal ganglia, (C) thalamus, (D) pons, and (E) cerebellum. (Reproduced from Manno et al. (2005), with permission from Elsevier.)

this disorder is CAA with cerebral edema. Indi- expected anatomical size and location often clini- viduals with this variant suffer sustained perihe- cally differentiates ICH from ischemic stroke of a matomal edema out of proportion to the similar anatomical location. Progressive or abrupt hematoma’s size due to ongoing inflammatory decline in the LOC is also characteristic of ICH as reaction to adjacent tissue. Coagulopathy (espe- compared to ischemic stroke. Despite these clas- cially warfarin-associated ICH) is another com- sic differentiating features, the clinical presenta- mon and important cause of spontaneous ICH. tion should never be relied upon as the means of Its risk and severity increase with higher PT/INR diagnosing ICH, which can only be reliably ascer- values, especially once the PT/INR exceeds 4.0, tained by obtaining a noncontrast head CT scan after which risk exponentially increases. Under- (or MRI). (Figure 7.2). lying structural lesions causing ICH include neo- plasms, vascular malformations, and infections Neurocritical Care of ICH (especially so-called “mycotic” aneurysms due to Neurocritical care of ICH begins with the ABCs subacute bacterial endocarditis-related septic ce- –airway, breathing, and circulation. ICH patients rebral emboli, and aspergillosis, which affects are often obtunded, stuporous, or comatose upon immunocompromised individuals). Primary or or shortly after initial presentation, rendering secondary CNS angiitis and Moya Moya dis- them unable to adequately protect their airway ease/syndrome rarely cause ICH. and increasing their aspiration risk. This is often compounded by dysphagia due to their associat- Presenting Clinical Features ed focal neurological injury. Timely elective The “classic” presentation of ICH is abrupt onset intubation assures adequate gas exchange and of headache, often with nausea þ/– vomiting and minimizes the risk of precipitous respiratory fail- smoothly progressive focal neurological deficits ure and aspiration pneumonitis. Intubation attributable to the anatomical location where should occur by experienced clinicians, with spe- the hematoma develops. A diminished level of cial care to avoid acute increases in intracranial consciousness (LOC) out of proportion to the hypertension (see Chapter 2). 7 Neurocritical Care of Intracerebral Hemorrhage . 57

Figure 7.2. Patient with multiple post-thrombolytic ICHs following IV tPA therapy for acute ischemic stroke on their 24-hour post-IV tPA CT scan (A) determined to be due to underlying cerebral amyloid angiopathy as evidenced by visualization of low signal microbleeds on axial gradient echo MRI images (B and C).

A history should be obtained whenever feasi- medication within 6 hours of clinical ICH onset. ble, with special attention to whether or not the Patients were randomized to a more aggressive patient became unresponsive, had or had not BP reduction strategy of a systolic BP < seizure activity, has a known history of hyper- 140 mmHg within 1 hour as compared to systolic tension, diabetes, or uses anticoagulant or BP < 180 mmHg. The results suggested a trend antiplatelet medications. toward better outcome in those patients assigned to the < 140 mmHg arm, but this difference was Initial Medical Critical Care of ICH not statistically significant. ATACH used a nicar- The initial vital sign assessment should focus on dipine drip to lower systolic BP in hypertensive uncontrolled hypertension which, in addition to ICH patients to one of three target ranges: 100– its own independent adverse effects on cardiac 139, 140–169, and 170–199. Current AHA clinical output and function, may, if not treated, increase practice guidelines (CPGs) provide no definitive the risk of rebleeding during the first 24 hours of or high evidence level specific BP management clinical presentation. Furthermore, a Cushing’s targets. response (hypertension, bradycardia, and wid- Rebleeding, defined as at least a 33% increase ened pulse pressure) may indicate markedly in hematoma volume from baseline noncontrast increased intracranial pressure. Erratic and irreg- head CT, occurs in up to 28% of hyperacute ular heart rhythms can occur and may indicate (presenting within 3 hours of clinical onset) ICH catecholamine-induced cardiac arrhythmias. patients within the first hour and 38% within the The first major medical critical care issue that first 24 hours of presentation. needs to be emergently treated when present is The second major medical critical care issue hypertension. Studies suggest, but do not prove, that needs to be emergently treated is correction that uncontrolled hypertension during the first 24 of coagulopathy in patients with thrombolysis or hours post-ICH onset is associated with a worse coagulopathy-associated ICH (TICH), especially clinical outcome and increased risk of rebleeding. in those with warfarin- and heparin-related ICH. Two important pilot studies, INTERACT and TICHs on average have three times greater vol- ATACH, have preliminarily investigated whether ume than noncoagulopathic ICH, and are more aggressive early therapeutic blood pressure (BP) likely to extend into the subarachnoid, subdural, lowering in hypertensive ICH patients is safe and and intraventricular spaces. They are associated feasible. INTERACT open label randomized 404 with a very high mortality rate, ranging from 70% ICH patients who could be evaluated and treated to >90% in most series. TICHs may be radiologi- with any available intravenous antihypertensive cally differentiated from non-TICHs by the 58 . Acute Management of Neurological Emergencies frequent presence of a blood-fluid level and lack 1 of 10,000 patients given IV vitamin K. For of early perihematomal edema, both of which heparin-associated ICH, rapid reversal is accom- indicate unclotted blood within the hematoma. plished with protamine sulfate. One milligram of protamine reverses per 100 units of unfractio- nated heparin, 1 mg of enoxaparin, or 100 u of TIPS & TRICKS antifactor Xa activity for daltaparin or tinzaparin. Maximum dose is 50 mg. It should also be ad- It is important to note that whereas the ministered slowly as an intravenous pyelogram window for risk of rebleeding essentially (IVP) over 10 minutes and the patient should be ends at 24 hours in patients with carefully observed for anaphylaxis. A STAT noncoagulopathic ICH, by contrast those repeat PT/INR should be obtained 5 minutes with TICH are at indefinite duration risk of after initial reversal agent for warfarin, with rebleeding until the coagulopathy has been follow-up PT/INR levels every 4 hours until two adequately reversed. This is true even for consecutive normal values are obtained. patients with initially small TICHs whose It should be noted that empiric treatment of clinical and radiological presentation patients with spontaneous, noncoagulopathic appears benign, but whom have high risk of ICH with rfVIIa was shown to have statistically subsequent or ongoing bleeding until their significantly less hematoma expansion in both coagulopathy is adequately corrected. phase IIb and phase III clinical trials (FAST trial). Unfortunately, this reduction of rebleeding did not translate into any improvement in clinical Some studies suggest that patients treated with outcomes, though median hematoma size in antiplatelet medication are also at increased risk these trials was small. Use of rfVIIa for spontane- of rebleeding and death due to ICH, but at pres- ous, noncoagulopathic ICH is currently not ent there is no evidence supporting the efficacy of recommended. empiric platelet transfusion to reduce THE risk of Initial ICH care should also include proactive ICH-related morbidity or mortality. measures to prevent deep venous thrombosis For patients with warfarin-associated ICH, ad- (DVT) formation, pressure ulcer formation, and ministration of recombinant factor VIIa (rfVIIa) aspiration. All ICH patients should be considered in a dose of 20 to 80 mg/kg is recommended to NPO until an initial swallow screen is performed immediately reverse warfarin coagulopathy, (followed by full speech pathology and a dys- though its effects are only temporary, lasting phagia evaluation) to assess the patient’s aspira- from 4 to 12 hours on average in this dosing tion risk. Pneumatic compression devices and range. Emergent administration of prothrombin elastic stockings should both be applied to ICH complex concentrate (PCC) is an alternative and patients and remain in place until the patients possibly more effective strategy for immediate are fully active and ambulatory. Pharmacological temporary reversal of the warfarin anticoagulant DVT prophylaxis with DVT prophylaxis dose effect. Dosing for reversal of the warfarin effect is subcutaneous (SQ) unfractionated heparin not well established, but a dose of 50 u/kg would (5000u SQ every 8 to 12 hours) or low molecular raise levels of factors II, IX, and X by approxi- weight heparinoids (enoxaparin 40 mg SQ daily) mately 50% of the normal levels, and raise factor can be initiated 48 hours post-ICH onset in VII levels by a small amount. patients with noncoagulopathy-related ICH. The After administration of an immediate reversal PREVAIL trial proved the superiority of enoxa- agent, fresh frozen plasma (2 to 8 units depend- parin 40 mg SQ daily over unfractionated hepa- ing on initial PT/INR value and subsequent rin 5000u SQ every 12 hours in stroke patients in follow-up values) should be transfused to main- preventing lower extremity DVT and pulmonary tain a more durable reversal of anticoagulation, embolism, but enoxaparin was also associated as well as 3–10 mg of IV vitamin K. This infusion with an increased risk of major bleeding events must be given slowly since anaphylaxis occurs in as well. 7 Neurocritical Care of Intracerebral Hemorrhage . 59

Initial Neurological Assessment and Acute obstructive hydrocephalus usually pre- Treatment of ICH sents as acute to subacute worsening of head- Initial neurological assessment should include a ache, a declining LOC, and loss of upgaze (or, in complete neurological examination (or coma ex- more severe cases, forced downgaze) with acute amination in unresponsive patients) to establish papilledema and loss of venous pulsations on a baseline against which future assessments can fundoscopic examination when it is sufficient to be compared. This should particularly focus on increase the ICP. As with IVH, although medical the LOC, signs of increased intracranial pressure therapy measures may temporarily ameliorate its such as sixth nerve palsies and papilledema, signs effects, EVD placement is the definitive therapy of hydrocephalus such as impaired upgaze or to effectively and durably alleviate ICP elevation forced downgaze, degree of dysphagia, and pres- and herniation due to this complication. Intra- ence of significant motor deficits that would ventricular (intrathecal) administration of tissue predispose to DVT formation. plasminogen activator (tPA) is being tested as a novel therapeutic approach in the CLEAR-IVH trial, but is not presently routinely recommend- ed in clinical practice. The development of TIPS & TRICKS hydrocephalus is also a poor prognostic feature The performance and careful documentation for ICH. of this initial assessment is particularly Herniation and consequent irreversible brain- important because most ICH patients who stem compression, resulting in coma and death, suffer early neurological deterioration do so is the most feared complication of ICH. Measures within the first 3 to 6 hours post-clinical to reduce the mass effect of the hematoma may onset. include the administration of mannitol (0.25 to 1g/kg IV every 4 to 6 hours and as needed) and other osmotic diuretics, hypertonic saline (1.5, 2, If the patient’s neurological examination has or 3%) titrated to desired ICP or mass effect/shift significantly deteriorated since arriving at the ED reduction. These work subacutely over 15 to 30 (or outside hospital ED if transferred), a STAT minutes. repeat head CT should be obtained as soon as feasible. In addition to rebleeding, other important CAUTION acute neurological complications include: (1) the Great care must be taken to maintain development of intraventricular extension (IVH); intravascular volume when administering (2) the development of acute obstructive osmotic diuretics. Otherwise, precipitous hydrocephalus which is often secondary to the diffuse cerebral arteriolar dilatation, which intraventricular extension of ICH; (3) herniation abruptly increases intracranial volume due to increasing mass effect; and (4) increased occupied by these vessels may be provoked intracranial pressure (ICP). and precipitate a dangerous or fatal spike or IVH is most common in deep hypertensive so-called “plateau wave” of increased ICP. ICHs and most often presents as abrupt deterio- ration in the LOC. Those who remain lucid will usually complain of abrupt onset of or abrupt worsening of headache, accompanied by nausea Hyperventilation to a pCO2 of 20–25 produces and vomiting. Treatment may include temporiz- an almost immediate reduction in cerebral ing measures to reduce the ICP, such as osmotic volume and ICP but is short-lived and not a diuretics (mannitol), hyperventilation, or hyper- viable long-term solution. Surgical evacuation of tonic saline, but the definitive treatment of symp- hematoma was first tested in four small clinical tomatic IVH is placement of an extraventricular trials, only one of which (by Auer et al., 1989, drain (EVD). The development of IVH is a poor which involved endoscopically guided hemato- prognostic feature for ICH. ma evacuation) showed any potential benefit. 60 . Acute Management of Neurological Emergencies

The definitive surgical management of an ICH to the periphery of the hematoma after the plas- clinical trial was the ISTICH trial, which random- ma, red cells, and platelets within the hematoma ized 1033 patients to early craniotomy (empiric have clotted. Patients with TICH and those with evacuation of the hematoma prior to any clinical actively bleeding ICH often lack this thin initial evidence of herniation or significant neurological rim of perihematomal edema. It does not con- deterioration) versus delayed craniotomy (crani- tribute to the mass effect of the hematoma and, in otomy only when marked clinical deterioration/ fact, as the hematoma clots and this initial hy- herniation was occurring despite initial conser- peracute rim of edema forms, hematoma volume vative care). No significant difference in good actually contracts approximately 6% on average outcome was observed between the early crani- over the first 24 hours. This type of edema does otomy group (26%) and the delayed craniotomy NOT result in neurological deterioration and group (24%, p ¼ 0.41). A trend toward improved does NOT result in reactive gliosis, blood–brain outcome was noted in young patients with lobar barrier breakdown, or inflammation. ICH within 1 cm of the cortex. This group is now Delayed perihematomal edema, by contrast, being studied in the STICH II trial. STICH I, like represents a substantial threat to neurological other trials of surgery for ICH, only included recovery and survival. It may occur as soon as patients with supratentorial ICH. 48 hours post-ICH onset or as late as 2 to 3 weeks The benefit of the surgical evacuation of after ICH onset, and may persist for days or weeks cerebellar ICH causing actual or threatened hy- before subsiding. Its pathophysiological basis is drocephalus or brainstem compression is well complex and multifactorial. Experimental and established. The MISTIE trial is investigating human evidence indicate that perihematomal whether or not stereotactically guided sequential inflammation occurs due to microglia activation, intrahematomal administration of tPA with direct injury to neurons, and direct injury to sequential aspiration of a liquefied clot is of cerebral blood vessel tight junctions due to benefit as a minimally invasive procedure for breakdown products of lysed red blood cells and hematoma evacuation. hemoglobin byproducts (iron free radicals). This This trial has recently been completed and results in the development of both vasogenic and revealed a significant improvement in outcome cytotoxic edema. Specific mediators of injury in patients (defined as a Modified Rankin Score of biochemically include matrix metalloprotease 0-3) that had at least 15 ml of blood removed. A 9, iron free radicals, and direct microglial inva- phase III trial has been submitted for funding. If sion. A pilot trial of desferoxamine (an iron che- the phase III trials can verify these findings, this later), has been completed and a larger trial is in will have a significant impact on how deep intra- progress examining the potential therapeutic cerebral hemorrhages are treated. effects of chelating away the iron free radicals and the oxidative injury they mediate. Subsequent Neurological Critical Care of Clinically, delayed perihematomal edema ICH presents most often as a delayed and subacute Similar to ischemic stroke patients, ICH patients onset of a declining LOC from a previously stable are at risk for delayed neurological deterioration. or even previously (transiently) improving focal Although delayed rebleeding may occur in TICH neurological deficits that were observed upon patients whose coagulopathy remains uncorrect- presentation. It may also present as a new or ed, rebleeding in noncoagulopathic ICH patients worsening focal neurological deficit. Delayed beyond 24 hours post-presentation is rare, occur- herniation and death may occur as far out as 3 ring in 1% of patients. Delayed hydrocephalus weeks post-presentation in rare instances, but and seizures can, however, occur. The most com- the typical period of concern ranges from 2 to mon delayed neurological complication of ICH is 14 days post-ICH onset. the development of perihematomal edema. Practitioners should prepare families for the Most patients have a thin (1 mm or less) low possibilityofadelayedandprolongedneurological attenuation rim of perihematomal edema evident decline and risk of death. Unexpected deteriora- on the baseline or 24 hour follow-up head CT. tion (especially when a patient is initially improv- This may represent serum proteins diffusing out ing),if unexplained, is an ideal environmentfor the 7 Neurocritical Care of Intracerebral Hemorrhage . 61 genesis of malpractice litigations. Ongoing com- There is a great need for drugs that will directly munication of realistic expectations with the fami- inhibit glial cell activation and perihematomal ly members of critically ill ICH patients generally inflammation that are not corticosteroids. In maximizes patient and family satisfaction. Estab- cases where delayed perihematomal edema is lishing and periodically re- evaluating the goals of intractable and refractory to medical therapy, care and level of aggressiveness desired to achieve hemicraniectomy is a reasonable consideration those goals, is advised. to prevent herniation and death. It may be par- ticularly useful in young patients with more su- CAUTION perficially located hematomas, though it could also be considered, in principal, for large deep Always prepare families for the distinct hematomas. possibility of delayed neurological deterioration after an initial improvement or stabilization. Analogously to acute traumatic TIPS & TRICKS epidural hematoma, ICH often has an initial “lucid interval” of neurological stability or For patients with large lobar or deep even improvement during the first 24–72 hematomas and medically refractory hours post-onset, followed by delayed perihematomal edema and/or increased ICP, neurological deterioration due to consider hemicraniectomy if an aggressive perihematomal edema, increasing ICP, or level of care is sought and the patient is a seizures in the ensuing days. suitable candidate for general anesthesia and subsequent rehabilitation.

Treatment of delayed perihematomal edema is often very challenging. Osmotic diuretics, hyper- Prophylactic treatment with anticonvulsants ventilation, and hypertonic saline are options. for patients with ICH is controversial. Seizures, While intuitively one might think that corticos- both clinical and “subclinical” nonconvulsive teroids would play a potentially useful role in this status epilepticus, represent another common setting, current guidelines recommend against cause of delayed neurological deterioration. Up their use. Two randomized clinical trials showed to 45% of patients with ICH in the NICU setting not only no benefit in outcome for using them, who undergo continuous bedside EEG monitor- but also an increased risk of hyperglycemic and ing have electrical evidence of seizure activity. infectious complications. Furthermore, their However, no difference in the rate of such activity mineralcorticoid effects lead to increased fluid was noted in those receiving “prophylactic” an- retention in the intravascular space, which may ticonvulsants who had not had clinical seizure exacerbate cerebral edema and hypertension. activity preceding such monitoring. If anticon- vulsants are used (mostly for superficial cortical TIPS & TRICKS or temporal lobe hemorrhages), levateracitam may be a good choice based on its accessibility Use of corticosteroids to diminish and safety profile. Valproic acid is generally perihematomal edema in ICH is tempting but avoided, especially during the first 24 hours ineffective. Two clinical trials not only failed post-ICH, and in those on antiplatelet medica- to show benefit but one actually showed a tions, due to its thrombocytopathic effects. Oral significantly increased risk of hyperglycemic anticonvulsants should initially be avoided and and infectious complications, both of which given only to those having passed a dysphagia have been linked to poor outcome in ICH evaluation. Continous bedside EEG monitoring patients. Current AHA CPGs also explicitly should be considered where available for any ICH recommend not using them. patient with unexplained paroxysmal or a persis- tent decline in the LOC. 62 . Acute Management of Neurological Emergencies

TIPS & TRICKS for spontaneous intracerebral hematoma: a randomized study. J Neurosurg 1989; 70: For ICH patients with a persistent or 530–535. paroxysmal unexplained decline in the LOC, Brott TG, Broderick JP, Kothari RU, et al. Early consider a 24-hour, or more, duration of hemorrhage growth in patients with intracere- continuous bedside EEG monitoring to rule bral hemorrhage. Stroke 1997; 28:1–5. out nonconvulsive status epilepticus. Avoid Gebel J, Jauch E, Brott T, et al. Natural history of narcotics (especially meperidine, tramodol, perihematomal edema in patients with hyper- and morphine) and other commonly used acute spontaneous intracerebral hemorrhage. NICU medications (“penem” antibiotics Stroke 2002; 33:2631–2635. [imipenem/meropenem], dopamine Gebel J, Jauch E, Brott T, et al. Relative edema agonists like bromocriptine, volume is a predictor of outcome in patients diphenhydramine) which may trigger with hyperacute spontaneous intracerebral seizures. hemorrhage. Stroke 2002; 33:2636–2641. Gebel J, Sila C, Sloan M, et al. Thrombolysis- ICP monitoring with preservation of cerebral related intracranial hemorrhage: a radiographic perfusion pressure of at least 50 mmHg (and analysis of 244 cases from the GUSTO-1 ideally 70 mmHg) may be useful in patients with trial with clinical correlation. Stroke 1998; large hematomas with substantial mass effect. Its 29:563–569. ability to improve the outcome is controversial. Manno EM, Atkinson JLD, Fulgham JR, Wijdicks EFM. Emerging medical and surgical Subsequent Medical Critical Care of ICH management strategies in the evaluation and The focus of medical care for the patient after treatment of intracerebral hemorrhage. Mayo ICH is to prevent subsequent medical complica- Clin Proc 2005; 80:420–433. tion. This can be accomplished through ongoing Mendelow AD, Gregson BA, Fernandes HM, et al. attention to DVT prevention and surveillance (STICH investigators.) Early surgery versus with bi-weekly lower extremity venous duplexes, initial conservative treatment in patients with skin breakdown assessment, prevention and spontaneous supratentorial intracerebral hae- treatment, aspiration prevention, regular matomas in the International Surgical Trial in changes of Foley catheters, central lines, and Intracerebral Haemorrhage (STICH): a ran- EVDs, which are all potentially effective strategies domized trial. Lancet 2005; 365:387–397. to minimize the risk of delayed medical compli- Morganstern L, Hemphill JC, Anderson C, et al. cations. Monitoring and treating fever with acet- Guidelines for the management of spontane- aminophen may improve neurological status. ous intracerebral hemorrhage: a guideline for Early discussion and consideration of tracheos- health care professionals from the American tomy and PEG in those ICH patients with larger or Heart Association/American Stroke Associa- poorer prognosis ICH in whom prolonged respi- tion. Stroke 2010; 41:2018–2129. ratory failure and/or aspiration risk is anticipat- Quereshi AI, Tuhrim S, Broderick JP, et al. Spon- ed, helps to minimize the risks of pulmonary taneous intracerebral hemorrhage. New Engl complications. J Med 2001; 344:1450–1460. Bibliography Qureshi A. Antihypertensive treatment of acute Andersen CS, Huang Y, Wang JG, et al. Intensive cerebral hemorrhage (ATACH) trial. Presented blood pressure reduction in acute intracerebral at the International Stroke Conference, New haemorrhage trial (INTERACT): a randomized Orleans, La, February 20–22, 2008. pilot trial. Lancet Neurol 2008; 7:391–399. Qureshi AI. Antihypertensive treatment of acute Auer LM, Deinsbergerg W, Niederkorn K, et al. cerebral hemorrhage (ATACH): rationale and Endoscopic surgery versus medical treatment design. Neurocrit Care 2007; 6:56–66. 8 Acute Management of Status Epilepticus Jan Claassen

Division of Neurocritical Care and the Comprehensive Epilepsy Center, Department of Neurology, Columbia University, New York, NY, USA

Introduction and Definition Diagnosis and Clinical Status epilepticus (SE) is an acute life-threaten- Presentation ing neurological emergency. Most recent litera- Convulsive SE presents classically with general- ture agrees that any convulsions lasting for ized tonic–clonic movements or rhythmic jerking more than 5 minutes, or two or more convul- of the extremities, mental status is impaired, and sions in a 5-minute interval without return to additional neurological findings such as aphasia, preconvulsive neurological baseline, are suffi- amnesia, staring, automatisms, blinking, facial cient to qualify for the diagnosis of SE. Since twitching, agitation, nystagmus, eye deviation, very few isolated seizures will last for 5 minutes and perseveration may be seen. Transient benign or longer the traditional requirement for sei- post-ictal focal findings such as Todd’s paralysis zures to last for a minimum of 30 minutes has may persist. Typically, patients with generalized been abandoned by most authors. Patients with convulsive SE are expected to awaken gradually nonconvulsive SE (NCSE) do not exhibit overt after the motor features of seizures disappear. signs of convulsions but have seizure activity Approximately half of all patients with generalized documented on the EEG. tonic–clonic seizures will have nonconvulsive sei- zuresafterconvulsionshavesubsidedand14%will have NCSE. Classic findings of NCSE include ictal SCIENCE REVISITED discharges on EEG, with or without subtle convul- sive movements that may include twitching of the In animal models permanent damage and arms, legs, trunk, or facial muscles, tonic eye devi- pharmacoresistance can be demonstrated ation, and nystagmoid eye jerking. earlier than 30 minutes after onset of The differential diagnosis for convulsive and seizures. The majority of clinical and NCSE includes movement disorders (myoclonus, electrographic seizures last less than asterixis, tremor, chorea, tics, dystonia), hernia- 5 minutes and seizures that last longer tion (decerebrate or decorticate posturing), limb- often do not stop spontaneously. shaking transient ischemic attacks (TIAs) most commonly associated with perfusion failure due

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

63 64 . Acute Management of Neurological Emergencies to severe carotid stenosis, and psychiatric disor- of these will be in NCSE. In one of the few pro- ders also known as pseudostatus. Findings that spective studies, 37% of 198 patients undergoing suggest the presence of pseudostatus include urgent EEG for altered MS were found to have poorly coordinated thrashing, back arching, eyes nonconvulsive seizures. Electrographic seizures held shut, head rolling, pelvic thrusting, and are more likely in those with coma, young age, preserved consciousness or purposeful move- a past medical history of epilepsy or remote risk ments. However, when in doubt, always assume factors for seizures, documented convulsive that status is real and treat it adequately. Addi- seizures prior to monitoring, periodic discharges tionally, the differential diagnosis for NCSE is (lateralized or generalized) or suppression-burst very broad and any condition that can lead to a patterns on EEG, oculomotor abnormalities (i.e. decreased level of consciousness (e.g. toxic-met- nystagmus, hippus, or eye deviation), cardiac or abolic encephalopathies, including hypoglyce- respiratory arrest, and sepsis. mia and delirium, anoxia, and CNS infections), transient global amnesia, disorders (e.g. Acute Management parasomnias), or syncope may be considered. Prehospital Treatment Several studies have shown that the most impor- tant variable predicting seizure control is the time TIPS & TRICKS that has elapsed prior to initiating antiepileptic If the level of consciousness is not improving drugs (AEDs). Following this principle, patients within 20 minutes of cessation of the should receive benzodiazepine treatment as soon movements, or if the patient’s mental status as they are diagnosed with SE. This may be in the remains abnormal 30 to 60 minutes after the form of the intravenous administration of loraze- convulsions cease, NCSE must be considered pam (4 mg IV given over 2 minutes) or diazepam, and urgent EEG is advised. or diazepam (5 mg IV), but alternative routes of administration are also possible, including 20 mg of diazepam per rectum, and intranasal, buccal, or intramuscular 10 mg of midazolam – all of which Epidemiology and Underlying were shown to be effective alternatives to IV ad- Etiology ministration (see Table 8.1). Convulsive SE occurs with an estimated inci- Other important considerations for the pre- dence of 5 to 30 per 100,000 person years. The hospital phase of SE treatment include airway most common cause of SE is a prior history of support, assuring stable circulation, if possible epilepsy (22–26%). However, more than half of obtaining IV access, diagnosing hypoglycemia the episodes of SE occur in patients without prior and administration of D50W 50 mL IV and thia- seizures, often precipitated by an acute illness. mine 100 mg IV for those found to be hypogly- In adults without a prior seizure history, stroke cemic. As a side note, lorazepam needs to be (19–20%) is the most frequent underlying etiolo- refrigerated; for this reason it is usually impracti- gy. In children, a major cause of SE is infection cal for emergency medical service (EMS) use and accompanied by fever, while alcohol intoxication diazepam or midazolam are used as alternatives. or withdrawal is very common among young adults. No good data exists on the incidence of NCSE. Case series have reported that 10–30% of EVIDENCE AT A GLANCE patients in neuro ICUs have nonconvulsive Alldredge et al. (2001) investigated if seizures or NCSE and found them to be particu- initiation of SE treatment in the prehospital larly prevalent in patients with epilepsy, CNS setting could be safely done and lead to a infections, brain tumors, post-neurosurgery, and better outcome. Patients treated with stroke. Interestingly, 10% of medical ICU patients lorazepam by the EMS prior to reaching the without brain injury (particularly those with hospital had better acute seizure control than sepsis) will have nonconvulsive seizures and most 8 Acute Management of Status Epilepticus . 65

those that received diazepam or a placebo. Table 8.2. Initial diagnostic work-up Importantly, these authors found that All patients respiratory decompensation was more 1. Fingerstick glucose commonly seen in patients who got a 2. Pulse oximetry, supplement as needed placebo than those who were given 3. Monitor BP, HR, O2 sat, support if needed benzodiazepine. Recently, Silbergleit et al 4. Obtain IV access (2012) demonstrated that intramuscular 5. Head CT (for most cases) midazoalm is at least as effective and safe for 6. Order labs: blood sugar, complete blood prehopsital treatment of status epilepticus count, basic metabolic panel, calcium, when compared to intravenous lorazepam. magnesium, liver function tests, troponin, toxicology screen (urine and blood), anti- convulsant levels (at least for phenytoin, valproate, carbamazepine), type and hold, Immediate Management Steps, coagulation studies Including First-Line Antiepileptic 7. continuous EEG monitoring – Notify EEG Medication tech if available (as soon as available unless In the emergency room the following should be patient returns to prestatus epilepticus addressed immediately: secure the airway and baseline) breathing, support the blood pressure, obtain IV Depending on clinical presentation access, and administer first-line antiepileptic 1. Brain MRI 2. Lumbar puncture 3. Toxins that are frequently associated with Table 8.1. Simplified outline for seizures (i.e. INH, tricyclics, theophylline, management of SE cocaine, sympathomimetics, alcohol, . Diagnose; ABCs, IV access, EKG monitoring; organophosphates, cyclosporine) draw blood 4. Labs: phosphorous, ABG, inborn errors of . Thiamine 100 mg, D50W 50 mL IV metabolism. . Lorazepam 4 mg/2 min IV (or diazepam 5 mg IV) or 10 mg IM midazolam # medication (see Table 8.2). It is crucial to diag- . Fosphenytoin load: 20 mg/kg IV at up to nose hypoglycemia promptly and, if present, 150 mg/min (phenytoin is an alternative) treat it with 50 mL of D50W IV together with (or valproate load: 40 mg/kg IV over 10 min) thiamine (100 mg IV). . May skip this step and go straight to the next Lorazepam (4 mg IV over 2 min) should be box if seizures continue after lorazepam given as the first-line antiepileptic medication . If possible connect to EEG unless the or,ifthisisunavailable,diazepam5mgIVmay patient wakes up or returns to preconvulsive serve as an alternative. In patients where IV baseline access cannot be secured, benzodiazepine ad- . Consider intubation if the patient requires ministration should not be delayed and diaze- more sedative medications pam 20 mg per rectum (given either as a diastat # or as an IV solution of diazepam), or midazolam . Continuous IV midazolam or continuous IV 10 mg intranasal, buccal, intramuscular, or IV propofol (dosing, see Table 8.2) are options. As mentioned above, the single . Alternative IV valproate most important factor in predicting seizure . Continuous EEG needed control is time elapsed prior to initiating AEDs. # If unable to get intravenous access, benzo- . Continuous IV pentobarbital (dosing, see diazepines should be given promptly via Table 8.2) an alternative route (i.e. rectal, buccal, or . Continuous EEG needed intramuscular). 66 . Acute Management of Neurological Emergencies

EVIDENCE AT A GLANCE TIPS & TRICKS

Treiman et al. (1998) foud that lorazepam Most physicians would not give first- and was superior to alternatives in this large second-line antiepileptic medications in a randomized, double-blind, multicenter trial sequential order, but together. Seizures of four regimens: diazepam plus phenytoin, may stop after the initial benzodiazepines phenytoin alone, lorazepam alone, and but have a high chance of recurrence if phenobarbital alone. The best seizure longer-acting antiepileptics are not started. control was seen with lorazepam.

CAUTION TIPS & TRICKS . Ongoing convulsions may be masked A complete work-up of the underlying when using paralytics for intubation. etiology needs to be initiated as soon as . Hypotension may be seen with loading possible since seizures due to underlying phenytoin or fosphenytoin. uncorrected metabolic problems (i.e. . Give a loading dose of phenytoin or hypoglycemia) are difficult to control fosphenytoin that is weight based, and with antiepileptic mediations. not 1 g for everyone. . Do not adjust loading doses for renal or hepatic insufficiency. Second-Line Antiepileptic Medications While most experts agree that benzodiazepines should be given as first-line therapy, a number of If logistics allow, all patients that do not return alternatives are recommended for additional treat- to a preconvulsive neurological baseline within ment. Generally, most physicians would load any 20 minutes after convulsions have ceased should patient that has received first-line therapy with be connected to EEG monitoring to diagnose phenytoin/fosphenytoin (load: 20 mg/kg IV at up nonconvulsive electrographic seizures. As men- to 150 mg/min, while phenytoin needs to be given tioned above, a substantial number of patients at a rate of up to 50 mg/min; more caution may be will continue to have electrographic seizures after needed with elderly patients) or valproic acid convulsions have stopped. Clinical expression of (load: 40 mg/kg IV over 10 min; an additional seizures may also be masked in patients that 20 mg/kg may be given over 5 min if still seizing) received paralytics for purposes of intubation. and start maintenance therapy with either medi- It is unclear how aggressive electrographic sei- cation. Blood pressure and heart rate should be zures and NCSE should be treated, but most monitored closely since hypotension can be seen evidence suggests that, in the acute brain injury during the loading of phenytoin or fosphenytoin. setting, electrographic seizures should be treated In patients in whom convulsions persist after the aggressively. administration of benzodiazepines, experts in- creasingly recommend skipping second-line anti- Refractory Status Epilepticus epileptic medications and starting continuous Patients are generally classified as refractory sta- antiepileptic medications, such as midazolam or tus epilepticus (RSE) if seizures persist after treat- propofol. This will be discussed in detail below. ment with standard regimens. Most experts Levetiracetam (load: 2.5 g IV over 5 min at 1–4 g would call any ongoing SE refractory after receiv- over 15 min) may be an attractive alternative as ing an initial benzodiazepine and a second ac- a second-line agent but data is limited so far. ceptable anticonvulsant agent. Recommendation Phenobarbital may be an alternative choice if the for treatment of RSE is primarily based on case above medications are contraindicated or not series and expert opinion and, as a result, prac- available (load: 20 mg/kg IV up to 60 mg/min; tices vary widely. Conceptually, therapeutic maintenance 1–3 mg/kg/day in2–3 divided doses). approaches should be stratified into an initial 8 Acute Management of Status Epilepticus . 67 approach for those that have failed second-line Table 8.4. Alternative therapies for AEDs and into those that require advanced treat- refractory status epilepticus ment of RSE. Most experts would recommend Pharmacological treatment with a continuous IV AED such as . Ketamine midazolam or propofol (see Table 8.3 for dosing . Corticosteroids and administration information) as the initial . Inhaled anesthetics step, but valproic acid may be a reasonable . Immunomodulation (IVIG or PE) alternative, particularly in patients that have Nonpharmacological previously expressed a desire not to be intubated. . Vagus nerve stimulation . Ketogenic diet . Hypothermia Table 8.3. Treatment of refractory . Electroconvulsive therapy status epilepticus . Transcranial magnetic stimulation . Surgical management Continuous infusions of midazolam Case reports and small case series . Load: 0.2 mg/kg IV over 2–5 min; repeat . Lidocaine 0.2–0.4 mg/kg boluses every 5 min until . Verapamil seizures stop, up to a maximum loading . Paraldehyde dose of 2 mg/kg . Azetazolamide . Initial rate: 0.1 mg/kg/h. Bolus and in- . Deep brain stimulation crease rate until seizure control . Maintenance: 0.05–2.9 mg/kg/h Continuous infusions of propofol . Load: 1–2 mg/kg IV over 3–5 min; repeat Most experts would not use phenobarbital in boluses every 3–5 min until seizures stop, these circumstances. (See alternative therapies up to maximum total loading dose of in Table 8.4.) 10 mg/kg There is controversy regarding the target of . Initial rate: 33 mg/kg/min (2 mg/kg/h). continuous drips. Some advocate for seizure Bolus and increase rate until seizure control or a burst suppression pattern on EEG control monitoring, while others argue for complete back- . Maintenance: 17–250 mg/kg/min ground suppression. The best duration of main- (1–15 mg/kg/h) taining continuous IV AEDs is similarly unclear. Valproic acid (if not chosen already as second- After seizures are controlled most physicians line agent) would continue IV therapy for at least 24 hours . 40 mg/kg IV over 10 min (may give ad- before starting to wean them. The speed of wean- ditional 20 mg/kg over 5 min if still ing is also controversial but should not be done seizing) too abruptly unless the agent is pentobarbital. Phenobarbital . Load: 20 mg/kg IV up to 60 mg/min . Maintenance: 1–3 mg/kg/day in 2–3 di- SCIENCE REVISITED vided doses All patients should be connected to Pentobarbital continuous EEG at this point if available . Load: 5 mg/kg IV up to 50 mg/min; repeat since breakthrough and withdrawal seizures 5 mg/kg boluses until seizures stop. are frequent when treating with continuous . Initial rate: 1 mg/kg/h IV AEDs. Initiate a consultation for a possible . Maintenance: 0.5–10 mg/kg/h tradition- transfer if continuous EEG monitoring is ally titrated to suppression-burst on EEG not available at the institution (Claassen but titrating to seizure suppression is et al., 2002). reasonable as well 68 . Acute Management of Neurological Emergencies

EVIDENCE AT A GLANCE IV AEDs. A long list of less-well-studied new approaches exists (see Table 8.4). Of particular It is unclear how aggressive electrographic interest are medications that target the refracto- seizures and nonconvulsive status riness of SE to treatment (see Science Revisited epilepticus should be treated, but most 8.3) and therapies that may also be neuroprotec- evidence suggests that, in the acute brain tive (i.e. therapeutic hypothermia). All of these injury setting, electrographic seizures should are currently poorly studied and at this point be treated aggressively (Vespa et al., 2010). should be considered investigational. There is evidence from animal literature and in humans in a number of acute brain injury settings that electrographic seizures may CAUTION cause additional brain injury. Hypotension is a frequent side effect of pentobarbital, and vasopressors should be TIPS & TRICKS readily available. Other side effects include gastric stasis, myocardial suppression, Be sure to continue all second-line thrombocytopenia, metabolic acidosis. antiepileptic medications when starting treatment with continuous IV AEDs and follow serum levels when available (i.e. SCIENCE REVISITED phenytoin or valproic acid). Serum levels may be obtained immediately post-infusion of Evidence from Chen and Wasterlain (2006) valproic acid but should not be drawn before suggests that a number of mechanisms 2 hours after the infusions of fosphenytoin primarily related to the impairment of GABA- and phenytoin have passed. mediated inhibition might be involved in the development of refractoriness to treatment. These include internalization of GABA receptors, reduced sensitivity of GABA Advanced Treatment of RSE receptors, increased numbers of AMPA and Many physicians will elect to use continuous NMDA receptors at the synaptic membrane, infusions of pentobarbital (see Table 8.3 for and drug efflux transporters. The dosing recommendations). All patients on pen- development of drugs that specifically target tobarbital for RSE will need continuous EEG these mechanisms may be most promising monitoring. Often switching to pentobarbital will for the treatment of RSE. be performed in the ICU setting but at times, with patients that are highly refractory, pentobarbital infusions may need to be started while in the ER and within the first hour of SE onset. Similar Treatment Endpoints controversies exist for treatment duration and As mentioned above, the duration of continuous titration goals for advanced therapy, as those IV AEDs is controversial but suppression should mentioned above for the initial treatment of RSE. be sufficient to prevent a recurrence of seizures, When comparing different treatment strategies of with 24–72 hours of EEG suppression most fre- RSE, pentobarbital was less frequently associated quently employed. When weaning is initiated this with breakthrough and withdrawal seizures and should be done under EEG monitoring. With- more frequently associated with hypotension drawal seizures may be seen in approximately when compared with propofol or midazolam. half of the patients and should be treated ade- Breakthrough seizures can be expected in 20– quately. One approach is to restart the continu- 50% of patients and are usually treated with ous IV AED at the same rate that the patient was extra boluses of the current c.IV AED, together having prior to the taper, maximize or add non- with optimization or addition of noncontinuous continuous IV AEDs and then repeat tapering 8 Acute Management of Status Epilepticus . 69 after 24 hours without seizures. Alternatively pa- . Electrolytes. Metabolic derangements (glucose, tients may be switched to a different continuous sodium, phosphate, calcium, pH) can be the IV AED. underlying cause or the effect of SE. These should be corrected aggressively as outlined Continuous EEG Monitoring above since seizures may be very difficult to As outlined above all patients that do not return control with persistent metabolic abnormalities. to their pre-SE baseline and those that have RSE . Renal. Rhabdomyolysis and myoglobinuria should undergo continuous EEG monitoring leading to renal failure may be seen after pro- since the majority of SE in the ICU is nonconvul- longed convulsive SE and should be treated sive. Intermittent EEGs will miss a large portion with adequate hydration. of seizures recorded in acutely brain-injured patients. Prognosis In population-based studies, 10–20% of patients TIPS & TRICKS admitted with convulsive SE are dead at hospital discharge. Survivors have an increased risk of Practically comatose patients should undergo developing epilepsy and 10–23% of them are left a minimum of 48 hours of monitoring, while with new or disabling neurological deficits such those that are noncomatose may only require as cognitive decline. The in-hospital mortality of 24 hours. In those patients where periodic patients with NCSE is 18–52% and goes up to 65% epileptiform discharges are recorded, at one month follow-up. Most studies found a prolonged monitoring may be warranted worse outcome in older patients, those present- since these patients may develop ing with an acute symptomatic etiology (i.e. an- electrographic seizures. Limited montages oxic brain injury or stroke), and particularly those are discouraged since focal seizures may be with a long duration of seizure. The presence of missed (minimum of 16–21 electrodes). electrographic status, and ictal and periodic dis- charges, carries a worse prognosis. On the other hand, patients with SE due to withdrawal from Effects of SE On Other Organ antiepileptics or alcohol have a better prognosis. Approximately half of all patients with RSE are Systems dead at hospital discharge in most studies and . Cardiac. Cardiac arrhythmias are frequent in the only a little more than half of survivors return to setting of ongoing SE. Interestingly, contraction their premorbid functional baseline. Predictors of band necrosis – presumably secondary to mas- poor outcome are similar to those reported for sive catecholamine release – has been associated convulsive and nonconvulsive SE. with death during SE. Patients with SE and particularly RSE should have cardiovascular Bibliography monitoring and cardiac enzymes checked. . Pulmonary. Many patients with SE and most Alldredge BK, Gelb AM, Isaacs SM, et al. with RSE warrant intubation. Hypoxia, pulmo- A vcomparison of lorazepam, diazepam, and nary edema, and aspiration are frequently seen placebo for the treatment of out-of-hospital after SE and a chest Xray should be obtained for status epilepticus. New Engl J Med 2001; most patients. 345(9): 631–637. . Infectious disease. Infections may be the cause Chen JW, Wasterlain CG. Status epilepticus: but also may be seen due to SE (i.e. pneumo- pathophysiology and management in adults. nia). Fever should prompt blood, urine, and Lancet Neurol 2006 Mar; 5(3): 246–256. CSF cultures as well as a chest X-ray. A mild Claassen J, Hirsch LJ, Emerson RG, Mayer SA. elevation in the white blood cell count may be Treatment of refractory status epilepticus with seen in the serum and CSF as a consequence of pentobarbital, propofol, or midazolam: a sys- ongoing seizure activity. tematic review. Epilepsia 2002; 43(2):146–153. 70 . Acute Management of Neurological Emergencies

DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. therapy for prehospital status epilepticus. New Persistent nonconvulsive status epilepticus af- Engl J Med. 2012 Feb 16; 366(7): 591–600. ter the control of convulsive status epilepticus. Towne AR, Waterhouse EJ, Boggs JG, et al. Preva- Epilepsia 1998; 39(8): 833–840. lence of nonconvulsive status epilepticus in Hesdorffer DC, Logroscino G, Cascino G, comatose patients. Neurology 2000; 55(9): Annegers JF, Hauser WA. Incidence of status 1421–1423. epilepticus in Rochester, Minnesota, 1965–1984. Treiman DM, Meyers PD, Walton NY, et al. Neurology 1998; 50: 735–741. (Veterans Affairs Status Epilepticus Cooperative Lowenstein DH, Alldredge BK. Status epilepticus. Study Group). A comparison of four treatments New Engl J Med 1998; 338(14): 970–976. for generalized convulsive status epilepticus. Manno EM, Pfeifer EA, Cascino GD. Cardiac pa- New Engl J Med 1998; 339(12):792–798. thology in status epilepticus. Ann Neurol 2005; Vespa PM, McArthur DL, Xu Y, et al. Nonconvul- 58(6): 954–957. sive seizures after traumatic brain injury are Rossetti AO, Oddo M, Logroscino G, Kaplan PW. associated with hippocampal atrophy. Neurol- Prognostication after cardiac arrest and hypo- ogy 2010 Aug; 75(9): 792–798. thermia: a prospective study. Ann Neurol 2010; Young GB, Jordan KG, Doig GS. An assessment of 67: 301–307. nonconvulsive seizures in the intensive care Silbergleit R, Durkalski V, Lowenstein D, Conwit unit using continuous EEG monitoring: an R, Pancioli A, Palesch Y, Barsan W; NETT In- investigation of variables associated with mor- vestigators. Intramuscular versus intravenous tality. Neurology 1996; 47(1): 83–89. Part II Cerebrovascular Critical Care 9 Post-procedural Management of Patients with Aneurysmal Subarachnoid Hemorrhage Tomoko Rie Sampson and Michael N. Diringer

Neurology/Neurosurgery Intensive Care Unit, Department of Neurology and Neurological Surgery, Washington University School of Medicine, Saint Louis, MO, USA

Introduction ensuing days and weeks involve minimizing the impact of DCI and complications. Morbidity and mortality related to aneurysmal Survival after aSAH is most affected by the subarachnoid hemorrhage (aSAH) has improved impact of DCI in the days after the initial bleed, greatly over the last 20 years. This is, in part, due accounting for approximately half of deaths of to the improved management of complications in those who survive to treatment. DCI is closely patients who survive the initial ictus. The com- linked to the narrowing of large cerebral arteries plications associated with aSAH can be some of (cerebral vasospasm) that can occur as early as the most difficult to manage in a critical care 3 days after hemorrhage, with maximal narrow- setting. ing occurring between 5 and 10 days after the In this chapter, we will discuss the manage- bleed. Patients with an increased risk of devel- ment of neurologic and medical complications of oping DCI include those with poor clinical grade, subarachnoid hemorrhage (SAH) after an aneu- thick subarachnoid clot or intraventricular hem- rysm has been secured. orrhage, evidence of early angiographic vaso- Vasospasm and Delayed Cerebral spasm, younger age, hypertension, or a history Ischemia of smoking. Once the offending aneurysm is repaired surgi- cally or endovascularly, the risk for rebleeding of the aneurysm is markedly reduced, thus empha- SCIENCE REVISITED sizing the need for early intervention. After the . Vasospasm in aneurysmal subarachnoid ruptured aneurysm is “secured,” the main con- hemorrhage: In subarachnoid hemorrhage cern then becomes the prevention and manage- (SAH), the development of vasospasm ment of delayed cerebral ischemia (DCI), as well reflects a very complex cascade of cellular as other medical complications associated with dysfunction in addition to pathologic SAH. Therefore, a major focus of care in the changes in the arterial walls of affected

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

73 74 . Cerebrovascular Critical Care

vessels. Though the actual mechanism of supplanted by the World Federation of post-SAH vasospasm remains unclear, it has Neurologic Surgeons (WFNS) scale and the been linked to the release of free hemoglobin Modified Fisher scale. The Modified Fisher from red blood cell lysis in the subarachnoid scale uses radiologic appearance to grade space. This may result in numerous severity, while the Hunt & Hess score and the mechanisms leading to vasospasm that WFNS scale grade the clinical condition. Both include, decreased nitric oxide (NO) scales provide best predictive value with production, changes in endothelin levels, evaluation at the initial clinical presentation. differential gene up-regulation, and Higher scores represent a worse grade and increased oxidative stresses on the cells. prognosis. . Anatomic changes in vessels: In addition to changes in vascular reactivity and enhanced WFNS scale vasoconstriction structural changes occur in Grade GCS score Motor deficit cerebral vessels following SAH. Vessel wall I 15 Absent thickness is increased due to the remodeling II 14–13 Absent of smooth muscle cells narrowing the lumen. III 14–13 Present In addition, collagen fiber reorganization im- IV 12–7 Present or absent pairs vessel dilation. V 6–3 Present or absent . Impaired vascular reactivity: In addition to luminal narrowing and impaired relaxation of large vessels, the function of small penetrat- Modified Fisher scale ing arterioles is impaired following SAH. Autoregulation of CBF in response to changes Score Radiologic appearance in perfusion pressure is frequently impaired, 0 No SAH or IVH as well as reactivity to changes in carbon 1 Minimal or thin SAH, no IVH in dioxide tension. This impaired reactivity is lateral ventricles more common in poor grade patients and 2 Minimal or thin SAH, with IVH in confers an increased risk of DCI. lateral ventricles . Other potential factors: Several other factors 3 Thick SAH (completely filling one or have been implicated in the development of more cistern or fissure), no IVH in DCI following SAH that are not related to lateral ventricles vessel constriction. Microthrombi may devel- 4 Thick SAH, with IVH in lateral op in regions with low flow. Spreading corti- ventricles cal depression, slow-moving waves of neuro- nal depolarization, have been associated with DCI, even in the absence of large vessel Angiographic vasospasm is seen in up to 70% of vasospasm. patients with aSAH (see Figure 9.1). Only about half of patients with angiographic vasospasm will actually develop clinical vasospasm, which em- phasizes that arterial narrowing and DCI are not TIPS & TRICKS synonymous. Clinically, DCI manifests as an acute or subacute change in neurologic status, Clinical grading of subarachnoid hemorrhage: including an altered level of consciousness, agi- Some of the scales that are used to gauge the tation, focal neurologic deficits, or a new-onset severity of subarachnoid hemorrhage (SAH) aphasia or abulia. Signs and symptoms may wax can help to predict the development of DCI in and wane. These deficits may be reversible with these patients. Traditionally the Hunt and treatment, but permanent ischemic damage is Hess score and the Fisher scales have been possible. used. More recently they have been 9 Post-procedural Management of Patients with Aneurysmal Subarachnoid Hemorrhage . 75

safe method, it is not without its disadvantages. About 10% of patients lack adequate “bone win- dows” making it impossible to detect blood flow velocities. As with other ultrasound modalities, it is a user-dependent technology. It also can be misleading when used to monitor the impact of interventions. In patients who are treated for vasospasm with hemodynamic augmentation, flow velocity can rise as blood pressure is elevat- ed and CBF rises, leading to a conclusion of worsening vasospasm when, in fact, the rising velocities reflect the desired response to induced Figure 9.1. Angiographic evidence of vasospasm. hypertension. This is from an angiogram performed on day 7 after There are other methods for the detection of aneurysm rupture and shows severe vasospasm of the DCI that are under investigation. Cerebral mi- left anterior cerebral artery (arrows). crodialysis may offer some insight in the under- standing and detection of DCI. This method can measure the level of substances in the extracel- Monitoring for DCI typically consists of serial lular fluid in a very small region of the brain. neurologic examinations, transcranial Doppler Increases in lactate, the lactate/pyruvate ratio, examination, and cerebral angiography. Angiog- and glycerol have been observed in patients raphy remains the gold standard for the detection with symptomatic vasospasm. Other focal of vasospasm. Newer, potentially useful monitor- probes are available that measure brain tissue ing tools include computed tomography (CT) and oxygen tension and local CBF. It remains to be magnetic resonance (MR) perfusion, and focal determined if DCI can be detected prior to the probes that perform microdialysis and measure onset of symptoms. Additionally, a major limi- brain oxygen tension. In addition to its diagnostic tation to these methods is that they sample a power, angiography also allows for the intrapro- single very small region of the brain that may or cedure treatment of vasospasm. may not include the areas susceptible for devel- oping DCI. Monitoring for DCI Imaging methods for the detection of vaso- Patients who have undergone the repair of an spasm include perfusion CT, Xenon CT, diffu- aneurysm are typically monitored in an intensive sion–perfusion MRI, and SPECT. These methods care unit setting. This allows for frequent serial offer the advantage of sampling a significant neurologic examination and prompt recognition volume of brain tissue but only provide a snap- and initiation of treatment for clinical vaso- shot of the physiologic state rather than the spasm. A change in neurologic status should continuous data provided by focal probes. Cur- always be investigated quickly and thoroughly. rent studies are investigating the clinical utility of Alternative causes for neurologic changes must these imaging techniques. They may be comple- be considered prior to making the diagnosis of mentary to established modalities and focal clinical vasospasm (see Figure 9.2). probes rather than sole methods for the diagnosis Transcranial doppler (TCD) examination in- of DCI. volves the serial measurement of blood flow ve- Treatment for clinical vasospasm is aimed at locities in cerebral vessels. The velocity rises minimizing permanent ischemic damage to the either as a vessel diameter decreases or cerebral brain parenchyma and is accomplished by at- blood flow (CBF) increases. This modality is best tempts to improve oxygen delivery to tissue at suited for the assessment of vasospasm in the risk. Vasospasm treatment involves a combina- larger caliber vessels, such as the middle cerebral tion of prophylactic treatment and intensive in- artery or the intracranial portion of the internal terventions that are instituted as vasospasm carotid artery. While TCD is a noninvasive and manifests. Prophylactic interventions include 76 . Cerebrovascular Critical Care

Figure 9.2. Flowchart for the evaluation of the patient with neurologic change.

nimodipine administration and the prevention of proves the functional outcome. It does not, how- hypovolemia. ever, affect the presence of angiographic vaso- Nimodipine, a calcium channel blocker, re- spasm. It can be given orally or via nasogastric duces the impact of cerebral ischemia and im- tube, dosed at 60 mg every 4 hours. Hypotension 9 Post-procedural Management of Patients with Aneurysmal Subarachnoid Hemorrhage . 77 is infrequent if the patient is well hydrated. Treat- circulating blood volume. This may be accom- ment with nimodipine begins at the time of plished by following volume balance, and body admission and should continue to 21 days out weight. The use of arbitrary central venous pres- from the ictus. sure (CVP) or pulmonary capillary wedge pres- sure (PCWP) targets does not appear to add additional benefit. Though no studies have ad- CAUTION dressed the use of continuous hemodynamic monitoring using either arterial pulse pressure IV administration of nimodipine: waveform analysis systems, these monitors can Nimodipine has no intravenous formulation; provide valuable information regarding cardiac however, the FDA had received several function. They can be useful in titrating hemo- reports on the IV administration of dynamic intervention, particularly in patients nimodipine, inducing the maker to put a with comorbidities, such as congestive heart fail- black box warning on the drug. There were ure or cardiomyopathy. several reports of adverse cardiovascular The trigger for more aggressive therapy for DCI events, including death. The drug comes in a varies across centers. In some the decision is capsule and requires aspiration of the guided by rising TCD velocities, angiographic contents with a standard needle. Careful vasospasm or clinical symptoms. These treat- labeling of syringes containing nimodipine ments include “triple-H” therapy, also referred with “NOT FOR IV USE” can be helpful in to as hemodynamic augmentation with various preventing inadvertent IV administration. degrees of volume expansion, augmentation of cardiac output, and elevation of blood pressure. Additionally, endovascular manipulation, includ- TIPS & TRICKS ing angioplasty and infusion of intra-arterial va- sodilators, is often employed. Adjusting nimodipine dosing: Nimodipine In most institutions implementation of hemo- administration can be adjusted to minimize dynamic augmentation is reserved for patients precipitous decreases in blood pressure by who have had the ruptured aneurysm repaired to giving it in smaller, more frequent doses minimize the risk of inducing rebleeding. Uncer- (30 mg every 2 h). tainty exists as to how safe the therapy is in patients with multiple aneurysms when only the ruptured aneurysm has been repaired. The goal of this approach is to improve CBF and oxygen Hemodynamic Interventions delivery. The relative contribution of each com- Several decades ago it was recognized that SAH ponent of hemodynamic augmentation has been patients tend to develop hypovolemia which was debated however, as the benefit of each approach associated with, symptomatic DCI and cerebral has never been subjected to a controlled trial. infarcts. While the mechanisms responsible for Of the three treatment modalities, induced this continue to be debated, the administration of hypertension probably provides the greatest con- large volumes of fluids has been widely accepted tribution in improving both the CBFand oxygen as a means of ameliorating hypovolemia. This led delivery. Agent selection will be dependent on the to the concept that inducing hypervolemia may patient’s cardiovascular function and comorbid- be useful in the prevention and treatment of DCI. ities. Phenylephrine and norepinephrine are the Prospective studies indicate that prophylactic most commonly used vasopressors, and the ino- hypervolemia does not improve CBF and is as- tropes commonly employed are dobutamine and sociated with increased risk of medical compli- milrinone. cations, including pulmonary and cerebral ede- The use of prophylactic hypervolemia does not ma. Current guidelines recommend maintenance improve the CBF or outcome and has been asso- of euvolemia in the prevention of symptomatic ciated with cardiovascular complications related vasospasm, and frequent assessments of volume to fluid overload. Acute volume expansion at the status should be made to determine the normal time of symptomatic DCI may result in a modest 78 . Cerebrovascular Critical Care improvement in the CBF in regions with low on both adrenergic and dopaminergic baseline flow. However, the verdict on its utility receptors. These may be used in conjunction is mixed. In patients who are well hydrated prior with inotropic agents to optimize cardiac to developing DCI, the administration of large output (CO) in the hypertensive state. volumes of fluid may result in increased medical complications, notably pulmonary edema. The . Phenylephrine is an alpha-1 agonist, which individuals most likely to benefit from the ad- increases blood pressure by increasing the ministration of large volumes of fluid are likely to systemic vascular resistance (SVR). It is well be those patients who are hypovolemic. tolerated in patients without heart disease, Hemodilution has been the least understood of and CO is not affected. In patients with poor the interventions considered in hemodynamic CO, increased afterload can precipitate augmentation. Reduction in the viscosity of congestive heart failure. In addition, in the blood by hemodilution results in improved CBF. presence of pre-existing coronary artery Unfortunately, this also results in a reduction of disease, phenylephrine can precipitate the oxygen-carrying capacity of the blood, ulti- myocardial ischemia. Usual dosing: mately reducing oxygen delivery. One study 10–1500 mg/min. found that hemodilution resulted in a net fall in . Norepinephrine is an alpha-1 and beta-1 oxygen delivery, and it has largely fallen out of agonist with dose-based receptor favor in the treatment of patients with aSAH. preference. At low doses it affects CO Induced hypertension with vasopressors has because of its preference for beta-1 been more consistently associated with an im- receptors; while at high doses it is provement in CBF, although this effect seems to associated with increased systemic vascular be limited to patients with impaired autoregula- resistance and to greater affinity for alpha-1 tion. There are differing approaches to the choice receptors. It is preferred over phenylephrine of blood pressure targets. Some target a particular in patients with impaired cardiac function. systolic blood pressure, others target mean blood Usual dosing: 2–80 mg/min. pressures. A more rational approach widely used . Vasopressin acts on V1 receptors to cause is to raise blood pressure by 15–20% from the vasoconstriction, leading to increased patient’s baseline pressures. Further adjustments vascular resistance. Because it also acts at V2 are guided by the patient’s clinical response and receptors as an ADH receptor, it must be ability to tolerate the use of vasopressors and/or used with caution due to the potential risk for inotropes. hyponatremia. Usual dosing: 0.04 units/min. . Dopamine acts on the dopamine receptor DA1, as well as adrenergic receptors TIPS & TRICKS alpha-1 and beta-1. Similar to norepinephrine, dopamine also has a dose- Inducing hypertension with pressors: The dependent profile. At moderate doses it can choice of vasopressors in hemodynamic result in increased SVR and CO, and at high augmentation should take into account the doses it primarily results in increased SVR goal of induced hypertension balanced with only. However, the use of dopamine is the patient’s underlying cardiovascular limited because dysrhythmias are often function and the risk of concomitant organ seen even at moderate doses. Usual dosing: damage (heart failure, etc.) by these agents. 1–20 mg/kg/min. The adrenergic vasopressors, phenylephrine, and norepinephrine act on alpha-adrenergic Although, under normal conditions, changes in receptors to produce vasoconstriction cardiac output have no effect on the CBF, there is Norepinephrine also has powerful beta- evidence to suggest that the use of inotropic adrenergic properties so that it improves agents can be helpful in treating DCI. In patients cardiac output. Vasopressin acts on with symptomatic vasospasm, improved cardiac vasopressin receptors; while dopamine acts output has been reported to improve the CBF. 9 Post-procedural Management of Patients with Aneurysmal Subarachnoid Hemorrhage . 79

Both dobutamine and milrinone have been used Emerging Therapies in this way. There are no recommended guide- Several emerging therapies for the treatment of lines for cardiac indices when intropic therapy is vasospasm are on the horizon. In addition to the used, but it is largely based on individual re- injection of vasodilators, which have a limited sponse to therapy. In these cases, patients may duration of action, there has been an investiga- benefit from the use of continuous hemodynamic tion into the implantation of drug-eluting nimo- monitoring to prevent complications such as dipine wafers at the time of surgery to allow for congestive heart failure. In the past, Swan–Ganz the extended release of vasodilators. Preliminary catheters were used for this purpose, but more studies suggest that this sustained release of recently devices that calculate cardiac output nimodipine reduces arterial narrowing and may using arterial pulse contour analysis, such as the improve the outcome. PiCCO or LiDCO, have become popular. There has been considerable excitement abouttheuseofstatinsinthepreventionand Endovascular Interventions treatment of DCI. Smaller studies have sug- for DCI gested some benefit, but larger studies are need- ed. Completed studies to date have been limited Endovascular manipulation is often undertaken in terms of sample size, heterogeneous outcome after patients fail to improve with optimal medi- definitions, and methodology. Larger trials cal management, or whose poor cardiac function are underway, and the routine use of statins makes the administration of vasopressors or ino- remains controversial in the care of patients tropes too risky. Both transluminal balloon an- with aSAH. gioplasty and intra-arterial infusion of vasodila- Hypomagnesemia is seen in about half of tors have been used to treat vasospasm. The patients with SAH and is associated with DCI timing of treatment is uncertain, as is the defini- and worsened long-term outcomes. There may tion for failure of medical management. be a theoretical benefit from a magnesium sup- Transluminal balloon angioplasty of the affect- plementation in patients with SAH, due to ed vessels can return the vessel caliber to normal magnesium’s effect on calcium voltage-gated and improve the CBF; however, correction of channels, resulting in vasodilation. Pilot studies angiographic vasospasm does not always lead to have shown feasibility and potential effective- clinical improvement. The use of prophylactic ness in prevention and treatment of DCI, but angioplasty among affected intracranial vessels in subsequent larger studies failed to demonstrate high-grade patients has been studied, and while it anyimpactonoutcome.Supplementationis appears to benefit some patients, this was more fairly well tolerated, but it can induce bradycar- than offset by complications of the therapy, in- dia, hypotension, or hypocalcemia. Currently, cluding vessel rupture and death. It continues, there are two ongoing randomized clinical trials however, to be used in symptomatic patients. As in magnesium supplementation which may help its application is limited by the ability to pass the to define the utility of this treatment. balloons into smaller diameter vessels, it has no Endothelin is an extremely potent vasocon- role in treating distal vasoconstriction. strictor and receptor antagonist that has been Intra-arterial infusion of vasodilators has been shown to reduce the incidence of angiographic used to treat distal vasospasm. Although initially vasospasm in animal models. very popular, most centers have abandoned the use of papaverine because of its short duration of action and increased risks of complications, in- cluding intracranial hypertension. Calcium- SCIENCE REVISITED channel blockers (nicardipine and verapamil) are Endothelin in vasospasm: While much of the now used because of their lower risk of compli- pathophysiology of vasospasm remains cations. Others have proposed the use of intra- unclear, endothelin is thought to play a arterial milrione because of its robust vasodila- significant role in the development of tory properties. 80 . Cerebrovascular Critical Care

vasospasm. Endothelin is a potent, long- a result of intra-operative brain retraction, ische- acting, endogenous vasoconstrictor. In SAH, mia and/or infarction. Unfortunately, there are vasospasm may be promoted by the elevation limited options for its treatment. Hyperosmotic of endothelin in the CSF, coupled with up- therapy such as the use of mannitol can be useful. regulation of endothelin receptors in the Care must be taken to balance the risk of hypo- cerebral vessels. volemia potentially worsening of DCI with the risk of intracranial hypertension. Hypertonic sa- line (23.4%) provides volume expansion with less Clazosentan, one such receptor antagonist, osmotic diuresis than that seen in mannitol. was shown to reduce angiographic vasospasm in Additionally, hypertonic saline may exert a ben- acute SAH patients in a Phase II study, although eficial effect on aquaporin-4 channels, which its use was associated with increased pulmonary may play a role in the development of cerebral complications, possibly related to fluid retention edema. If intracranial hypertension is recalcitrant induced by the study drug. Unfortunately a to medical management, decompressive cra- phase 3 trial of the endothelium antagonist niectomy can be considered. The utility of this Clazosentan failed to show a benefit. procedure, however, is not yet known. Hydrocephalus and Edema Hydrocephalus (defined by the presence of ven- TIPS & TRICKS tricular enlargement) often occurs early (within Dosing of hypertonic saline for cerebral 72 hours) in the course of hospitalization for edema: Dosing for hypertonic saline (23.4%) approximately 20–30% of patients with SAH. Ear- is weight-based. One gram of mannitol is ly hydrocephalus may be associated with intra- equiosmolar to 0.686 mL of 23.4% saline. For ventricular blood or have a higher burden of a 70-kg individual, mannitol would be given subarachnoid blood. The significance of asymp- as an initial dose of 70–105 g (0.5–1 g/kg). An tomatic hydrocephalus in the acute period is equivalent dose of 23.4% saline would be unclear, as many of these patients do not deteri- approximately 25–50 mL. Remember that orate. Many patients who have a decreased level 23.4% saline must be given via central line. of consciousness and undergo extraventricular drain placement display improvement in their symptoms (improvement is seen in about 40– 80% of patients). Late or chronic hydrocephalus Cardiopulmonary Complications can occur after 72 hours, and several risk factors Patients with aSAH can show signs of early cardiac have been identified for the development of dysfunction with arrhythmias and electrocardio- chronic hydrocephalus, including older age, early gram (EKG) changes that often differ from those of ventriculomegaly, intraventricular hemorrhage, acute myocardial infarction. These should be trea- high-grade SAH, and female gender. Rates of ted expectantly with serial EKGs and cardiac bio- chronic hydrocephalus do not differ by aneurysm markers, as well as echocardiogram. treatment. Up to a quarter of these patients may A more severe form of cardiac dysfunction require permanent shunting. There are no estab- following SAH is neurogenic stunned myocardi- lished protocols examining the time with which um. This, is likely related to excessive catechol- external ventricular drains (EVDs) are weaned in amine release at the ictus and is characterized by patients with hydrocephalus. The time required cardiogenic shock, severe heart failure, pulmo- to discontinue an EVD does not appear to affect nary edema, and hypotension. Older age patients the need for permanent shunting. (>50 years) with a poor clinical grade have a higher risk of developing this complication. The Cerebral Edema management of neurogenic stunned myocardi- Poor grade patients commonly develop diffuse um may require the use of pressors and inotropic cerebral edema. Cerebral edema may develop as agents, as well as strict control of fluids. 9 Post-procedural Management of Patients with Aneurysmal Subarachnoid Hemorrhage . 81

The most common pulmonary complications must be considered; a large prospective trial of include pulmonary edema (both cardiogenic liberal and conservation transfusion thresholds is and neurogenic) and ventilator-associated planned. pneumonia. Neurogenic pulmonary edema is seen in about 30–70% of patients with aSAH. This occurs soon after the ictus, and can resolve TIPS & TRICKS over several days. Ventilator-associated pneu- monia is a well-known complication of mechan- Considering transfusion in the aSAH patient: ical ventilation and typically develops several Many questions remain with regard to the days after intubation. threshold hemoglobin or hematocrit for Occasionally aSAH patients may develop acute transfusion. Raising hemoglobin improves respiratory distress syndrome with marked im- arterial oxygen content and, if cerebral blood pairment of oxygenation. This complication is flow (CBF) is unchanged, it will improve associated with an increased length of stay and cerebral oxygen delivery. As hemoglobin a worse short-term outcome. It does not, howev- increases, however, viscosity rises which can er, affect long-term outcome. lower theCBF.It is thenet balance of these two factors that ultimately determines if transfusion will improve oxygen delivery. Anemia and Transfusion Preliminary studies with PET suggest that Anemia in aSAH has been a subject of consider- raising hemoglobin to 10 or 11 g/dL improves able interest. When defined as a hematocrit < 30% oxygen delivery in SAH patients at risk for DCI; or hemoglobin concentration <9 g/dL, anemia is however, raising hemoglobin to higher levels seen in a substantial proportion of patients. It has does not appear to confer additional benefit. been associated with more DCI and worse out- The age of transfused blood is also important. come. There are several reasons why these pa- When blood is stored, 2–3 DPG and NO levels tients develop anemia, including extracorporeal fall over time, which favor vasoconstriction blood loss, hemodilution from volume expan- and potentially offset any beneficial effect on sion, and female gender. The threshold and sys- arterial oxygen content. Finally, transfused temic effects of transfusion after aSAH are ill blood has been associated with an increased defined; thus transfusion to correct anemia re- riskofinfectionandworseoutcomeinmedical mains controversial. patients. In critically ill medical patients, a randomized clinical trial indicated improved outcomes if a conservative threshold were used to trigger trans- Erythropoietin has been investigated as a po- fusion (<7.0 g/dL). This study, however, did not tential treatment for anemia after aSAH. A limi- include patients with cardiac or cerebral ische- tation of this treatment is its delayed effect on mia. It is argued that a more liberal transfusion blood hemoglobin (usually seen more than threshold (10 g/dL) would result in an improve 1 week after administration). Data has been lim- oxygen delivery to ischemic brain regions. This ited, though somewhat promising. Its benefit must be balanced with concerns that the rise in may potentially be derived from the secondary blood viscosity with transfusion and nitrous ox- mechanisms of erythropoietin, rather than the ide (NO) depletion in stored blood might lead to a correction of anemia. This approach must be reduced CBF and actually reduce oxygen deliv- considered in the light of a recent randomized ery. Retrospective reviews have suggested that trial in ischemic stroke where high-dose erythro- this might be the case, but PET studies indicate poietin resulted in a worse outcome. that transfusion improves oxygen delivery, though a definitive target hematocrit level has not been determined. Additionally, the systemic Thermoregulation consequences of transfusion, such as increased Fever (defined as temperature > 38.3 C) is seen in risk for infection and their impact on outcome, up to 70% of patients during the first week after 82 . Cerebrovascular Critical Care

SAH. Up to 50% of these patients do not appear to considered carefully, as hypoglycemia is also have an infection as the cause of fever. There is associated with worse long-term outcomes in considerable evidence from animal studies that patients with brain injury, including SAH. an elevated temperature worsens the impact of cerebral ischemia and that hypothermia is pro- tective. There has been some research examining Hyponatremia fever control in SAH patients, but the results have Hyponatremia is a common complication seen in not been definitive. about one-third of patients after aSAH. Mild Fever, however, likely improves the ability to hyponatremia is often asymptomatic, but acute fight infection and treating fever due to an infec- decrements in sodium concentrations can lead to tion is associated with longer courses of illness. cerebral edema, decreased mental status, and Therefore, hyperthermic SAH patients should be potential seizures. Hyponatremia in aSAH is most evaluated for potential infectious sources prior to commonly attributed to cerebral salt wasting treating for hyperthermia. The decision to treat (CSW) syndrome, though it appears that the Syn- fever must balance the risk for ongoing cerebral drome of Inappropriate Secretion of AntiDiuretic ischemia with that of the beneficial effects of Hormone (SIADH) may play a role. fever in treating infections. Cerebral salt wasting is a syndrome character- There are a variety of interventions used to ized by inappropriate natriuresis, leading to vol- lower temperature. Many units have protocols ume contraction and hyponatremia. The mecha- for fever management for those with no identified nism responsible for this syndrome is unknown, source of infection. These protocols involve an although elevated levels of natriuretic factor and escalation of interventions, which typically start the effects of sympathetic activation on renal with scheduled antipyretics (acetaminophen, function have been implicated. The SIADH oc- ibuprofen, or both), with or without a water- curs when the central osmotic regulation of the circulating cooling blanket. If the patient con- release of antidiuretic hormone is impaired, re- tinues to have prolonged hyperthermia despite sulting in ADH release in hypo-osmolar states. these measures, cold intravenous fluids may be These entities have different effects on intra- infused prior to employing surface or intravascu- vascular volume; CSW can lead to marked hypo- lar cooling devices. volemia whereas in SIADH intravascular volume is normal or elevated. Given the strong associa- tion between hypovolemia and delayed cerebral Glucose Management ischemia, the appropriate management of hypo- Hyperglycemia is a common medical complica- natremia is crucial. SIADH is often treated with tion of SAH. It occurs in about one-third of fluid restriction – a strategy that has been linked patients, though, dependent on the definition to more infarcts in SAH patients with DCI. used, it may include all patients with aSAH. It is The aggressive administration of isotonic fluids associated with increased risk of DCI and worse (2–3 mL/kg/h), and the restriction of free water long-term outcome. Despite the potential for intake in oral fluid and tube feeding, can help to altered cerebral metabolism of glucose after prevent hypovolemia and ameliorate hyponatre- SAH, there is no known optimal glycemic range. mia. More severe or symptomatic hyponatremia For many, moderate control of hyperglycemia is can often be treated with mild hypertonic saline the goal in the care of these patients, but solutions (1.5%, 3%). Fludrocortisone and hydro- this must be balanced with the concern for cortisone have been utilized to reduce fluid re- cerebral hypoglycemia in the setting of serum quirements and natriuresis, but while they re- euglycemia. duce the sodium and volume administered they Hypoglycemia should be avoided. Studies in have no impact on hyponatremia. Conivaptan head injury suggest that tight glucose control blocks the effect of ADH on the kidneys and is (80–100 g/dL) may impair cerebral metabolism effective in correcting hyponatremia via aquar- and less strict control has been recommended. esis, but must be used with caution to avoid The use of intensive insulin therapy should be hypovolemia. 9 Post-procedural Management of Patients with Aneurysmal Subarachnoid Hemorrhage . 83

CAUTION CAUTION

Conivaptan and volume status: Use Hypotonic saline in SAH: Do not use conivaptan with extreme caution when in the hypotonic fluids for volume expansion in window for vasospasm, as it can cause a patients with SAH. While hypervolemia may significant rise in urine output and lead to be helpful in CSWS, the use of hypotonic hypovolemia. fluids may worsen hyponatremia.

CAUTION Seizures and Prophylaxis Induced hypertension with only one of multiple Patients with aSAH may present with reports of aneurysms repaired: About 20% of patients seizure-like activity at the ictus. The true nature presenting with aSAH have more than one of these events, epileptic or posturing due to a aneurysm detected on evaluation. While some sudden rise in intracranial pressure, is debated. centers consider more conservative blood The risks for and implications of subsequent pressure goals when inducing hypertension seizures are not well understood. Antiepileptic for the treatment of DCI to minimize the risk of drugs (AEDs) are commonly used in the acute bleeding from the unprotected aneurysms, period following SAH for seizure prophylaxis, others consider the risk low and focus on the although its benefit has recently been ques- treatment of symptomatic DCI. tioned. The presence of cortical hematomas and DCI-related infarcts may increase the risk of delayed seizures. Of note, early and delayed seizures do not appear to confer an increased Bibliography risk for long-term epilepsy. Recent studies sug- Bederson JE, Connolly ES Jr, Batjer HH, et al. gest that the use of AEDs may actually worsen Guidelines for the Management of Aneurysmal thecognitiveoutcome,possiblybyimpairing Subarachnoid Hemorrhage: A Statement for brain recovery. Their routine use is being re- Healthcare Professionals from a Special Writ- evaluated. ing Group of the Stroke Council, American Questions remain with regard to the specific Heart Association. Stroke 2009; 40;994–1025. anticonvulsant and the duration of treatment. Diringer MN. Management of aneurysmal sub- Phenytoin was commonly used for prophylaxis, arachnoid hemorrhage. Crit Care Med 2009; partly because it can be given intravenously, but 37:432–440. its use is not without consequences. A few ob- servational studies have shown that the short- Macdonald RL, Higashida RT, Keller E, et al. Clazo- term use of phenytoin (3 days) does not signifi- sentan, an endothelin receptor antagonist, in pa- cantly differ from longer courses of treatment in tients with aneurysmal subarachnoid haemor- the development of seizures. Levetiracetam has rhageundergoingsurgicalclipping:arandomised, become popular of late due to its more favorable double-blind, placebo-controlled phase 3 trial side effect profile, but its efficacy in SAH and its (CONSCIOUS-2). Lancet Neurol 2011; 10: 618–25. effect on long-term impairments in SAH are un- Piuta RM, Hansen-Schwartz J, Dreier J, et al. known. Current practice is to administrator pro- Cerebral vasospasm following subarachnoid phylactic AEDs from several days to 1 week after hemorrhage: time for a new world of thought. SAH. Routine long-term prophylaxis for seizures Neurol Res 2009; 31:151–158. after SAH is no longer recommended. Rabenstein AA, Lanzino G, Wijdicks EFM. Multi- disciplinary management and emerging thera- peutic strategies in aneurysmal subarachnoid hemorrhage. Lancet Neurol 2010; 9:504–519. 10 Care of the Neurointerventional Patient in the Neurointensive Care Unit Rishi Gupta

Department of Neurology, Neurosurgery and Radiology, Emory University School of Medicine, Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Atlanta, GA, USA

Introduction as a bolus intravenously in addition to flush lines that are connected to each catheter. Although Patients are admitted to the neurointensive care weight-based approaches are used to determine unit for emergent and elective endovascular and dosing, there is inconsistency in achieving target neurosurgical procedures. This chapter will re- anticoagulation levels leading to either under- or view the patients frequently admitted after pro- over-treatment. The half-life for unfractionated cedures and the potential complications that heparin is roughly 1 to 2 hours and thus patients may occur during their stay in the intensive care will return to the intensive care unit fully antic- unit. Many of the key principles will overlap the oagulated after many types of endovascular medical management of the disease states de- procedures. More recently, there has been scribed in earlier chapters. The first section will consideration for the use of direct thrombin in- review medications employed during endovas- hibitors such as Bivalirudin to replace unfractio- cular procedures and the potential complications nated heparin as they have the advantage of a relevant to the management from a critical care shorter half-life and may avoid the phenomenon perspective. Individual procedure types will be of heparin-induced thrombocytopenia. The cor- reviewed for more specific details on potential onary literature has shown that, compared to issues that may occur with each type of unfractionated heparin, the use of Bivalirudin intervention. was associated with less bleeding complications without any differences in thromboembolic Medications Used complications. Heparin Intravenous heparin is commonly used during Clopidogrel endovascular interventional procedures to pre- Clopidogrel is commonly used in patients under- vent thromboembolic complications from cath- going stenting or angioplasty. Stents may be used eter manipulations along the arterial vessels. The for wide-necked cerebral aneurysms that require target for achieving adequate anticoagulation is a bridge to maintain the coil mass in the aneu- an activated clotting time 1.5 to 2 times that of rysm. Additionally stents are used for intracranial normal value. Heparin is typically administered and extracranial atherosclerosis. Bleeding risks

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

84 10 Care of the Neurointerventional Patient in the Neurointensive Care Unit . 85 associated with antiplatelets are well established, There have been case series describing the use with rare complications such as neutropenia of both agents intraprocedurally that report the and thrombotic thrombocytopenic purpura also safety of using these drugs either through direct being reported. More recently, there have been infusion into the thrombus or via intravenous reports of patients who are poor metabolizers of approaches without significant hemorrhagic clopidogrel due to variants in CYP2C19 and its complications. Given the limitation of the small association with ischemic events. Point of care single center case series it is difficult to ascertain testing such as the Verify Now may aid clinicians the true incidence of complications arising from in determining if patients are biochemical non- the utilization of these agents. responders to clopidogrel. Similarly, genotyping kits are available to assess for the gene mutation. Many interventionalists adjust dosing of clopido- TIPS & TRICKS grel based on point of care testing in order to reduce thromboembolic complications after Anticoagulants and antiplatelet medications the placement of the stent. Unfortunately, there are commonly utilized during endovascular is no prospective data correlating biochemical procedures. Understanding which drugs are nonresponders to clinical events with neurovas- used during the procedure can help better cular stent procedures. There is also variability in tailor the care of the critical care patient response of critically ill patients with infections particularly with regards to monitoring for that may alter the efficacy of the drug. Addition- bleeding complications. ally the use of proton-pump inhibitors concomi- tantly has been shown to reduce the efficacy of platelet inhibition. Patients who develop bleed- Carotid Revascularization ing complications due to clopidogrel are typically transfused with platelets although the efficacy Procedures of such an approach has not been proven to Carotid artery stenting (CAS) and carotid endar- improve outcomes in intracranial hemorrhagic terectomy (CEA) are utilized in patients with complications from the drug. symptoms of ischemic stroke or TIA that is refer- able to the ipsilateral vessel or in patients with Glycoprotein IIb/IIIa Antagonists severe luminal narrowing in asymptomatic pa- Glycoprotein IIb/IIIa antagonists are used in tients. The procedure selected depends upon the patients who are biochemical nonresponders to anatomy, medical comorbidities, and presence clopidogrel or in patients that have an in situ of a contralateral carotid occlusion. There have thrombus discovered at the time of angiography. been several randomized-controlled studies Abciximab is a large compound with a strong assessing the efficacy of either approach for receptor affinity and a long half-life. This makes patients with high risk (medical comorbidities) it difficult to reverse bleeding complications that and conventional risk patients. Due to differ- may occur as a result of infusion of this drug. ences in trial designs and operator experience Platelet transfusions can be given, but with a there has been variable complication rates biological half-life of 12–24 hours, the additional reported in patients treated with CAS. platelets will potentially be inactivated with ab- During CAS, patients are fully heparinized to ciximab. Eptifibatide is a smaller molecule with help to reduce the risk of thromboembolic a lower receptor affinity and shorter half-life. events. Additionally patients are placed on dual The biological half-life is 2 to 4 hours and the antiplatelet agents in anticipation of stent use of cryoprecipitate, fresh frozen plasma, deployment. Such procedures are typically per- and platelet transfusions may aid in reversing formed with conscious sedation to reduce the the bleeding issues that may arise from the potential increased risk of myocardial infarction medication. One of the rare complications asso- when general anesthesia is used. Neurological ciated with eptifibatide is the development of exams are performed at each step of the proce- thrombocytopenia. dure. If any focal neurologic deficit is detected, 86 . Cerebrovascular Critical Care

Figure 10.1. A 75-year-old man with a history of a symptomatic left internal carotid artery stenosis deemed high risk for CEA due to need for coronary revascularization. (A) Angiography of the left common carotid artery showing the stenosis prior to treatment (black solid arrow). (B) Angiography of the left common carotid artery showing the stent implanted with reduction of the stenosis (black dashed arrow).

angiography is performed to assess for an embo- and increased parasympathetic tone. The phe- lus. After placement of a guide catheter in the nomenon is common during CAS procedures, target carotid artery, a distal protection device is and requires vasopressor support in roughly placed distal to the stenosis. The stent is deployed 20% of procedures. Patients with calcified pla- and typically angioplasty is performed to post- ques located at the carotid bulb appear to be dilate the stent. Figure 10.1 shows an example of a most vulnerable, while diabetic patients who patient who underwent successful placement of a have had prior CEA appear to have a lower fre- carotid stent. quency of hemodynamic perturbations. When The most common complication from either patients require vasopressor support post-oper- procedure is hemodynamic instability due to atively they appear to be at a higher risk for manipulation of the carotid bulb during balloon periprocedural stroke and myocardial infarction. angioplasty. Patients treated with CAS may expe- Careful hemodynamic monitoring is required rience hypotension or bradycardia at the time of post-CAS. Care should be taken to monitor for balloon inflation or stent implantation. This is the hypertension to avoid reperfusion injury partic- result of compression of the carotid barorecep- ularly in patients with severe contralateral carotid tors that lead to inhibition of adrenergic output stenosis. Such patients appear to have the highest 10 Care of the Neurointerventional Patient in the Neurointensive Care Unit . 87 risk for reperfusion hemorrhage when blood edema in the ipsilateral hemisphere. Additional- pressure is poorly controlled after the procedure. ly, hemorrhage may occur in the region of the Patients typically present with bradycardia af- infarct or remote from the infarct (Figure 10.2). It ter CAS. This can be treated with robinal or is vital to keep the blood pressure close to a mean atropine, particularly if symptomatic. Pseudo- arterial pressure of 65 to 70 mmHg when this phedrine 30 to 60 mg every 8 hours can be given occurs. orally to help with vasoconstriction and reduce If clinical fluctionations occur post-procedure, the vasodilatation that occurs after CAS. In rare monitoring for subconvulsive seizures with con- instances, persistent bradycardia may arise due tinuous EEG monitoring may be helpful. There to the development of an AV block. Such patients have been reports of utilizing hypothermia for may require a pacemaker to prevent further he- patients with reperfusion syndromes even in the modynamic instability. setting of a hemorrhage. Further data is required Intracranial Stenting to determine if this approach is efficacious. and Angioplasty Acute Endovascular Stroke Intracranial atherosclerosis is the etiology of is- Reperfusion chemic stroke in 5 to 10% of cases. There appears There are currently roughly 750,000 ischemic to be a higher prevalence of the disease in China strokes in the United States each year. Intrave- and Japan where reported rates are as high as nous tPA is utilized for patients who present 30%. Patients with a stroke due to a severe (>70%) under 3 hours from symptom onset that meet intracranial stenosis have a risk of subsequent inclusion and exclusion criteria. Recently, there is stroke of 23% at one year. There are two types of evidence that IV tPA has a modest benefit when stents currently utilized. The Wingspan stent administered within 4.5 hours of symptom onset. (Boston Scientific, Natick, MA) is a self-expand- Unfortunately due to time delays in patients ing stent that is FDA approved. The balloon presenting to the emergency room, poor recog- expandable coronary stent is also commonly nition of stroke symptoms, the utilization of in- used but is difficult to deliver in tortuous intra- travenous tPA remains under 3% for all stroke cranial vessels. patients. Moreover, tPA does not seem to have a Given the risk of subsequent stroke, some pa- tremendous impact on reperfusion for large ves- tients are considered for endovascular stenting sel occlusion. Patients with carotid terminus oc- and angioplasty. Currently there are two random- clusions who are treated with IV tPA have a 4% ized-controlled studies assessing the effective- chance of successful recanalization. In recent ness of stenting compared to medical therapy years, there has been rapid advancement of the for symptomatic lesions. Patients who may not development of endovascular techniques to treat meet criterion for these trials may be offered acute ischemic stroke. Roughly 75% of all ische- endovascular therapy outside of the trials. mic strokes are due to the occlusion of a large to The procedure is typically performed under medium-sized cerebral vessel. In 1999, the general anesthesia. Care must be taken to main- PROACT II study was performed to determine if tain mean arterial pressure during the induction intra-arterial pro-urokinase was superior to pla- of anesthesia. Patients are given aspirin and clo- cebo in patients with MCA occlusion. The study pidogrel prior to the procedure and receive sys- revealed an absolute benefit of 15% in achieving a temic heparinization intraprocedurally. After modified Rankin Score less than or equal to 2. deployment of the stent, the blood pressure is Based on this, the use of intra-arterial thrombol- typically reduced to achieve lower mean arterial ysis is now a level of evidence IB in the American pressures in order to avoid reperfusion hemor- Stroke Association guidelines for MCA occlusion rhage (Figure 10.2). The incidence of this entity is under 6 hours. rare; however patients with more severe lesions Patients who are candidates for endovascular may be more prone to develop this phenomenon. therapy are rapidly triaged to the angiography The clinical syndrome of reperfusion injury suite (Figure 10.3). At this point, there has been typically manifests with seizures and cerebral debate in the recent literature regarding whether 88 . Cerebrovascular Critical Care

Figure 10.2. A 48-year-old man with recurrent strokes and transient ischemic events within 2 months who was noted to have a left middle cerebral artery occlusion. (A) Angiography in the AP projection confirms the subtotal left MCA occlusion (circle). (B) 3D rotational angiography post-stenting shows marked improvement in antegrade flow with reduction of the stenosis. The patient returned post op day 6 with aphasia and seizures. (C) CT scan of the brain showing a left posterior temporal lobe intraparenchymal hemorrhage due to reperfusion injury. (D) MRI of the brain showing extensive edema around the hemorrhage. The patient was placed on antiseizure medication and the blood pressure was further reduced. His examination markedly improved but he remained with a partial receptive aphasia.

to utilize a general anesthesia to limit the move- come. Patients who undergo acute interventional ment of the patient and perhaps improve the stroke procedures with conscious sedation have a safety of the procedure versus conscious sedation low rate of conversion to general anesthesia. The that may be associated with better clinical out- concern with anesthesia is that during induction 10 Care of the Neurointerventional Patient in the Neurointensive Care Unit . 89

Figure 10.3. A 71-year-old man with atrial fibrillation who presented with acute onset of aphasia and right-sided hemiplegia. The patient was 4 hours and 30 minutes from symptom onset and brought to angiography after a CT of the brain was negative. (A) An AP projection angiogram reveals the presence of a left mid M1 middle cerebral artery occlusion (black arrow). (B) The Merci device was deployed (circle) distal to the thrombus and the clot was removed via an embolectomy. (C) Post-embolectomy angiography reveals successful removal of the thrombus.

there is significant hemodynamic variability that TIPS & TRICKS may impact the ischemic penumbra. Additional- ly, the patients who are intubated tend to remain The need for intubation should be assessed intubated for a longer period of time thereby for each individual patient prior to initiating impacting rates of pneumonia and perhaps the the endovascular procedure as there may be family’s perception of the severity of the condi- an association of poor clinical outcomes with tion. After an endovascular stroke intervention, a the use of general anesthesia during these CT of the brain immediately after the procedure procedures. can help to determine the presence of a hemor- rhage. Intra-arterial tPA is often administered. If hemorrhage does occur, assessing a fibrinogen level can help to determine if patients may bene- Coil Embolization of Cerebral fit from cryoprecipitate to help with hemostasis. Some centers also administer glycoprotein IIb/ Aneurysms IIIa antagonists during the procedure. If success- Patients harboring ruptured or nonruptured ce- ful reperfusion has been achieved, the blood rebral aneurysms are frequently treated with coil pressure can be lowered to a mean arterial pres- embolization. The decision of the surgical ap- sure of 65 to 75 mmHg in order to reduce the risk proach should be performed by an open vascular of reperfusion bleeding. Patients are typically surgeon and endovascular specialist to deter- placed in the intensive care unit for careful neu- mine the best and safest treatment strategy for rological and blood pressure monitoring. Many of the patient. Patients with subarachnoid hemor- these patients require antihypertensives after re- rhage have been studied as part of the ISAT perfusion. Continuous infusions of these medi- study which randomized patients to microsurgi- cations is typically required. cal clipping and coil embolization. Patients trea- Post-reperfusion edema has also been reported ted with coil embolization were noted to have a and may lead to rapid development of swelling 6.9% absolute reduction in mortality compared with significant midline shift and possible hernia- to clipping. Figure 10.4 shows an example of a tion. Hemicraniectomy can be utilized in patients patient who has undergone successful emboliza- with large ischemic strokes at risk for herniation or tion of a ruptured anterior communicating artery patients with extensive reperfusion injury. aneurysm. 90 . Cerebrovascular Critical Care

Figure 10.4. A 66-year-old man presented with a Hunt–Hess grade I subarachnoid hemorrhage and was found to have a narrow-necked anterior communicating artery aneurysm. (A) A 3D rotational angiogram showing the 5.5 mm aneurysm. (B) After coil embolization of the aneurysm.

Patients undergoing coil embolization in the aneurysm or thromboembolic events. Patients setting of a ruptured aneurysm can be challeng- are typically given intravenous heparin during ing to manage in the endovascular suite. Patients the procedure to prevent thromboembolic events with subarachnoid hemorrhage tend to have a and thus protamine must be readily available in hypercoagulable state and thus care must be the case of intraprocedural rupture. After the taken during the procedure to avoid thromboem- aneurysm has been secured, many operators bolic events. This is particularly concerning if the prefer the use of an antiplatelet agent to prevent patient is placed on amicar (episilon caproic platelet aggregation at the site of the coil mass acid) prior to the procedure. Additionally, endo- and neck interface. The risk of platelet aggrega- vascular procedures are performed with the pa- tion is likely linked to wider-necked aneurysms tient lying flat, and this may make the treatment with larger amounts of coil mass. Blood pressure of intracranial hypertension more difficult. Dur- can be liberalized particularly in patients who ing the procedure, protocols should be imple- may be at risk for vasospasm after the aneurysm mented with the anesthesiologist regarding the has been secured. external ventricular drainage catheter. Arteriovenous Malformations Arteriovenous malformations (AVMs) have been TIPS & TRICKS associated with the development of seizures or intraparenchymal hemorrhage. Treatment of The table position is frequently manipulated such lesions requires a multidisciplinary ap- to identify the optimal working projection to proach with specialists in radiosurgery, open neu- treat an aneurysm. Intracranial pressure rovascular surgery, and endovascular surgery. readings may not be accurate unless the Embolization of an AVM is performed for cure if drainage system is adjusted to the height of the lesion is small or for treatment of intranidal the table. aneurysms. More commonly, however, emboliza- tion is used to reduce the volume of the lesion for surgical resection or targeted radiosurgery. The most concerning complications from the The biggest challenge in the treatment of these procedure include intraprocedural rupture of the lesions is blood pressure control. Arteriovenous 10 Care of the Neurointerventional Patient in the Neurointensive Care Unit . 91 malformations have surrounding areas of brain during endovascular therapy for acute anterior that have disturbed cerebral autoregulation. circulation stroke: preliminary results from a Patient’s presenting with intracerebral hemor- retrospective, multicenter study. Stroke 2010; rhage have an ischemic penumbra surrounding 31:1175–1179. the hematoma. Preservation of this penumbra by Combescure C, Fonana P, Mallouk N, et al. Clo- avoiding steep reductions of blood pressure may pidogrel and vascular ischemic events meta- improve clinical outcomes. Patients being con- analysis study group. J Thromb Haemost 2010; sidered for embolization procedures may have 8(5):923–933. challenging hemodynamics. Fiorella D, Albuquerque FC, Han P, McDougall There are two theories of how intracerebral CG. Strategies for the management of intrapro- hemorrhage and edema occur during emboliza- cedural thromboembolic complications with tion. The first is normal perfusion pressure break- abciximab (Reopro). Neurosurgery 2004; through. This theory stipulates that the tissue 54(5):1089–1097. around the AVM is under-perfused and thus Gupta R, Abou-Chebl A, Bajzer CT, et al. Rate, there is maximal vasodilatation of the arterioles. predictors and consequences of hemodynamic After embolization these vessels are unable to depression after carotid artery stenting. JAm constrict, thereby leading to impaired autoregula- Coll Cardiol 2006; 47(8):1538–1543. tion and increased flow causing hemorrhage. The second theory is that partial embolization of the Hassan AE, Memon MZ, Georgiadis AL, et al. venous side of the AVM prior to complete cure Safety and tolerability of high-intensity antic- leads to outflow obstruction. In this condition, a oagulation with bivalirudin during Neuroendo- reduction in blood pressure may theoretically vascular procedures. Neurocrit Care 2010; Aug exacerbate the condition and lead to hemorrhage. 19 (EPub ahead of print). In clinical practice it is important to communi- Kasner SE, Chimowitz MI, Lynn MJ, et al. Pre- cate with the endovascular specialist post-proce- dictors of ischemic stroke in the territory of dure to understand the details of the procedure. symptomatic intracranial stenosis. Circulation Aggressive embolizations of larger AVMs with 2006; 113:555–563. poorly controlled blood pressure can lead to cat- Kollmar R, Staykov D, Dorfler€ A, et al. Hypother- astrophic hemorrhages. In scenarios where the mia reduces perihemorrhagic edema after in- vein may have been partially occluded consider- tracerebral hemorrhage. Stroke 2010; 41:1684– ation can be given for emergent open surgical 1689. evacuation of the AVM in order to prevent rupture. Leslie-Mazwi TM, Sims JR, Hirsch JA, Nogueira Additionally, in planning AVM resections, mini- RG. Periprocedural blood pressure manage- mizing the time from embolization to surgical ment in neurointerventional procedures. resection may be the safest approach. J Neurointerv Surg 2011; 3:66–73. Molyneaux A, Kerr R, Stratton I, Sandercock P, Conclusions Clarke M, Shrimpton J, Holman R. Internation- Endovascular therapies are rapidly evolving with al subarachnoid aneurysm trial (ISAT) of neu- technological advancements. Optimizing clinical rosurgical clipping versus endovascular coiling outcomes requires a team approach with the in 2143 patient with ruptured intracranial an- intensivist having a thorough understanding of eurysms: a randomized trial. Lancet. 2002; the details of the procedure and how best to 360:1267–1274. manage the hemodynamics and anticoagulants. Yi HJ, Gupta R, Jovin TG, et al. Initial experience with the use of intravenous eptifibatide Bibliography bolus during endovascular treatment of intra- Abou-Chebl A, Lin R, Hussain MS, et al. Con- cranial aneurysms. Am J Neuroradiol 2006; scious sedation versus general anesthesia 27:1856–1860. 11 New Treatment Strategies in the Management of Large Hemispheric Strokes and Intracerebral Hemorrhages Edward M. Manno

Neurocritical Critical Care, Cleveland Clinic, Cleveland, OH, USA

Introduction ma of significant magnitude to lead to the dis- placement of brain tissue shifts associated with Large hemispheric strokes and intracerebral neurological deterioration. hemorrhage is a mainstay of patients treated in Mortality rates vary among studies but all are neurological intensive care units and continue to greater than 50%. Mortality approaches 80% with have significant morbidity and mortality. Recent medical management alone for patients that de- changes in our understanding of the underlying velop malignant cerebral edema. Morbidity in physiological mechanisms involved with the de- survivors has been significant and has only re- velopment of post-ischemic stroke cerebral ede- cently been better documented. ma and intracerebral hemorrhage have altered our approach to the management of these dis- eases. This chapter will review our historical History and Background understanding of these processes, discuss how The initial studies and clinical observations of our understanding has changed, and examine the patients with large strokes were documented in recent strategies designed to implement this new the late 1950s and early 1960s. Through serial understanding. neurological assessments performed rigorously and continually over several days, the progres- Large Hemispheric Strokes sion of neurological deterioration was documen- Large hemisphericstrokes refer toischemicstrokes ted. This documentation was recorded in that involve greater than 50% of the middle cere- McNealy and Plum’s monograph on brainstem bral artery (MCA) territory. They primarily occur dysfunction and supratentorial lesions and due to occlusions of the MCA stem or through served as the basis for Plum and Posner’s text- occlusion of the internal carotid artery (ICA). book the diagnosis of stupor and coma. The The most common mechanisms include direct conclusion from these observational studies carotid thrombosis of a severely stenotic carotid was that clinically patients displayed evidence lesion or are secondary to cardiogenic emboli. of increased intracranial pressure. Neurological The term “malignant cerebral edema” was uti- deterioration was attributed to transtentorial lized to denote the development of cerebral ede- herniation due to central or downward tissue

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

92 11 New Treatment Strategies in the Management . 93 shifts caused by increased intracranial hyperten- than edematous tissue (Figure 11.1). Manno sion. Treatment strategies were subsequently et al. (1999) directly measured horizontal and designed to lower the intracranial pressure. vertical tissue shifts radiographically in patients Pathological studies, however, began to docu- with large hemispheric infarctions after large ment horizontal (not vertical) tissue shifts with doses of mannitol. Significant tissue shifts could large hemispheric infarctions. Ropper’s seminal not be documented but subsequent volumetric radiographic study on horizontal tissue shifts analysis did report an 8% decrease in the (Ropper, 1986) documented neurological deteri- noninvolved hemisphere. oration associated with horizontal displacement of the pineal. Finally, direct measurements of intracranial pressure found increased intracrani- SCIENCE REVISITED al pressure in only a minority of patients with large hemispheric infarctions. Thus, it was pre- Much concern has been raised about the sumed that neurological deterioration after large effects of mannitol or hypertonic solutions on hemispheric infarctions occurred secondary to damaged brain tissue: the theory being that horizontal displacement of the rostral dienceph- mannitol can leak into brain tissue and alon (the pineal serves as a marker for this). These become trapped inside this tissue thus tissue shifts did not occur secondary to global worsening focal brain edema. Radiographic increases in intracranial pressure, but were due labeling of mannitol used in a stroke patient to hemispheric pressure differentials established undergoing dialysis, however, suggested that by a focal expanding mass lesion. damaged blood–brain barriers allow for both the influx and efflux of mannitol depending upon the local osmotic gradient. SCIENCE REVISITED

The Monroe–Kellie doctrine states that the cerebral contents inside of the skull represent Medical Management a fixed volume. Any increase in contents The results of medical management for patients (i.e. hemorrhage, edema, tumor) must be met with large hemispheric infarcts have been disap- with an equal displacement of some brain pointing. Supportive management, including contents. Intracranial pressure in this mechanical ventilation, has not improved hypothesis represents the pressure needed to results. In fact the mortality for stroke patients displace certain fluids (i.e. CSF, blood, or undergoing mechanical ventilation for any brain). A corollary of this hypothesis is that reason is 66–75%. intracranial pressure is equal in all areas of Also, measures designed to lower the intracra- the brain. This has been proven not to be true. nial pressure have not proved to be effective in Cushing first described intracranial pressure decreasing mortality. Mannitol has not been gradients that could lead to intracranial shown to improve mortality after large strokes. tissue shifts. Subsequent studies with Schwab et al. (1997) utilized barbiturates titrated bihemispheric ICP monitoring with to burst suppression on EEG monitoring to treat expanding mass lesions have documented malignant cerebral edema. Intracranial pressure these pressure gradients. did not respond in 20% of patients and all pa- tients returned to similar intracranial pressure within 3 hours of treatment. Induced hypother- In addition to the documentation of horizontal mia was also used in a series of 25 patients. tissue shifts as the source for neurological dete- Mortality improved to 53% compared to histori- rioration, concerns were raised that treatments cal controls, with most deaths occurring after designed to lower intracranial pressure may passive rewarming. Steiner (2001) has suggested worsen neurological deterioration by preferen- that more controlled rewarming protocols may tially shrinking normal tissue to a greater degree improve outcomes. 94 . Cerebrovascular Critical Care

Figure 11.1. Methods to decrease intracranial pressure (i.e. use of hyperventilation, placement of an external ventricular drain, use of osmotic agents) may preferentially shrink tissue with an intact blood–brain barrier. This will decrease the pressure in nondamaged tissue and may potentially increase the pressure gradients that can worsen midline tissue shifts associated with neurological deterioration. (Reproduced from Frank (1995) with permission from LWW.)

Hemicraniectomy results revealed a trend toward improved out- The discovery of intracranial pressure differen- come with surgery. tials and the significant limitations of medical management mandated a new approach to the management of malignant cerebral edema post TIPS & TRICKS large hemispheric infarction. The concept of The key to performing a hemicraniectomy is performing a hemicraniectomy to allow the ex- to ensure that the craniectomy is large pansion of edematous tissue outside of the enough to allow complete expansion of skull was actually proposed and initiated in a edematous tissue outside of the skull. Some series of case studies in the 1970s and 1980s. early studies did not perform a large enough Rodent studies suggested that hemicraniectomy craniectomy. The result was incarcerated performed early post-infarct may actually pre- tissue coming out of the skull leading to serve cerebral tissue through increased collateral worse edema and tissue shifts. circulation. The first randomized study evaluating hemi- craniectomy was the hemicraniectomy and durotomy upon deterioration from infarction- This trend for improvement encouraged sever- related swelling trial (HEADFIRST). This study al European studies evaluating the effectiveness randomized 26 patients with large hemispheric of hemicraniectomy after large hemispheric in- infarctions and neurological deterioration to farcts. The hemicraniectomy after MCA infarc- standard medical management versus hemicra- tion and life-threatening edema trial (HAMLET), niectomy. The surgery involved a large hemicra- decompressive craniectomy in malignant middle niectomy with durotomy to allow for brain cerebral artery trial (DECIMAL), and decompres- expansion outside of the skull (Figure 11.2). The sive surgery for the treatment of malignant 11 New Treatment Strategies in the Management . 95

significant factor on defining the outcome. 80% of patients older than 50 were dead or disabled compared to only 32% of patients younger than 50. The clinical trials suggest that the utility of hemicraniectomy may be limited to patients un- der 60. DESTINY II is currently enrolling patients to evaluate this. Interestingly, hemispheric side and the timing of surgery have not been shown to affect quality outcome years. Post-hoc surveys have found that 83% of survivors at one year found life “satisfying” and that 80% of survivors would have surgery again if faced with the same circumstances. Identifying those patients who are going to deteriorate and require surgery has also proved problematic. A review of the thrombolytic stroke trials involving tPA and streptokinase revealed several possible radiographic predictors, includ- Figure 11.2. Schematic representation ing > 50% MCA involvement, hyperdense MCA of a hemicraniectomy with the bone flap removed, incision of the dura, and placement of a sign, decreased perfusion or increased diffusion dural sac to accommodate for expanding brain tissue on MRI diffusion/perfusion imaging, early mid- outside of the cranial cavity. (Reproduced from line shift, and effacement of the basilar cisterns. Wijdicksl (2000) with permission from Dowden Health Manno et al. (2003), in a retrospective analysis of Media.) CT data from the Mayo clinic, identified a posi- tive predictive value of 0.93 for the hyperdense MCA sign found anytime post-infarction. In- volvement of > 50% of the MCA territory was infarction of the middle cerebral artery trial only predictive of neurological deterioration if (DESTINY) were all initiated soon after. Individ- found within 12 hours of the initial infarct. The ually, each of these studies did not reach com- Heidelberg group has been developing comput- pletion due to limited enrollment or a predeter- erized anatomic models to predict tissue shifts mined or pooled analysis suggesting a significant and subsequent deterioration. benefit to surgery. A meta-analysis of these stud- ies enrolling 93 patients aged 18–60 years of age Intracerebral Hemorrhage undergoing randomization within 48 hours of infarction revealed a significant impact on both Introduction morbidity and mortality. Mortality was reduced Our recent understanding of the dynamic from 71 to 21% in these studies. Modified Rankin changes that occur after intracerebral hemor- Scores (MRS) analyzed for scores of 0–3 and 0–4 rhage (ICH) has altered both our study and ap- revealed an absolute risk reduction of 51% with proach to this disease. Several demographic surgery. The numbers needed to treat for survival changes have occurred in the last few decades: were 2 and for a MRS of 0–3 were 4. improved control of hypertension in some popu- The success of the hemicraniectomy trials led lations has decreased the number of ICH attrib- to considerable interest in defining the timing uted to this disease; the aging of the population and indication for surgery. Also, long-term out- and increased use of anticoagulation has in- comes for survivors became scrutinized. Gupta creased the number of hemorrhages attributed et al. (2004) reviewed a series of 15 studies en- to amyloid angiopathy and/or use of anticoagu- rolling 138 patients: 7% were independent, 35% lation. Clearly studies designed to limit or control were mild or moderately disabled, and 58% were hemorrhages secondary to anticoagulation will severely impaired or died. Age appears to be a be paramount in the future. 96 . Cerebrovascular Critical Care

ICH was originally believed to be a monophasic oagulation effect. More recently a radiographic event, but recent radiographic evidence has “spot sign” has been identified on early CT clearly documented that ICH is a dynamic pro- imaging, suggesting active bleeding of the hem- cess often evolving over several hours. Hemato- orrhage. Treatment focused on these patients ma expansion is common and mortality is direct- may prove beneficial. Subgroup analysis of the ly correlated with the size of the hemorrhage. phase III study suggested that patients younger Thus, new treatment strategies have been ex- than 70 had an improved outcome with plored to prevent or decrease this expansion. recombinant factor VII. The long-term functional deficit after ICH is The management of hypertension after ICH disproportionately larger than the actual cellular has been debatable. Patients after ICH have mul- loss discovered at pathology, suggesting that tiple reasons to be hypertensive. These include there is some post-ICH secondary damage that the population being hypertensive at the must occur to account for these differences. baseline, a large sympathetic response with the Pathologically, iron (Fe) has been suggested as hemorrhage, pain, etc. Historically, there had a possible source of this secondary damage act- been some concerns that over-aggressive treat- ing as both a metabolic poison and increasing ment of hypertension post-ICH could lead to an focal cerebral edema through the breakdown of extension of the hemorrhage. This was based on the blood–brain barrier. Recent treatment strate- PET data, suggesting that a ring of dysautoregu- gies have thus focused on preventing expansion lated brain surrounded the initial hemorrhage. of the initial hematoma and subsequent second- Subsequent studies, however, identified the peri- ary damage. lesional area as having matched perfusion to metabolism. Similar studies revealed that a Prevention of Hematoma Expansion modest control of hypertension post-ICH did not Treatments designed to decrease hematoma extend the size of the hemorrhage. expansion have included the trials using recom- A systemic review of hypertension after ICH binant factor VII and more recently trials suggested that hypertension was correlated with to decrease post-hemorrhage hypertension. hematoma expansion and poorer outcomes. A phase II block trial randomized 399 patients The intensive blood pressure reduction in acute to placebo or escalating doses of recombinant cerebral hemorrhage (INTERACT) trial was a factor VII within 4 hours of ICH. The initial results radiographic study that evaluated the role of acute were promising, revealing an overall decrease in blood pressure reduction in hematoma expansion hematoma size by 14%, improved stroke scale and the subsequent development of cerebral and modified Rankin scores, and a 38% decrease edema. The study randomized patients post-ICH in mortality. However, concerns with increased to blood pressure management of less than thromboembolic complications in the treatment 180 mmHg (considered standard management) group mandated a phase III study. A phase II versus less than 140 mmHg (considered aggressive study randomized 841 patients to a placebo or 20 management). Baseline 24 hour and 72 hour CAT or 80 mg of recombinant factor VII. The 80 mg dose scans were obtained. The results revealed 2.8 mL reduced hematoma size by 11%; however, there less hematoma expansion and 10 mL less perihe- was no difference in outcomes between groups. matomal edema. The antihypertensive control of In addition, there were increased arterial throm- acute cerebral hemorrhage (ATACH) trial random- boembolic complications in the 80 mg group. The ized patients to aggressive blood pressure reduc- discrepancy between studies may have repre- tion post-ICH, defined as greater than a 60 mmHg sented either randomization imbalances or im- reduction in systolic blood pressure compared to a provement in overall treatment since the placebo less aggressive group. Hematoma expansion and groups did much better in the phase III trial. perihematoma edema was reduced and modified There has been interest in attempts to identify Rankin scores were similarly improved. These specific groups that could benefit from the use of promising preliminary results have led to the recombinant factor VII. Patients receiving war- development of ATACH II, a phase II trial currently farin may benefit from rapid reversal of the antic- enrolling patients. 11 New Treatment Strategies in the Management . 97

Prevention of Secondary Injury of the previous negative trials in ICH. Secondary Medical and surgical strategies have been de- tissue injury due to the release of inflammatory signed to decrease secondary injury after ICH. mediators can be mediated through the removal Deferoxamine, an iron chelator, has shown of the clot. promising results in a rodent model, decreasing The initial study on this topic used urokinase perihematomal edema and improving post-ICH for clot lysis but had to be abandoned after performance. Clinical trials are currently under- discontinuation of this drug in the United States. way evaluating the effectiveness of this medica- Follow-up studies substituting tPA were thus tion after ICH. initiated. The CLEAR IVH trial enrolled patients One rational for surgery after ICH is to remove within 48 hours of IVH. Patients were random- blood prior to the formation of toxic byproducts. ized to placebo or 1–3 mg of tPA every 12 hours Unfortunately almost all randomized surgical for eight doses. Dosing was developed after a trials have shown no benefit to surgery post-ICH. dose escalation scale and safety study. IVH reso- The most recent trial for the surgical treatment of lution is followed with CT-guided measurements. intracerebral hemorrhage (STICH) similarly did Preliminary results on the first 36 patients have not find a benefit to surgery post-ICH. Subgroup revealed adequate safety and improved lysis analysis, however, did suggest that lobar ICH rates. Clear IVH is currently a phase III trial within 1 cm of the surface of the brain did better enrolling 48 active sites. with surgery. This study, however, was not pow- ered to evaluate this possibility and STICH II is currently underway to study this population. SCIENCE REVISITED The failure of surgical trials to show a benefit Recombinant tPA must be given early to the after ICH has renewed interest in minimally in- patient with intraventricular hemorrhage vasive efforts to remove intracerebral blood while (IVH). Clot resolution within the first 72 hours preserving normal neurological tissue. The mini- follows first-order kinetics suggesting that the mally invasive surgery plus tPA (MISTIE) trial is clot resolution is dependent upon the amount currently being evaluated. In this study deep of drug administered. Some time after this basal ganglia hemorrhages greater than 30 cc in period, clot resolution follows zero-order volume will be treated with CT-guided insertion kinetics which is independent of drug and initial aspiration of the clot. Subsequently, concentration. 2 mg of tPA will be instilled into the catheter (clamped for 1 hour) and drained every 12 hours while the patient is in the ICU. The intra-opera- tive CT-guided endoscopic surgery for ICH Conclusions (ICES) trial has recently joined with MISTIE in- vestigators to compare the safety of endoscopic Our understanding of the cerebral hemodynam- clot removal with sterotactic thrombolysis. ics involved with expanding supratentorial mass Other surgical possibilities include hemicra- lesions and ICH have increased significantly over niectomy for large basal ganglia hemorrhages. the last few decades. Hemicraniectomy, allowing for the expansion of edematous cerebral contents Treatment of Intraventricular outside of the skull, appears crucial for decreas- ing the secondary compressive injury to vital Hemorrhage neurological structures. Patients must be select- Intraventricular hemorrhage (IVH), whether pri- ed on an individual basis. Identifying patients mary or secondary to parenchymal ICH, portends prior to neurological deterioration and the timing a worse outcome for patients. Treatment has of surgery remain under study. been largely supportive and may include external The treatment for ICH has focused on pre- ventricular drainage if obstructive hydrocephalus venting or limiting hematoma expansion or develops. The amount of IVH correlates directly decreasing secondary neurological injury. with outcome and may be responsible for some Initial promising results of recombinant factor 98 . Cerebrovascular Critical Care

VII could not be validated on the phase III Mayer SA, Brun NC, Begtrup K, et al. Efficacy and analysis. Blood pressure management is cur- safety of recombinant activated factor VII for rently being investigated. acute intracerebral hemorrhage. New Engl J Surgical treatment designed to prevent sec- Med 2008; 358:2127–2137. ondary damage has similarly not proved benefi- Plum F. Brain swelling and edema in cerebral cial. The concerns over structural damage during vascular disease. Res Publ Assoc Res Nerv Men- open surgery has led to renewed interest in mini- tal Dis 1966; 41:318–348. mally invasive surgical methods to decrease or Plum F, Posner JB. The Diagnosis of Stupor eliminate ICH. The instillation and aspiration of and Coma (3rd edition). F.A. Davis Company: thrombolytics both for ICH and IVH are currently Philadelphia, 1980. being investigated. Qureshi AI, Palesch YY, Martin R, et al. (ATACH Bibliography study investigators). Effect of systolic blood pressure reduction on hematoma expansion, Anderson CS, Huang Y, Arima H, et al. (INTER- perihematomal edema, and 3-month outcome ACT study investigators). Effects of early inten- among patients with intracerebral hemor- sive blood pressure lowering treatment on the rhage: results from the antihypertensive treat- growth of hematoma and perihematoma ede- ment of acute cerebral hemorrhage study. Arch ma in intracerebral hemorrhage: the intensive Neurol 2010; 67:570–576. blood pressure reduction trial after cerebral hemorrhage trial (INTERACT). Stroke 2010; Ropper AH. Lateral displacement of the brain and 41:307–312. level of consciousness in patients with acute hemispheric mass. New Engl J Med 1986; Delgado, Almandoz JE, Yoo AJ, Stone MJ, et al. 31:953–958. Systemic characterization of the computed tomography angiography spot sign in primary Schwab S, Schwartz S, Spranger M, et al. Moder- intracerebral hemorrhage identifies patients ate hypothermia in the treatment of patients at highest risk for hematoma expansion: with severe middle cerebral artery infarctions. the spot sign score. Stroke 2009; 40:2994– Stroke 1998; 29:2461–2466. 3000. Schwab S, Spranger M, Schwarz S, Hacke W. Frank JI. Large hemispheric infarction, clinical Barbiturate coma in severe hemispheric deterioration, and intracranial pressure. Neu- stroke: useful or obsolete? Neurology 1997; rology 1995; 45:1286–1290. 28:1608–1613. Gupta R, Connolly ES, Mayer S, Elkind MSV. Steiner T, Friede T, Aschoff A, et al. Effect and Hemicraniectomy for massive middle cerebral feasibility of controlled rewarming after mod- artery territory infarction. A systematic review. erate hypothermia in stroke patients with ma- Stroke 2004; 35:539–543. lignant infarction of the middle cerebral artery. Stroke 2001; 32:2833–2835. Hanley DF. Intraventricular hemorrhage. Severity factor and treatment target in spontaneous Vahedi K, Hofmeijer J, Juettler E, et al. Early intracerebral hemorrhage. Stroke 2009; decompressive surgery in malignant infarction 40:1533–1538. of the middle cerebral artery: a pooled analysis of three randomized controlled trials. Lancet Manno EM, Adams RE, Derdeyn CP, et al. The Neurol 2007; 6:215–222. effects of mannitol on cerebral edema after large hemispheric cerebral infarct. Neurology Videen TO, Zazulia AR, Manno EM, et al. Manni- 1999; 52:583–587. tol bolus preferentially shrinks non-infarcted brain in patients with ischemic stroke. Neurol- Manno EM, Nichols DA, Fulgham JR, Wijdicks ogy 2001; 57:2120–2122. EFM. Computed tomographic determinants of neurological deterioration in patients with Wijdicksl EF. Management of massive hemi- large middle cerebral artery infarctions. Mayo spheric cerebral infarct: is there a ray of hope? Clin Proc 2003; 78:156–160. Mayo Clinic Proc 2000; 75:945–952. 12 Presentation and Management of Acute Cerebral Venous Thrombosis Patrı´cia Canhao~ and Jose M. Ferro

Department of Neurosciences, Servico¸ de Neurologia, Hospital de Santa Maria, University of Lisbon, Lisboa, Portugal

Introduction . Isolated intracranial hypertension syndrome (headache with or without vomiting, papillede- Thrombosis of the dural sinuses and cerebral ma, and visual problems) veins is a distinct cerebral vascular disease, less . Focal syndrome (focal deficits, seizures, or both) common than other types of stroke (0.5–1% of all . Encephalopathy (multifocal signs, mental sta- strokes). It can occur at any age, but is more tus changes, stupor or coma) frequent in children and young adults. Among adults, it predominates in females (3:1) Cerebral Less common syndromes include cavernous si- venous thrombosis (CVT) has a wide spectrum of nus syndrome (cavernous sinus thrombosis), clinical presentation and a multiplicity of causes thunderclap headache, pulsating tinnitus, and or predisposing risk factors. The increasing clin- multiple lower cranial nerve palsies (lateral sinus ician’s awareness for the diversity of symptoms thrombosis). and signs that CVT can present, and the wide- Clinical presentation may be influenced by the spread use of neuroimaging, now allows for early site and number of occluded sinuses and veins, recognition and treatment of patients. Although the presence and type of parenchymal lesions, the overall prognosis is good, a few patients that the age and gender of the patient, and the under- have poor neurological condition at admission, lying disease. or those who worsen during hospitalization, may Headache is usually the first symptom of CVT. require more intensive care. It can be the only symptom or precede other symptoms and signs by days or weeks. It is more Clinical Presentation frequent in females and young patients than in CVT can have an acute, subacute, or less often males or older patients. It can be localized or chronic presentation. The most frequent symp- diffuse, usually increasing over several days. Typ- toms are headaches, seizures, focal deficits, al- ically, headache caused by intracranial hyperten- tered mental status, decreased consciousness, sion from CVT is severe, dull, generalized, and diplopia, and visual loss. Symptoms and signs of worsens with Valsalva maneuvers and with CVT can be grouped in three major syndromes: recumbence. Occasionally, headache may

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

99 100 . Cerebrovascular Critical Care resemble migraine with aura. Some patients with Diagnosis CVT describe sudden explosive onset of severe The diagnosis of CVT requires the demonstra- head pain (i.e. thunderclap headache) mimicking tion of an occluded dural sinus or vein by subarachnoid hemorrhage. neuroimaging. Motor weakness with monoparesis or hemipar- In clinical practice, computed tomography esis, sometimes bilateral, is the most frequent focal (CT) is usually the first investigation to be per- deficit associated with CVT, affecting more than formed. It is useful to rule out cerebral disorders one-third of the patients. Aphasia is particularly which have similar clinical presentations, such frequent in thrombosis of the left lateral sinus. as brain tumors, subdural hematoma, subarach- Focal or generalized seizures, including status noid hemorrhage, or encephalitis. It may be nor- epilepticus, are more frequent in CVT than in mal in up to 30% of cases, and most of the other types of stroke. In the International Study findings are nonspecific. CT may show: (1) direct on Cerebral Vein and Dural Sinus Thrombosis signs of thrombosis, such as the cord sign and (ISCVT) cohort of 624 patients, seizures at pre- the dense triangle sign due to the hyperdensity sentation occurred in 39%, and seizures after the of a thrombosed cortical vein or dural sinus; diagnosis of CVT occurred in 7%. Supratentorial (2) indirect signs, such as parenchymal abnor- parenchymal brain lesions, superior sagittal si- malities, small ventricles and dilated transcereb- nus (SSS), cortical vein thrombosis, and motor ral veins. After contrast injection the occluded deficits are associated with the occurrence of sinus appears as the empty delta sign and there seizures. Seizures are also frequent in children may be intense contrast enhancement of the (including neonates) with CVT. falx and tentorium or areas of gyral enhancement A small percentage of patients (less than 6%) are (Figure 12.1). comatose at thetime ofthe diagnosis. In theISCVT Parenchymal abnormalities may occur in 60– cohort, patients with a Glasgow Coma Scale score 80% of cases. This may include intracerebral <9 were more likely to have an acute onset, sei- hematomas, hemorrhagic infarcts, areas of hy- zures, motor deficits, occlusion of the SSS and of podensity due to focal edema or venous infarc- the deep venous system, and parenchymal lesions tion, and diffuse brain edema. Rarely, subarach- (in particular bilateral brain lesions). noid hemorrhage along the convexity or subdural In children, signs of diffuse brain injury, hematoma may be observed. In repeated scans, coma, and seizures are the main clinical man- new lesions may appear, some may undergo ifestations, especially in neonates. In older hemorrhagic transformation and some may van- children, the manifestations of CVT resemble ish or disappear. those in adults, with headache and hemiparesis. Elderly patients have more vigilance and mental status disturbances. TIPS & TRICKS

Some brain locations are suggestive to CVT. These include frontal or parietal paramedian TIPS & TRICKS lesions in SSS thrombosis, posterior temporal The clinical spectrum and presentation of lesions in the case of lateral sinus thrombosis, cerebral venous disease is broad. Given the or bilateral thalamic lesions in cases of deep nonspecificity of the signs and symptoms of venous system thrombosis. CVT, the key for a prompt diagnosis is having a high clinical suspicion for high-risk patients. These include women taking oral CT venography is useful to demonstrate filling contraceptives, pregnant or puerperal defects in an occluded sinus or veins, sinus wall females, patients with ear or sinus infection, enhancement, and increased collateral venous known acquired or genetic prothrombotic drainage. Drawbacks to CT venography include condition, malignancies, or other systemic radiation exposure, contrast and the pos- diseases with prothrombotic potential. sibility of worsening of renal function. 12 Presentation and Management of Acute Cerebral Venous Thrombosis . 101

A B

Figure 12.1. Direct signs of thrombosis of right lateral in CT scan: (A) CT scan without contrast shows a hyperdense signal in the right lateral sinus; (B) after contrast injection, there is poor visualization of the same sinus, consistent with the diagnosis of thrombosis.

Magnetic resonance imaging (MRI), combined chronically thrombosed sinus may still demon- with MR venography (MRV), is the most sensitive strate a low signal on gradient echo (GRE) and technique for the diagnosis of CVT. susceptibility weighted imaging (SWI). After contrast (Gadolinium) injection the thrombus appears as a central isointense lesion in a dural TIPS & TRICKS sinus with surrounding enhancement. Specific MRI sequences should be used for The diagnosis of CVT requires the improving the differential diagnosis of two tricky demonstration of an occluded dural sinus or conditions: (1) isolated cortical venous throm-

vein. MRI with T1, T2, fluid-attenuated bosis, where gradient echo T2*-weighted images inversion recovery, and T2* sequences enable the diagnosis of CVT by the identification combined with magnetic resonance of the occluded vein as a hypointense linear area; venography are the most sensitive (2) nonthrombosed hypoplastic sinus, where examination techniques for the diagnosis. GRE and/or SWI will show a normal signal in the sinus. MRI is also useful in showing the parenchymal The combination of an abnormal signal in a lesions secondary to dural or venous occlusion. It sinus and a corresponding absence of flow on is useful in differentiating vasogenic edema from MRV support the diagnosis of CVT (Figure 12.2). venous infarct, where there is an increased signal The thrombus may be difficult to be visualized in diffusion-weighted imaging (DWI). in the first days, because it may be isointense Intra-arterial angiography is now rarely per- on T1-weighted images and hypointense on formed. It is reserved for cases with inconclusive T2-weighted images. In these circumstances, or contradictory findings in other imaging mo- the MR venography is essential to confirm the dalities, or when endovascular treatment is absence of flow. After 5 days, the diagnosis planned. becomes easier due to an increased signal on Independent of the modality (CT, MR, or IA), both T1- and T2-weighted images. The diagno- venography has limitations related to anatomical sis again becomes difficult after the first month, venous variations, such as hypoplasia of the an- while the thrombus may become isointense. A terior part of the superior sagittal sinus (SSS), 102 . Cerebrovascular Critical Care

ABC

Figure 12.2. Acute thrombosis of the torculae and left lateral sinus diagnosed by MRI: (A) T1 sagittal MRI shows an isointense signal in the torculae (arrow); (B) in T2 axial MRI the thrombus has an isointense/ hypointense signal (arrow); and (C) MR venography confirms the absence of flow in the corresponding dural sinus. duplication of the SSS, intrasinus septa, giant been identified. The diagnosis of APL requires arachnoid granulations and hypo- or aplasia of abnormally high titters of lupus anticoagulant, the transverse sinuses, which may be misdiag- anticardiolipin IgG or anti-b2-glycoprotein IgG nosed as thrombosis. antibodies on 2 or more samples at least 12 A screening laboratorial test with a high sensi- weeks apart. Testing for deficiencies of protein tivity for CVT would be of clinical importance in C, S, and antithrombin must be performed at emergency settings where MR is not readily avail- least 6 weeks after the thrombotic event, and able. Unfortunately, this test does not exist. Mea- should be confirmed with repeat testing and surement of D-Dimers, a product of fibrin deg- genetic studies. Heparin reduces antithrombin radation, could be helpful to identify patients levels, and protein C and S levels are lowered by with a low probability of CVT. However, CVT oral anticoagulants. High levels of Factor VIII patients presenting with isolated headache, those are also found in some CVT series, but high with a subacute or chronic presentations, and Factor VIII levels may be secondary to acute those with lesser clot burden may have normal CVT or to systemic disease underlying CVT. D-Dimers levels. For that reason, D-Dimers can- ENT consultation may be required if otitis not be used in clinical practice to rule out CVT. or sinusitis is suspected, and cerebrospinal fluid examination through lumbar puncture is Evaluation of CVT indicated if there is a clinical suspicion of The search for risk factors of CVT should be part meningitis. of the evaluation of these patients. The more The risk factors associated with CVT vary frequent risk factors are prothrombotic condi- throughout life. In neonates, acute systemic tions, either genetic or acquired, oral contracep- illness, such as perinatal complications and tives, puerperium or pregnancy, malignancy and dehydration, occurred in 84% of patients in the infection. Canadian Pediatric Ischemic Stroke Registry. In Multiple risk factors may be found in about half infants older than 4 weeks of age and in children, of patients. Some of the risk factors are persistent head and neck disorders, mostly infections and and deserve life-long therapy, but others are chronic systemic diseases (e.g. connective tissue transient predisposing the occurrence of CVT disease, hematological disorder, and cancer) are (Table 12.1). common. A prothrombotic state was found in Testing for the antiphospholipid syndrome 41% of these patients, most often in infants older (APL) and for genetic prothrombotic conditions than 4 weeks of age, and children. is recommended in all CVT patients, even The most frequent risk factor in young women when another associated condition had already is the use of oral contraceptives. The risk for CVT 12 Presentation and Management of Acute Cerebral Venous Thrombosis . 103

Table 12.1. Risk factors for cerebral months after the acute phase or after repeated venous thrombosis testing. Persistent risk factors Clinical Course and Prognosis Genetic prothrombotic conditions (protein C, protein S and antithrombin deficits; CVT usually has a favorable prognosis compared Factor V Leiden and prothrombin G20210A with other types of stroke. However, the polymorphism clinical course should be monitored because Malignancies about one-fourth of patients suffer neurological Hematological diseases (polycythemia, deterioration after admission, and 5% of thrombocythemia) patients die during hospitalization. Neurological Antiphospholipid syndrome worsening can occur several days after diagnosis Behcet’s¸ disease and the initiation of treatment. Symptoms can Systemic lupus erythematous, and other consist of depressed consciousness, and mental connective tissue disease or vasculitis status disturbance while new signs may include Other inflammatory systemic conditions (e.g. seizures, Worsening of prior deficit or onset of inflammatory bowel disease) new focal sign, increase in headache intensity, or Nephrotic syndrome visual loss. Some features that are associated with Homocystinuria higher risk of early death include depressed con- Intracranial causes (meningeoma, brain vas- sciousness at admission, altered mental status, cular malformations) thrombosis of the deep venous system, right Transient risk factors hemisphere hemorrhage and posterior fossa Pregnancy and puerperium (or post-abortion) lesions. The main cause of acute death is trans- Oral contraceptives and post-menopausal tentorial herniation secondary to a large hormonal therapy hemorrhagic lesion followed by herniation due Other drugs with prothrombotic effect to multiple lesions or to diffuse brain edema. Intracranial infection, including meningitis Status epilepticus, medical complications, and Infection of neighboring structure (eye, sinus, pulmonary embolism are among other causes of ear, tooth, skin of face, scalp) early death. The acute mortality in children with Other infections CVT is similar to that in adults. In a European Mechanical causes (head trauma, lumbar cohort of 396 children with CVT (median age puncture, jugular catheter, neurosurgery) 5.2 years), 3% of the patients died in the first Hyperhomocysteinemia 2 weeks after presentation. Severe dehydration The large majority of patients achieve com- Severe anemia plete neurological recovery on long-term follow- up (80% in the ISCVT). In a systematic review of prospective cohort studies the overall long-term death and dependency rate was 15%. Factors in women using oral contraceptives is increased associated with the risk of poor long-term prog- if they have a prothrombotic defect. In the elderly nosis in the ISCVT cohort were: central nervous patients of the ISCVT, the proportion of patients system infection, any malignancy, thrombosis of with malignancies and hematological disorders, the deep venous system, intracranial hemorrhage such as polycythemia, was higher than in youn- on the admission CT/MR, Glasgow Coma Scale ger patients. Therefore in the elderly patient and (GCS) score <9, mental status disturbance, age in cryptogenic CVT, a search for an occult neo- >37 years, and male gender. Isolated intracranial plasm is recommended. hypertension at the time of CVT diagnosis is In almost 15% of adult CVT patients an exten- usually associated with good outcome. After dis- sive search is unable to identify an underlying charge, some patients may have long-term com- cause. Sometimes the cause (e.g. vasculitis, anti- plications such as seizures, headaches, visual phospholipid syndrome, malignancy, polycyte- loss, dural arteriovenous fistulae, and recurrent mia, thrombocytemia) is revealed weeks or thrombotic events. 104 . Cerebrovascular Critical Care

TIPS & TRICKS 0.08–1.21) for death and 0.46 (95% CI 0.16– 1.31) of death or dependency after anticoagulant Coma or mental status disturbance at therapy as compared to placebo. admission, thrombosis of the deep venous A nonmatched case control study of cases system, brain hemorrhage, malignancy, treated with IV heparin and LMWH in the ISCVT central nervous system infection, older age, cohort showed that LMWH is at least equally as and male gender, are features associated with effective as IV heparin for the treatment of CVT. poor prognosis for CVT. Patients with such In this large cohort, death or dependency was features should be closely monitored and more frequent in patients treated with IV heparin selected for intensive treatments. than with LMWH (16% vs. 9%, p ¼ 0.05). Several observational series showed that hepa- rin is also safe and can be used in acute CVT Comatose patients have a poor prognosis. patients with intracranial hemorrhagic lesions. In the ISCVT cohort, among 31 patients with a Similarly, observational data from single and GCS score <9 at admission, 16 (52%) worsened multicenter case series suggest that anticoagu- after diagnosis. More than half of patients who lant therapy is safe in children with CVT. had repeated CT/MR had new cerebral hemor- Endovascular Thrombolysis rhages or new venous infarcts. Mortality was high (35%, 9 acutely and 2 during the follow-up), but Direct endovascular thrombolysis is an alterna- among the survivors the outcome was good: all tive treatment in severe cases or in patients who but one patient acquired full independence, and fail to improve despite anticoagulation. The aim none was left severely disabled. Patients without is to dissolve the clot and reopen the occluded thrombosis of the deep venous system had a sinus or vein. The goal is to restore the venous better prognosis. outflow and decrease intracranial pressure. Catheterization of the sigmoid, transverse, Treatment straight and superior sagittal sinuses via the fem- Treatment of CVT includes: (1) treatment of the oral venous, or jugular approach is followed by associated risk factors; (2) specific antithrombo- local injection of tPA or urokinase. Mechanical tic treatment; and (3) symptomatic treatment thrombolysis by disruption, removal or suction and management of CVT complications. may be additionally performed or utilized alone. No randomized trials of endovascular treat- Treatment of the Associated Risk Factors ment for sinus thrombosis have been performed to assess its efficacy and safety. Data from the Although the treatment of the multiple possible literature, including a systematic review (169 CVT risk factors or diseases associated with CVT is out patients treated with thrombolysis) and several of the scope of this chapter, we would stress the other series suggest that thrombolytics may re- importance of appropriate antibiotic treatment, duce case fatality in critically ill patients. These whenever there is meningitis or other intracranial data, however, may reflect publication bias. infection or an infection of a neighboring struc- A recent Dutch series (20 patients) could not ture (e.g. otitis, mastoiditis). confirm these findings. Patients that are good candidates for endovascular therapy are those Specific CVT Treatment patients with thrombosis of the deep venous Heparin system that progress to coma despite There is a general consensus that anticoagulation anticoagulation. with unfractionated or low molecular weight A randomized trial (TO-ACT) to compare en- heparin (LMWH) is the main treatment for acute dovascular treatment vs. heparin in acute CVT is CVT. The use of heparin in acute CVT is sup- in its final preparation stages and will randomize ported by four clinical trials and a meta-analysis patients with severe forms of CVT, as defined of two of these trials. These trials showed a by the presence of one or more intracranial nonsignificant relative risk of 0.33 (95% CI hemorrhage, mental status disturbance, coma, 12 Presentation and Management of Acute Cerebral Venous Thrombosis . 105 or thrombosis of the deep cerebral venous sys- nial hypertension can be reduced and symptoms tem. Pending the results of this trial, endovascu- relieved through a therapeutic lumbar puncture. lar thrombolysis should be considered a treat- This must be performed after CT, or MR excludes ment option for CVT patients who worsen despite large parenchymal lesions or hydrocephalus. anticoagulant therapy. Those with thrombosis of Corticosteroids do not improve the outcome of the cerebral deep venous system, and without CVT patients and should not be prescribed unless large hemispheric lesions with mass effect, they are indicated to treat the cause of CVT. should be considered. Acetazolamide may be used, despite lack of sup- porting evidence. Patients may need to be admit- Oral Anticoagulation ted to an intensive care unit. Measures to control Prolonged oral anticoagulation with warfarin acutely increased ICP include elevating the head should be started after the acute phase of CVT to of the bed, osmotic diuretics with mannitol, and prevent further venous thrombotic events. Opti- initiating hyperventilation to a target PaCO2 of 30 mal duration of anticoagulation has not been to 35 mmHg. addressed. Oral anticoagulation aims at an inter- national normalized ratio (INR) of 2 to 3. The EFNS Decompressive Surgery Guidelines recommend that anticoagulants Herniation due to unilateral mass effect is the should be given for 3 months if CVT is related to major cause of death in CVT. Decompressive a transient risk factor. In patients with cryptogenic surgery can be life saving in these patients CVT or in those with mild thrombophilia, the (Figure 12.3). A recent case-control study, retro- period of anticoagulation must be extended for spective registry, and a systematic review of 6 to 12 months. Patients with “severe” thrombo- 68 cases treated by decompressive surgery philia or recurrent venous thrombosis, should be (hemicraniectomy or hematoma drainage) given anticoagulants for life. showed that in patients with large parenchymal lesions causing herniation, decompressive surgery Symptomatic Treatment was life-saving and often resulted in good func- and Management of CVT Complications tional outcome. This was irrespective of age, co- Treatment of Intracranial Hypertension ma, aphasia, bilateral lesions, or bilateral fixed In patients presenting with increased intracranial pupils. A prospective registry is under way to pressure, headache, and papilloedema, intracra- confirm these encouraging results.

A B

Figure 12.3. Large parieto-occipito-temporal venous infarct, with mass effect secondary to thrombosis of the left lateral sinus. CT (A) before and (B) after decompressive hemicraniectomy. 106 . Cerebrovascular Critical Care

TIPS & TRICKS Bibliography Bousser MG, Russell RR. Cerebral venous Heparin is the first-line treatment, but in a thrombosis. In: Major Problems in Neurology, few cases more aggressive treatment may Vol 33 (Warlow CP, Van Gijn J, eds.). London, be attempted, such as local intravenous WB Saunders, 1997. thrombolysis for patients with deep cerebral Bousser MG, Ferro JM. Cerebral venous thrombo- venous thrombosis progressing to coma, or sis: an update. Lancet Neurol 2007; 6:162–170. decompressive hemicraniectomy for large ~ ~ hemispheric lesions with impending Canhao P, Falcao F, Ferro JM. Thrombolytics for herniation. cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis 2003; 15:159–166. Canhao~ P, Ferro JM, Lindgren AG, et al. ISCVT Shunting Investigators. Causes and predictors of death in Ventriculostomy or ventriculoperitoneal shunts cerebral venous thrombosis. Stroke 2005; are usually not indicated in acute CVT. Excep- 36:1720–1725. tions can be made for the patients that develop Dentali F, Gianni M, Crowther MA, Ageno W. hydrocephalus in response to CVT of the poste- Natural history of cerebral vein thrombosis: a rior fossa. In patients with increased intracranial systematic review. Blood 2006; 108:1129–1134. pressure, a lumboperitoneal shunt may be indi- deVeber G, Andrew M, Adams C, et al. Cerebral cated if severe headaches or visual loss develop or sinovenous thrombosis in children. New Engl J do not improve with measures to reduce intra- Med. 2001 Aug; 345(6):417–423. cranial pressure. Einhaupl€ K, Stam J, Bousser MG, et al. EFNS Visual Loss guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Visual loss due to CVT rarely occurs (2–4%). Neurol. 2010 Oct; 17(10):1229–1235. Patients with papilledema or visual complaints Ferro JM, Canhao~ P, Stam J, et al. ISCVT Inves- should have a complete neuro-ophthalmological tigators: Prognosis of cerebral vein and dural study, including visual acuity and visual field sinus thrombosis: results of the International testing. The rapid diagnosis of CVT and treatment Study on Cerebral Vein and Dural Sinus of intracranial hypertension are the main mea- Thrombosis (ISCVT). Stroke 2004; 35:664–670. sures to prevent visual loss. Surgical fenestration of the optic nerve may be performed in special- Idbaih A, Boukobza M, Crassard I, et al. MRI of ized centers, but is rarely required. clot in cerebral venous thrombosis: high diag- nostic value of susceptibility-weighted images. Treatment and Prevention of Seizures Stroke 2006; 37:991–995. Prophylactic administration of antiepileptic Kenet G, Kirkham F, Niederstadt T, et al. Risk drugs is not indicated. Anticonvulsants should factors for recurrent venous thromboembolism be reserved for high-risk patients. These include in the European collaborative paediatric data- patients with seizures prior to, or at, admission base on cerebral venous thrombosis: a and those with supratentorial lesions. In these multicentre cohort study. Lancet Neurol 2007 patients, anticonvulsants reduce the risk of sub- Jul; 6(7):595–603. sequent seizures and should be prescribed during Moharir MD, Shroff M, Stephens D, et al. Antic- the acute phase. Anticonvulsants may also be oagulants in pediatric cerebral sinovenous considered in the patient with a single seizure thrombosis: a safety and outcome study. Ann even in the absence of parenchymal lesions. Neurol 2010 May; 67(5):590–599. Prophylactic antiepileptics for a defined duration Pfefferkorn T, Crassard I, Linn J, et al. Clinical (usually 1 year) should be prescribed in patients features, course and outcome in deep cerebral with early seizure and parenchymal lesions and venous system thrombosis: an analysis of 32 in those with post-CVT epilepsy. cases. 2009 Nov; 256(11):1839–1845. 12 Presentation and Management of Acute Cerebral Venous Thrombosis . 107

Stam J, de Bruijn SF, deVeber G. Anticoagulation Stam J, Majoie BLM, van Delden OM, et al. for cerebral sinus thrombosis. Cochrane Data- Endovascular thrombectomy and thromboly- base Syst Rev 2002; 4:CD002005. sis for severe cerebral sinus thrombosis: Stam J. Thrombosis of the cerebral veins and a prospective study. Stroke 2008; 39: sinuses. New Engl J Med 2005; 352:1791–1798. 1487–1490. Part III Infections of the Nervous System 13 Infections in the Neurocritical Care Unit Denise H. Rhoney1, Karen J. McAllen2 and Dennis Parker3

1UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 2Department of Pharmacy Services, Spectrum Health Hospitals, Grand Rapids, MI, USA 3Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI, USA

Introduction incidence of nosocomial infections (20–30%) with pneumonia and urinary tract infections be- Patients in the NCCU can present with com- ing the most common. munity-acquired infections (CAIs), but most commonly will develop nosocomial or hospital- acquired infections (HAIs) as a result of endoge- Fever and the NCCU nous colonized flora that become virulent from Fever is a common complication in NCCU the hospital environment. Recent statistics have patients. The presence of fever has recently been shown that the four most common nosocomial shown to increase intensive care unit (ICU) infections (bloodstream, urinary tract, surgical length of stay by 5.7 days. The definition of site, and ventilator-associated pneumonia) ac- fever is variable. Recent recommendations count for up to 800,000 preventable infections, define “febrile” in critically ill patients as a 60,000 preventable deaths, and $27 billion in temperature equal to or greater than 38.3 C. excess costs annually in the United States. These However, it is important to consider that the patients have many risk factors for developing definition of fever in patients with brain injury infections, including the exposure to invasive has not been clearly defined and the threshold devices, mechanical ventilation, severity of the to treat is often lower since brain temperature is injury, surgical intervention, impaired protective higher than body temperature. oropharyngeal reflexes, co-administration of cor- Noninfectious causes account for half of the ticosteroids, stress hyperglycemia, presence of fevers in the general critical care units. Common coma, and altered cellular immunity as a result noninfectious causes that are commonly present of the neurologic injury. While there are numer- in NCCU patients include: central fever, posterior ous studies addressing nosocomial infections fossa syndrome, intracranial bleeding, seizures, in medical and surgical intensive care units, thyroid storm, stroke, venous thromboembolism, there is limited information specifically for the drug fever, post-operative fever, fever from trans- NCCU. The limited studies available in the fusions, alcohol/drug withdrawal, and adrenal NCCU have reported a moderate to high insufficiency.

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

111 112 . Infections of the Nervous System

TIPS & TRICKS (nonquantitative) or by bronchoalveolar lavage (BAL) with protected brush samples (quantita- The most common classes of drugs that are tive) methods. Early and aggressive treatment associated with drug fever include b-lactam with appropriate intravenous antibiotics is indi- antibiotics, antiseizure agents (especially cated in all patients requiring ICU admission. phenytoin), and antiarrhythmics. The time of A study in patients with VAP had higher mortality onset of drug fever is not immediate, and may when appropriate antibiotics were delayed by arise 3 weeks after initiating therapy and can more than 24 hours. take over 1 week to abate after discontinuing the offending agent. SCIENCE REVISITED

Fever is believed to provide immunologic pro- There is conflicting data regarding the use tection from infection, but in patients with neu- of invasive quantitative sputum culture rologic injury it has been shown to be associated sampling methods such as PSB and/or BAL with a worse outcome. Fever is aggressively man- as opposed to obtaining nonquantitative aged in the NCCU although there is currently no cultures via endotracheal aspirates. To date, evidence to demonstrate that this is associated there is no definitive benefit of invasive with improved outcomes. methods over tracheal aspirates. Although either approach is acceptable, tracheal Respiratory Tract Infections aspirates are much easier and cheaper to Lower respiratory infections are associated with obtain. Furthermore, a negative bacterial substantial morbidity and mortality in patients in culture result using tracheal aspirates carries the ICU. Hospital-acquired pneumonia (HAP), a strong negative predictive value (>90%), particularly ventilator-associated pneumonia which can be helpful in guiding appropriate (VAP), occurs in approximately 20% of all venti- antimicrobial therapy. lated patients and is associated with twice the mortality rate of patients without VAP. Health- care-associated pneumonia (HCAP) is the largest group of patients affected by pneumonia, and Appropriate Empiric and Treatment includes patients with recent exposure to the Recommendations healthcare environment that may be at risk for The most common organisms associated with multidrug-resistant pathogens. A joint consor- community-acquired pneumonia (CAP), HCAP, tium of the American Thoracic Society and the and VAP, along with empiric antibiotic selections, Infectious Diseases Society of America has are listed in Table 13.1. Risk factors for infections published recommendations for the diagnosis, with multidrug-resistant organisms (MDRO) prevention, and treatment of pneumonia. include prior antibiotic exposure, prolonged hospitalization (>5 days) and the presence of a Diagnosis MDRO within the hospital unit. The diagnosis of pneumonia is based largely For patients with CAP, empiric antibiotic upon symptoms such as fever, increased sputum therapy must provide coverage against penicil- production, and poor oxygenation, as well as the lin-resistant Streptococcus pneumoniae, along presence of leukocytosis or leukopenia and infil- with enteric gram negatives and atypical trate on Chest X-ray. If clinical signs are present pathogens such as Legionella,andChlamydia in the absence of a pulmonary infiltrate, then a pneumoniae. If patients have CAP requiring ICU diagnosis of tracheobronchitis can be made. admission, it is reasonable to suspect a MDRO. Once a diagnosis of pneumonia is made, sputum Furthermore, community-acquired methicillin- and blood cultures should be obtained to aid in resistant Staphylococcus aureus (MRSA) infection the identification of the infecting pathogen. Spu- has been reported, particularly in patients with tum may be obtained via endotracheal aspirates recent influenza infection. Patients with HCAP, Table 13.1. Treatment strategies for pneumonia Diagnosis Most Common Pathogen Empiric Regimen Community-acquired Outpatient Streptococcus pneumoniae, 1. Azithromycin 500 mg daily OR Haemophilus influenzae, 2. Doxycycline 200 mg daily OR Mycoplasma, Chlamydia, viruses 3. Moxifloxacin 400 mg daily OR 4. Levofloxacin 750 mg daily Inpatient (non-ICU) Same as Outpatient PLUS Legionella 1. Moxifloxacin 400 mg daily OR and Chlamydia pneumoniae 2. Levofloxacin 750 mg daily OR 3. Ceftriaxone 1–2 g daily OR ampicillin-sulbactam 1.5–3 g q6h PLUS azithromycin 500 mg daily Presence of CA-MRSA 1. Add vancomycin OR linezolid 600 mg q12h Risk Factors Inpatient (ICU) Same as Inpatient non-ICU PLUS 1. Piperacillin-tazobactam 4.5 g q6h OR cefepime 1–2 g q8 h OR Unit Care Neurocritical the in Infections 13 Pseudomonas aeuroginosa and other meropenem 500 mg q6h PLUS azithromycin OR moxifloxacin OR Gram-negative organisms levofloxacin Healthcare-Associated MSSA/MRSA, Streptococcus pneumoniae, 1.Vancomycin or linezolid PLUS cefepime OR ceftazidime 1–2 g OR Hospital acquired/ Haemophilus influenzae, enteric Gram-negative q8h OR piperacillin-tazobactam OR meropenem Ventilator-associated bacilli, Pseudomonas aeuroginosa, Acinetobacter 2. May add gentamicin (dosed for trough <1 mg/mL) OR amikacin baumanii, Klebsiella spp. (dosed for trough <4 mcg/ml) OR tobramycin (dosed for trough <1 mg/mL) to broaden initial coverage MSSA ¼ methicillin sensitive Staphylococcus aureus; MRSA ¼ methicillin resistant Staphylococcus aureus . 113 114 . Infections of the Nervous System

HAP, or VAP are all at risk for a MDRO such as patients at low risk for this complication. The Pseudomonas aeruginosa, Acinetobacter bauma- prophylactic use of chlorhexidine and oral nii, and MRSA. Vancomycin or linezolid plus antibiotics (selective gut decontamination) has piperacillin/tazobactam or cefepime or a carba- shown benefit in reducing the occurrence of penem (meropenem or imipenem) are all VAP in some studies, however the routine use appropriate empiric options in most of these of these agents remains controversial. The circumstances. use of systemic antibiotics routinely is discour- aged over concerns of subsequent infections with MDROs. Recently, the Brain Trauma TIPS & TRICKS Foundation recommended utilizing periproce- dural antibiotic prophylaxis prior to intubation Double-coverage against pseudomonas has (Level II). Although the specific antibiotic to been historically advocated for synergy; be used is not stated, it would be appropriate to however, there is little clinical data to support choose an antibiotic that covers common this practice. The most appropriate reason pathogens that colonize the respiratory tract, to use combination therapy is to broaden such as a second- or third-generation coverage against MDRO. cephalosporin. Urinary Tract Infections Many pathogens may be isolated from sputum The annual incidence of urinary tract infection cultures but differentiating the pathogens from (UTI) has been reported to be as high as 20%. colonizing organisms is often difficult. A negative Urinary tract infections account for approxi- sputum culture result is fairly reliable in ruling mately 30% of all nosocomial infections diag- out infecting organisms. Appropriate antimicro- nosed each year. Symptoms range from bial therapy should result in signs of clinical asymptomatic to urosepsis, resulting in signifi- improvement within 72 hours of initiation of cant morbidity and mortality in some patient therapy. If patients exhibit clinical improvement populations. This section will focus primarily (absence of fever, reduction in WBC, improved on the healthcare, catheter-associated symp- oxygenation), antibiotics should continue for no tomatic UTI. longer than 8 days. If symptoms continue or worsen, re-evaluation should include additional Risk Factors sputum cultures and assessment for other poten- Numerous risk factors have been shown to be tial diagnoses. associated with developing UTI in hospitalized patients. These include the presence of an in- Prevention dwelling catheter, increased length of hospital Several strategies have been evaluated for the stay (LOS), age, invasive procedures, diabetes, prevention of pneumonia in hospitalized pa- other urinary tract disorders, prior surgery, dura- tients. Endotracheal intubation increases the tion of surgery, reoperation, other sites of infec- incidence of pneumonia more than any other tion, malnutrition, need for mechanical ventila- risk factor, and reintubation further enhances tion, and serum creatinine greater than 2 mg/dL this risk. Elevation of the head of the bed 30–45 at time of catheterization. Spinal cord injury degrees should be maintained in all eligible patients suffering from paralysis are at a very neurological patients to prevent aspiration. high risk of developing a UTI. Neuromuscular blocking agents should be avoided as they can suppress protective cough- Diagnosis ing mechanisms. Prophylaxis for stress-related Differentiating catheter-associated urinary tract mucosal bleeding, using acid suppressive ther- infections from bacteriuria or contamination apy with histamine receptor 2-blocking agents may be difficult. In addition, in neurologically or proton-pump inhibitors, may increase the impaired patients it is often challenging to risk of pneumonia and should not be used in determine whether the patient is exhibiting 13 Infections in the Neurocritical Care Unit . 115 symptoms. The current recommendations indi- CAUTION cate that patients with indwelling catheters should have signs and symptoms of urinary tract Prophylactic antibiotics are not a infection along with >105 cfu/mL of at least one recommended strategy for the prevention bacterial species in a single catheter urine of CA-UTI or CA-bacteriuria. specimen.

Bloodstream Infections CAUTION Bloodstream infections can arise from infection A positive culture of a urinary catheter tip is anywhere in the body or exogenously from intra- not an acceptable laboratory test to diagnose venouslinesorcatheters.Nosocomialbloodstream a urinary tract infection. Urine cultures must infections are defined as clinically significant posi- be obtained using an appropriate technique, tive cultures for bacteria or fungus obtained more such as clean catch collection or than 72 hours after admission, or positive blood catheterization. cultures obtained within 72 hours with the use of invasive lines. Primary nosocomial bacteremia is from an intravenous device while secondary Symptoms of urinary tract infection in patients infections are from a distant site. Catheter-related with spinal cord injury may include increased bloodstream infection (CRBSI) is a common cause spasticity, autonomic dysreflexia or a sense of ofHAIintheICUwithanincidenceof10 infections/ unease. 1000 catheter days.

Appropriate Empiric and Treatment Risk Factors Recommendations Risk factors for bloodstream infections in the ICU Common empiric antibiotic choices include include: anatomic catheter insertion site, type of trimethoprim/sulfamethoxazole, second- and catheter used, number of ports, number of manip- third-generation cephalosporins and quinolones. ulations, length of time inserted, and the patient When candiduria is present, no therapy is population (age, severity of underlying illness, indicated in asymptomatic patients, but patients presence of neutropenia, loss of skin integrity). with fever or symptoms should be treated with an appropriate antifungal agent. Fluconazole is Diagnosis recommended for candida species that are Clinical signs of the systemic inflammatory re- susceptible. Alternative antifungal agents sponse associated with sepsis include fever or should be chosen for organisms that are not sus- hypothermia, change in leukocyte counts, chills, ceptible to fluconazole. If the urinary catheter has tachypnea, and tachycardia. Clinical signs of a been in place for longer than a week, the catheter CRBSI include difficulty drawing or infusing should be removed and replaced. The duration of through the catheter, presence of inflammation therapy will depend on the patient’s response to at the insertion site, and recovery of microorgan- treatment. A 7-day course of antibiotics is appro- isms in multiple blood cultures. A definitive priate for patients who have prompt resolution of diagnosis of a CRBSI requires the presence of symptoms and a 10–14-day course may be re- intravascular access with at least one positive quired for patients who have a delayed response blood culture obtained from a peripheral vein, to therapy. For symptomatic candida UTI, a clinical manifestation of infection, no other course of 14 days is recommended. apparent source of bloodstream infection and, additionally, one of the microbiological methods: Prevention a positive result of semiquantitative (15 colony The most important factor in the prevention of forming units per catheter segment) or quantita- UTI is to promptly remove indwelling catheters tive culture (>103 cfu per catheter segment) with when they are no longer needed. the same organism, paired quantitative blood 116 . Infections of the Nervous System cultures with a 5:1 ratio device versus periph- hours of emergency department admission or eral, differential time to positivity (blood culture 1 hour for non-ED ICU admissions), appropriate obtained from a central venous catheter is posi- empiric antimicrobial intervention can reduce tive at least 2 hours earlier than a peripheral mortality. blood culture). The catheter should be removed The current guideline for CRBSI recommends if purulence or erythema is present. The catheter vancomycin for empiric therapy in healthcare tip can be sent for culture and confirmation of the settings with an elevated prevalence of MRSA, diagnosis for the presence of the same organism and for institutions in which the preponderance on the tip and in the blood. These blood cultures of MRSA isolates have vancomycin minimum should be sent prior to the initiation of empiric inhibitory concentration (MIC) values of antibiotics. If the fever persists after 48 hours 2 mg/mL, alternative agents such as daptomycin despite empiric antibiotics and without a specific should be used. Empirical coverage for Gram- cause having been isolated, the patient should be negative bacilli should be based on local antimi- assessed for fungal infections. crobial susceptibility data and the severity of disease. Initial broad-spectrum antibiotic thera- Microbiology py for bloodstream infections should be directed The most common pathogens associated with toward Pseudomonas aeruginosa and Staphylo- secondary bloodstream infections include staph- coccus aureus. For the empirical treatment of ylococci and Gram-negative bacilli. The most a suspected CRBSI candidemia, may be used an common bacteria associated with a CRBSI in- echinocandin or, in selected patients, flucona- clude Staphylococcus epidermidis (37%), zole. Fluconazole can be used for patients with- Staphylococcus aureus (13%), Enterococcus out azole exposure in the previous 3 months and (13%), Klebsiella-Enterobacter (11%), Candida in healthcare settings where the risk of Candida spp. (8%), and Serratia (5%). krusei or Candida glabrata infection is very low. Therapeutic recommendations for selected pathogens are contained in Table 13.2. TIPS & TRICKS Systemic antibiotic prophylaxis does not sig- nificantly reduce the risk of CRBSI and may Gram-negative bacteria and Candida sp. have increase MDRO in the ICU. Guidelines for CRBSI been associated with a higher incidence of advise against a course of antibiotics in patients severe sepsis and septic shock while with an infected catheter and negative blood coagulase-negative staphylococci have a cultures unless the patient appears to be septic. reduced risk of severe sepsis relative to these Generally the length of therapy for these CRBSIs other organisms. is 7–14 days unless there is concurrent osteomy- elitis or endocarditis, where therapy is for 6–8 weeks. These guidelines recommend as few as 5–7 days of therapy for some coagulase-negative Appropriate Empiric and Treatment staphylococci. Recommendations Bloodstream infections in the ICU represent se- Prevention rious infections that can cause septic shock. The Numerous infection control procedures have mainstay of therapy includes antimicrobial been directed toward preventing CRBSI, includ- agents in conjunction with supportive care (refer ing maximal sterile barrier precautions during to Surviving Sepsis Campaign recommenda- insertion, structured educational programs on tions). Sepsis bundles have been developed to the use of sterile precautions, maintaining non- improve patient outcomes by combining compo- soiled dressing at the catheter insertion site, and nent therapies.1 When initiated early (within 3 the use of antibiotic or antiseptic-coated cathe- ters. A meta-analysis suggests that chlorhexidine 1 http://www.survivingsepsis.org/Bundles/Pages/de- gluconate solutions reduce the incidence fault.aspx. of CRBSI by 50% when compared to aqueous 13 Infections in the Neurocritical Care Unit . 117

Table 13.2. Intravenous Antimicrobial Agent Selection for Selected Pathogens in Nosocomial Bloodstream Infections* Pathogen Preferred Antimicrobial Alternative Antimicrobial Agent Agent Staphylococcus aureus: Methicillin sensitive Nafcillin or Oxacillin 2g q4h Cefazolin 2 mg q8h Methicillin resistant Vancomycin Daptomycin 6–9 mg/kg/day or Linezolid Coagulase-negative staphylococci: Methicillin sensitive Nafcillin or Oxacillin Cefazolin 2 mg q8h 2g q4h Daptomycin Methicillin resistant Vancomycin 6–9 mg/kg/day or Linezolid Enterococcus faecalis: Amp senstive Amp 2 g q4h or 6h AG Vancomycin Amp resistant, Vanco Vancomycin AG Linezolid or Daptomycin sensitive Amp resistant, Vanco Linezolid or Daptomycin Quin/Dalf resistant Escherichia coli or Klebsiella spp.: ESBL negative 3rd or 4th generation Csp Ciprofloxacin or Aztreonam (Ceftriaxone 1–2 g q24h or Cefepime 2 g q8h) ESBL positive Carbapenem (Imi 500 mg q6h; Ciprofloxacin or Aztreonam Mero 1 g q8h; Erta 1 g q24h; doripenem 500 mg q8h) Enterobacter spp. or Carbapenem (Imi 500 mg q6h; Cefepime or Ciprofloxacin Serratia marcescens Mero 1 gm q8h; Erta 1g q24h) Acinetobacter spp. Ampicillin/Sulbactam 3 g q6h — or Carbapenem (Imi 500 mg q6h; Mero 1 g q8h) Pseudomonas aeruginosa Cefepime 2 g q8h or — Carbapenem (Imi 500 mg q6h; Mero 1 g q8h) or Pipercillin/ Tazobactam 4.5 g q6h AG (dose to desired conc) Candida albicans Echinocandin (Caspofungin Lipid Amphotericin B 70 mg LD then 50 mg/day; micafungin 100 mg/day; anidulafungin 200 mg LD then 100 mg/day) or Fluconazole 400–600 mg/day

Amp ¼ ampicillin; AG ¼ aminoglycoside; Quin/Dalf ¼ quinupristin/dalfopristin; ESBL ¼ extended spectrum beta lactamase; CSP ¼ cephalosporin; Imi ¼ imipenem; Mero ¼ meropenem; Erta ¼ ertapenem; conc ¼ concentration; LD ¼ loading dose *Use this in conjunction with local antibiograms, which assess local susceptibility and resistance patterns 118 . Infections of the Nervous System providone-idodine. In regards to impregnated and HIV infection. Other associated risk factors catheters, the use of chlorhexidine/silver sulfadi- include gastrointestinal surgery, gastrostomy, azine catheters significantly reduces the risk of nasogastric tube, and prolonged length of hospi- CRBSI, with larger risk reductions with minocy- tal stay. cline-rifampin-coated catheters. Current guide- lines suggest using these impregnated catheters Diagnosis only in patients with limited venous access, his- Clostridium difficile infection is defined as: tory of recurrent CRBSI, and patients with a (1) the presence of diarrhea (3 or more unformed heightened risk for severe sequelae from CRBSI. stools in no longer than 24 hours); (2) stool test The best prevention is limiting the duration of result for the presence of toxigenic C. difficile or its use of these catheters. The practice of converting toxins; or (3) colonoscopic or histopathologic central catheters to peripherally inserted central findings demonstrating pseudomembranous co- catheters (PICC) may not reduce infection rates. litis. The clinical suspicion and evaluation of risk factors is important in the diagnosis of C. difficile infection. This infection is most often associated TIPS & TRICKS with antibiotic administration, but is not a re- quirement for diagnosis. Testing should be per- Central catheters should be removed as soon formed on diarrheal stool unless ileus due to the as possible and should have the least amount infection is suspected. Diagnostic testing can be of lumens required. completed in a number of methods, including stool culture, ELISA immune assay (EIA), and polymerase chain reaction (PCR). The stool cul- ture is the most sensitive but is clinically imprac- Gastrointestinal Infections tical due to the time needed to receive results. The Diarrhea is common in hospitalized patients and EIA has low sensitivity. PCR is gaining more pop- may be due to either infectious or noninfectious ularity since it is rapid, sensitive, and specific. causes. Clostridium difficile, a spore-forming an- aerobic bacillus, is the most common cause of Appropriate Empiric and Treatment infectious diarrhea. Although it accounts for only Recommendations 10–30% of antibiotic-associated diarrhea, up to Treatment for Clostridium difficile depends upon 30% of hospitalized patients who receive anti- the severity of the infection as well as whether biotics can become asymptomatic carriers. it is an initial infection, reinfection, or relapse Clostridium difficile has been shown to increase (Table 13.3). Probiotics are not recommended to ICU costs, and is associated with prolonged prevent C. difficile infection in critically ill or im- length of hospital stay, especially if the infection munocompromised patients due to the risk of is acquired in the ICU. More recently, a newer developing bloodstream infections from the probi- strain called NAP1/BI/027 appears to result in a otic. The use of antidiarrheal medications in the more severe disease and has an increased pro- patientwithC.difficileinfection shouldbeavoided. pensity for quinolone resistance. Prevention Risk Factors Methods to prevent C. difficile infection include There are numerous factors that have been asso- minimizing the use of unnecessary antimicrobials, ciated with the development of Clostridium handwashing,andimplementationandadherence difficile infection. Therapy-related risk factors to antimicrobial stewardship programs. include antibiotic treatment, chemotherapy treatment, proton pump inhibitors, stool soft- Central Nervous System (CNS) eners, enemas, gastrointestinal stimulants, and antiperistaltic medications. Patient risk factors Infections include severity of the patient’s underlying ill- Infections complications encountered in the ness, age > 65, malnutrition, chronic renal failure, NCCU include meningitis, ventriculitis, enceph- 13 Infections in the Neurocritical Care Unit . 119

Table 13.3. Treatment of Clostridium difficile infection Definition Clinical Information Treatment Duration Initial episode, mild or WBC < 15,000 cells/mL, Metronidazole 500 mg 10–14 days moderate Serum creatinine PO TID* < 1.5 baseline Initial episode, severe WBC > 15,000 cells/mL, Vancomycin 125 mg PO 10-14 days Serum creatinine QID > 1.5 baseline Initial episode, severe, Hypotension or shock, Vancomycin 500 mg PO 10–14 days complicated ileus, megacolon QID and Metronidazole 500 mg IV q8h*,** First recurrence Same as initial episode Second recurrence Vancomycin PO tapered orProlonged pulse regimen** regimen can be used

*If complete ileus, consider adding rectal instillation of vancomycin **Metronidazole should not be used beyond the first recurrence

alitis, brain abscess, and subdural or epidural Appropriate Empiric and Treatment empyema. (Please refer to Horan et al. (2008) for Recommendations the current Center for Disease Control diagnostic Empiric antimicrobial regimans for intracranial definitions of CNS infections.) infectious complications consists of ceftazidime 2gm q8h or cefepime 2gm Q6–8h with vancomy- Risk Factors cin dosed to achieve a serum trough concentra- The risk of infection is primarily due to the tion of 15–20 mg/mL. placement of invasive, intracranial monitoring devices. Risk factors include; prolonged duration, underlying diagnosis of brain injury, concurrent TIPS & TRICKS infection in other body systems, open skull While vancomycin is a preferred agent for fracture, hyperglycemia, neurosurgical interven- common pathogens related to ventriculitis, it tion, CSF leakage, catheter exchange, and has very poor tissue penetration particularly technique of catheter placement. Infection is into the central nervous system. Thus it is generally related to skin flora along the catheter important to achieve and maintain higher tract or from direct inoculation when the system trough concentrations. is accessed. Thus, the majority of isolates related to intracranial infectious complications are con- sistent with skin flora: Staphylococcus aureus and Staphylococcus epidermidis. Gram-negative For patients with basilar skull fractures, metro- pathogens are generally a result of contamination nidazolecanbeaddedtothisregimen.Therapycan from a poor aseptic technique on insertion or be streamlined once culture and sensitivity results from a concurrent systemic infection. The diag- are obtained. The general length of therapy is 14 nosis is made with clinical signs of infection or days. The infected catheter should be removed. deterioration in the level of consciousness in conjunction with positive CSF cultures and Prevention increased CSF white blood count and reduced Strategies for the prevention of ventriculitis in CSF glucose levels. patients with EVD include inserting the catheter 120 . Infections of the Nervous System under sterile conditions and minimizing manip- 37 C. Drugs that are metabolized via the cyto- ulation and flushing. Antibiotic-coated catheters chrome P450 include the macrolides, fluoroqui- may reduce the infection rate in patients with nolones, rifampin, and tetracyclines. During EVD placement. hypothermia the volume of distribution also Currently, the Brain Trauma Foundation does changes, which may lead to therapy failure or not advocate prophylactic ventricular catheter toxicity. Rewarming patients to normothermia exchange at 5 days or antibiotic prophylaxis. can also result in toxicity or therapy failure. Unfortunately, the lack of well-controlled trials Unfortunately there is a paucity of information continues to keep the issue of antibiotic prophy- on the impact of hypothermia on these agents, laxis controversial. If antibiotic prophylaxis is but it is important that clinicians are aware of used, prolonged antibiotics (greater than 24 these possibilities. hours) should be avoided. Antimicrobial Considerations Pharmacodynamic Considerations in the NCCU Correct dosing of antimicrobial agents requires adherence to principles of pharmacodynamics. Use of antimicrobial agents in the NCCU requires Time-dependent antimicrobial agents (e.g. beta- a systemic approach, starting first with a thor- lactams, carbapenems, glycopeptides, oxazolidi- ough assessment of the suspected source of the nones) need to maintain plasma concentrations infection. Next, the possible source of infection higher than the minimum inhibitory concentra- should be thoroughly investigated and appropri- tion (MIC). The administration of concentration- ate specimens should be collected for testing dependent antimicrobial agents (e.g. aminoglyco- prior to the initiation of antimicrobial agents. sides, fluorquinolone) should be based on either Optimizing initial empiric therapy with broad- the ratio between the area under the curve and the spectrum coverage is critical followed by de- MIC or the ratio between plasma peak concentra- escalation of the regimen once a source and tions and the MIC. pathogen have been isolated. The final step is appropriate antimicrobial selection with corresponding monitoring of the drugs and Risk of Seizures response to the therapy selected. The key is to Antibiotics may lower the seizure threshold mak- individualize therapy and select and monitor ing seizures more likely. Many antibiotics act by for not only the desired response but also for antagonizing the action of GABA by various me- possible adverse effects. chanisms. The clinician can minimize this risk by identifying predisposing conditions such as renal Pharmacokinetic Alterations in NCCU insufficiency, age, pre-existing CNS disease, and Patients the use of proconvulsant drugs which may alter There are many possibilities for alterations in the pharmacokinetic profile. pharmacokinetics of drugs administered to pa- Beta-lactams, isoniazid, and carbapenems are tients in the NCCU. Some of the key alterations antibiotic classes most commonly associated that may occur include reduced oral absorption, with adverse CNS events. Traditionally, carbape- changes in volume of distribution, reductions in nem, imipenem/cilastatin, has been associated plasma proteins, and reduced or increased renal with seizures at lower concentrations than other or hepatic elimination of agents. The potential antibiotic agents and has a reported incidence of exists for the underdosing of antibiotics in pa- 1.8–6%. The proconvulsant effects of quinolones tients with high volumes of distribution, such as have been attributed to direct pharmacodynamic trauma or septic patients. It is essential to indi- effects and to pharmacokinetic and dynamic in- vidualize therapy and monitor frequently when teractions with co-administered drugs. Direct there is a suspicion of alterations. pharmacodynamic proconvulsant mechanisms Induced hypothermia can result in a 7–22% of quinolones may relate to gamma-aminobuty- reduction in clearance of drugs metabolized by ric acid (GABA)-like substituents, which act as the cytochrome P450 system for every 1 C below GABA-receptor antagonists. 13 Infections in the Neurocritical Care Unit . 121

Antimicrobial Resistance antibiotic selection. Susceptibility patterns may The utilization of broad spectrum antibiotics has also vary between ICUs within the same institu- led to the emergence of MDRO in all ICUs. tion. Antimicrobial stewardship programs in- Approaches to limiting drug resistance includes volve a multidisciplinary approach to optimize prompt de-escalation and a reduction in the the safe and appropriate use of antibiotics. duration of treatment. These are designed to enhance clinical outcome, while minimizing the unintended consequences of antimicrobial use (e.g. toxicity, resistance), and SCIENCE REVISITED reduce healthcare costs without adversely affect- ing the quality of care. Pathogens continually exposed to multiple classes of antibiotics will acquire multiple mechanisms of resistance including: (1) Conclusion production of antibiotic degrading enzymes; Although infections are very commonly encoun- (2) mutations that prevent antibiotic binding tered in the NCCU, every effort should be directed to bacterial targets; (3) efflux pumps that toward the prevention of infections and the sub- remove the antibiotic from the cell; and/or sequent development of MDROs in order to im- (4) down-regulation of outer membrane prove patient outcome. The choice of empiric protein that prevent antibiotic penetration antibiotics is based upon the treatment of the most into periplasmic space. likely infecting pathogens based upon institution- al data as well as pharmacokinetic, pharmacody- namic, and cost considerations pertaining to an- TIPS & TRICKS tibiotic utilization. The initiation of antibiotics should be timely and include broad-spectrum The correct selection of empiric therapy is coverage that can be de-escalated once the source critical to ensure a favorable prognosis. The of infection is identified. current approach is to initiate broad- spectrum therapy, which is then de-escalated Bibliography or discontinued based on culture results. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the Manage- The use of cultures or biomarkers, such as ment of Adults with Hospital-acquired, Venti- procalcitonin, may facilitate these strategies. lator-associated, and Healthcare-associated Pneumonia. Am J Respir Crit Care Med. 2005 TIPS & TRICKS Feb 15; 171(4):388. Bayston R, de Louvois J, Brown EM, et al. Infec- Procalcitonin is a biomarker that is elevated tion in neurosurgery. Working Party of British in the serum of patients who are exposed to Society for Anticmicrobial Chemotherapy. bacterial pathogens or who currently have an Use of antibiotics in penetrating craniocerebral active bacterial infection. Low serum levels injuries. Lancet 2000: 355:1813–1817. of procalcitonin (<0.5 mg/L) suggest that an initial use of antibiotics is not warranted. Beer R, Pfausler B, Schmutzhard E. Infectious A decrease of 80% from peak concentration intracranial complications in the neuro-ICU suggests the need to discontinue antibiotics. patient population. Curr Opin Crit Care 2010; Note: This should not be applied to serious 18:117–122. infections such as sepsis and meningitis. Bratton SL, Chestnut RM, Ghajar J, et al. Guide- lines for the management of severe traumatic brain injury. IV. Antibiotic prophylaxis. J Neu- Every institution has different susceptibility rotrauma 2007; 24(Suppl 1):S26–31. patterns, therefore it is essential to assess local Coffin SE, Klompas M, Claassen D, et al. antibiotic profiles to assist in appropriate empiric Strategies to prevent ventilator-associated 122 . Infections of the Nervous System

pneumonia in acute care hospitals. Infect Mandell LA, Wunderink RG, Anzueto A, et al. Control Hosp Epidemiol 2008 Oct; 29(Suppl Infectious Diseases Society of America/Ameri- 1): S31–40. can Thoracic Society consensus guidelines on Cohen SH, Gerding DN, et al. Clinical practice the management of community-acquired guidelines for Clostridium difficile infection in pneumonia in adults. Clin Infect Dis 2007 Mar adults: 2010 update by the Society for Health- 1; 44(Suppl 2): S27–72. care Epidemiology of America and the Infec- Mermel LA, Allon M, Bouza E, et al. Clinical tious Diseases Society of America. Infect Con- practice guidelines for the diagnosis and man- trol Hosp Epidemiol 2010; 31(5). agement of intravascular catheter-related in- Dellinger RP, Levy MM, Carlet JM, et al. Surviving fection: 2009 update by the Infectious sepsis campaign: international guidelines for Diseases Society of America. Clin Infect Dis management of severe sepsis and septic shock, 2009; 49:1–45. 2008. Crit Care Med 2008 Jan; 36(1):296–327. Muscedere J, Dodek P, Keenan S, et al. VAP Dellit TH, Owens RC, McGowan JE Jr, et al. In- Guidelines Committee and the Canadian fectious Diseases Society of America and the Critical Care Trials Group. Comprehensive ev- Society for Healthcare Epidemiology of Amer- idence-based clinical practice guidelines for ica guidelines for developing an institutional ventilator-associated pneumonia: diagnosis program to enhance antimicrobial steward- and treatment. J Crit Care 2008 Mar; 23 ship. Clin Infect Dis 2007 Jan; 44(2):159–177. (1):138–147. Hooten TM, Bradley SF. Diagnosis, prevention O’Grady NP, Alexander M, Dellinger EP, et al. and treatment of catheter-associated urinary Guidelines for the prevention of intravascular tract infection in adults: 2009 international catheter-related infections. 2002 Dec; 30 clinical practice guidelines from the infectious (8):476–489. disease society of America. Clin Infect Dis 2010 O’GradyNP,BariePS,BartlettJG,etal. Mar: 50:625–663. Guidelines for evaluation of new fever in Horan TC, Andrus M, Dudeck MA. CDC/NHSN critically ill adult patients: 2008 update from surveillance definition of health care-associat- the American College of Critical Care ed infection and criteria for specific types of Medicine and the Infectious Diseases Socie- infections in the acute care setting. Am J Infect ty of America. Crit Care Med 2008 Apr; 36 Control 2008 Jun; 36(5):309–332. (4):1330–1349. 14 Diagnosis and Management of Bacterial and Viral Meningitis Maxwell S. Damian

Department of Neurology and the Neurocritical Care Unit, Cambridge University Hospitals, Cambridge, UK

Introduction estimated 1.5–6 per 100,000 annually in Europe and the USA. Fever, headache and neck stiffness are the clini- Streptococcus pneumoniae and Neisseria men- cal hallmarks of inflammation of the meninges, ingitides cause >75% of cases in immunocompe- of which bacterial meningitis is the most severe. tent patients; S. pneumoniae is the leading agent Acute bacterial meningitis (ABM), which devel- world wide (47% of cases in the western popula- ops within hours to 1–3 days, most frequently tion), and its relative frequency is increasing. The presents with altered mental status. Viral menin- frequency of particular bacterial agents varies gitis in contrast is, in most cases, a self-limiting over time and in different environments. Menin- aseptic meningitis with good prognosis that re- gococcal outbreaks are associated with crowded quires supportive treatment only. Chronic men- populations (colleges, the military). Hemophilus ingitis is caused by many different organisms as influenzae type B has become rare due to wide- well as noninfectious conditions, and has a highly spread immunization programs, but less so in the variable course; it is only briefly summarized in developing world; other vaccination programs the differential diagnostic discussions. may have significant future impact, for example This chapter gives an overview of the back- conjugate pneumococcal vaccines and serotype ground and clinical features of bacterial and viral C meningococcal vaccine. Listeria monocyto- meningitis and provides a guide to the appropri- genes occurs more frequently in the elderly; ate prevention and management. listeria, staphylococci and Gram-negative bacilli Acute Community-Acquired (Escherichia coli, Klebsiella, Enterobacter and Bacterial Meningitis (ABM) Pseudomonas) are particularly common in im- Epidemiology and Etiology munocompromised patients. Pathophysiology ABM is the prototype of an infectious neurologi- cal emergency and is a leading cause of infection- Bacterial meningitis develops mainly through he- related death. Young children and the elderly are matogenous spread, often from colonization in more frequently affected; in developing countries the nasopharynx or respiratory tract; S. pneumo- the incidence may be 10 times higher than the niae is a common colonizer of the nasopharynx

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

123 124 . Infections of the Nervous System

(up to 10% of healthy adults and >20% of chil- The systemic investigation of the patient with dren). Less common sources are the gastroin- meningitis should include a careful search for a testinal or genitourinary tract, or infections of rash (petechiae or purpura in meningococcal the skin. Direct spread from parameningeal sites disease; vesicular or morbilliform rashes in viral (sinusitis, traumatic defects to the meninges or infections) and an examination for sinusitis, base of skull) is a less common path of infection. otitis, and pharyngeal infections. Evidence of Retrograde neuronal spread through the ol- embolism should prompt a search for endocar- factory tract is particularly recognized in amebic ditis. Signs of a bleeding tendency or peripheral meningoencephalitis due to Naegleria fowleri circulatory failure indicate a potential need for or Acanthameba. Limited defences within resuscitation. the blood–brain barrier facilitate the agents’ The overall mortality averages around 20%, but survival. rises to 50% or more with rapid onset and early Cytokines, especially TNF-alpha and interleu- severe neurological impairment. Patients under 5 kin-1, play a prominent role in the early inflam- or over 60 years are at increased risk of death and matory process and are activated by bacterial residual disability. products. Secondary mediators potentiate this Differential Diagnosis inflammatory cascade. The inflammation starts in the subarachnoid space, where it causes head- The differential diagnosis of ABM includes other ache and meningismus, and progresses to the infective meningoencephalitic diseases (tubercu- subpial brain, causing encephalopathy, and in lous, fungal, leptospiral, parasitic, and viral), para- 25% of cases, seizures. Complement-mediated menigeal infections,orother forms of aseptic men- blood–brain barrier breakdown, brain swelling, ingitis. Fungal and tuberculous meningitis often and impaired cerebrospinal fluid flow result in present with a protracted course, featuring intrace- rising intracranial pressure, and decreased cere- rebral or meningeal granulomas and subacute cra- bral blood flow. As the brain becomes ischemic, nial nerve involvement. Hydrocephalus is particu- anaerobic metabolism will develop with the for- larly common due to the preferential basal menin- mation of lactate and reactive oxygen species. geal inflammation encountered in this meningitis. Clinically, patients at this point will become ob- Patients with tuberculous meningitis often feature tunded and can progress to coma. Focal signs generalized tuberculous infection. Amebic menin- may indicate vasculitis or the development of a goencephalitis can present with a fulminant cerebral abscess. meningoencephalitis syndrome. The key to early recognition of this meningitis is a history of poten- tial exposure, i.e. swimming in warm freshwater Clinical Features lakes and rivers in Naegleria fowleri; contact with Two-thirds of patients will present with the full soil through gardening or leisure sports in Bal- clinical triad of fever (in 95% of cases with bacte- muthia mandrillaris. Viral meningitis normally rial meningitis), headache and photophobia, and presents with a less severe meningitic syndrome signs of meningeal irritation (nuchal rigidity, without systemic instability, but acute viral menin- Kernig and Brudzinski signs). goencephalitis, most often due to Herpes simplex Patients with altered mental status, papillede- type 1 can have a fulminant course. ma, and focal signs are highly likely to have Parainfectious immunological diseases such as intracranial hypertension and/or focal brain hemorrhagic leukoencephalitis, Weston Hurst, or swelling. More subtle manifestations are com- the severest forms of noninfectious inflammatory mon in the elderly, who frequently appear lethar- disease such as acute disseminated encephalo- gic but have few meningeal signs. Children may myelitis (ADEM), should be included in the dif- present with vomiting and irritability but less ferential diagnoses, particularly where brain often display nuchal rigidity. Also, many patients swelling prevents CSF samples. Similarly, severe with bacterial meningitis are partially treated immune reactions such as graft-versus-host dis- with antibiotics on admission and may present ease in transplanted patients can cause acute with an incomplete meningitis syndrome. brain swelling and meningeal signs. 14 Diagnosis and Management of Bacterial and Viral Meningitis . 125

Figure 14.1. (A). Sulcal effacement and loss of basal cisterns in brain swelling due to acute bacterial meningitis in a noncontrast CT. (Courtesy of Dr. John Morlese, Department of Radiology, University Hospitals of Leicester, UK.) Figure 14.1(B). Post-contrast CT showing acute frontal empyema, sulcal effacement and cerebral edema together with generalized leptomeningeal enhancement. (Courtesy of Dr. John Morlese, Department of Radiology, University Hospitals of Leicester, UK.)

The past history can indicate potential entry pressure such as coma and pupillary distur- ports (ventriculoperitoneal shunt; cochlear bances are ominous prognostic signs but cannot implants) or provide evidence for a relapsing be adequately treated or monitored outside the disease such as the recurrent bouts of meningitis hospital. Patients may need to be empirically seen in Mollaret meningitis. Time of year (warm- hyperventilated as a bridging measure until some er months for arboviruses, colder for measles and form of intracranial pressure monitoring can be varicella zoster), geographic location (especially arranged. for specific parasitic infections), exposure to af- After hospital admission, baseline investiga- fected individuals (meningococcal disease), sex- tions include blood cultures, full blood count, ual contacts (Herpes simplex, HIV), occupation, and C-reactive protein. The diagnosis should be diet and animal contacts (leptospirosis, brucello- confirmed as soon as possible with a lumbar sis) can all help to indicate potential infectious puncture, as long as it is considered safe. A CT agents. scan of the head should be performed immedi- ately if clinical features suggest potentially raised Emergency Management of ABM intracranial pressure (i.e. presence of focal neu- Management starts with the immediate admis- rological deficits, seizures, or reduced level of sion to a hospital with adequate facilities for consciousness) (Figures 14.1a, 14.1b). Circulatory assessment and treatment as soon as ABM is compromise and coagulation problems should suspected. Prehospital antibiotics are recom- be stabilized before lumbar puncture is per- mended when the delay to hospital admission formed; platelets levels below 50,000 per mL may exceed 90 minutes, or when an acute should be substituted. Absolute contraindica- course and skin rash give suspicion for menin- tions to lumbar puncture include infection at gococcemia, in order to reduce the risk of acute the puncture site, or clinical signs of raised in- adrenocortical necrosis with circulatory collapse tracranial pressure such as papilledema, or CT (Waterhouse-Friderichsen syndrome). Recurrent evidence of obstructive hydrocephalus, brain seizures, status epilepticus, and cardiorespiratory edema, or herniation. compromise need to be stabilized according to Figure 14.2 provides an algorithm for the emer- standard guidelines. Signs of raised intracranial gency management of bacterial meningitis, 126 . Infections of the Nervous System

0 min Suspected case of ABM: Headache,Fever, Meningismus

Rapidly Ye s evolving skin No rash ?

30 min Assume Meningococcemia.Immediately commence an Arrange immediate transfer to nearest antibiotic after collecting blood sample for culture. secondary care

60 min Hospital admission

Evaluate for: shock, DIC, GCS and focal neurological deficit Secure: IV access, blood sample for culture and other tests

90 min Ye s Is LP clinically No safe?

Is CT facility readily available? Ye s

Review 1. Commence on empiric antibiotics (see Table) 120 min imaging. No 2. Add dexamethasone if focal neurological deficit Proceed to No 3. Add acyclovir if HSE is a possibility LP?

No

Ye s Safety of LP reconfirmed by a neurologist? Ye s Stabilise patient Definitive Imaging (MR)

1. Send CSF sample to microbiology 150 min 2. Commence on empiric antibiotics 3. Add dexamethasone if focal neurological deficit

Delayed LP (if 3-12 hours safely possible)

12-24 hours Review results. Confirm choice of antibiotics, cont inuation of steroids and duration of antibiotic therapy

24-48 hours Response to Ye s therapy No satisfactory?

Reassess clinical, Continue imaging and laboratory treatment data

Figure 14.2. Flowchart of emergency management of patients with suspected bacterial meningitis. ABM, acute bacterial meningitis; DIC, disseminated intravascular coagulation; GCS, Glasgow Coma Scale; HSE, herpes simplex encephalitis; LP, lumbar puncture. (Courtesy of Dr. A. Chaudhuri; reproduced from Chaudhuri et al., 2008.) 14 Diagnosis and Management of Bacterial and Viral Meningitis . 127 included in the European Federation of Neuro- mortality in ABM occurs if antibiotics are delayed logical Sciences (EFNS) guidelines. for more than 3–6 hours after contact with medi- cal professionals. Third-generation cephalosporins are the cur- CAUTION rent standard of care in the empiric management of ABM. The efficacy of cefotaxime (2 g tid) or 1. Patients with ABM require immediate ceftriaxone (2 g bid) is equivalent to newer and admission with adequate diagnostic (24/7 more expensive agents such as meropenem (2 g CT scanner þ laboratory) and treatment tid), which can be used if there is beta-lactam (ICU) facilities. allergy. Variations in empiric therapy can include 2. Prehospital antibiotics are necessary if there benzyl penicillin if a rash suggests meningococ- is strong clinical evidence of meningococcal cal meningitis; amoxicillin 2 g q4h if Listeria is disease of if hospital management is likely to suspected or in an immunocompromised pa- be delayed. tient, or IV cotrimoxazole 20 mg/kg tid if there 3. LP is contraindicated if there are clinical or is penicillin allergy. Vancomycin 60 mg/kg/day CT signs of raised intracranial pressure. may be added if penicillin or cephalosporin re- sistance is suspected. The results of cultures and sensitivity testing may indicate a change of the The cerebrospinal fluid (CSF) is typically clou- subsequent antibiotic regimen. The emergence dy or purulent and opening pressure is often of penicillin-resistant strains is a cause for con- raised. The white cell pleocytosis in most cases cern; and patterns of resistance change over time exceeds 500 per mL (more often, several thou- and geographically. sand) with a neutrophilic predominance. Pa- Methodologic considerations may be impor- tients may have a lower CSF leukocytosis if the tant. In 1997 a CDC survey reviewed 3237 iso- patient has been partially treated with antibio- lates of invasive pneumococcal disease in eight tics. Bacterial infections, which may present with US states; 25% of isolates were nonsusceptible a “viral” type CSF profile in acute meningitis, (11.4% intermediate susceptibility, 13.6% resis- include Mycoplasma, Listeria, and Leptospira. In tant), and resistance rates ranged from 15.3% in these, meningitis CSF protein is elevated and CSF Maryland to 38.3% in Tennessee. This survey did glucose is reduced below 2.5 mM with a CSF/ not separate meningitis and nonmeningitis serum glucose ratio under 0.4. CSF lactate is cases. In a more recent CDC report from 10 US often increased. CSF cultures are also more likely states in 2006–2007 redefining susceptibility to be negative if the patient has been pretreated breakpoints, the overall susceptibility rate in- with antibiotics. In children the CSF is sterilized creased from 74.7% under former breakpoints to of meningococci within 2 hours, and S. pneumo- 93.2% using the new breakpoints for intrave- niae in 4 hours. Rapid methods for the detection nous treatment. Resistance, however, was dif- of bacteria are available. Immune-based meth- ferent among isolates associated with meningi- ods include antigen detection, ELISA, and latex tis. Due to variations in CSF penetration of agglutination which have a sensitivity of 60–90% antibiotics, isolates previously categorized as and a specificity >90%. PCR methods are increas- having intermediate susceptibility to penicillin ingly available and may have higher sensitivity. were recategorized as penicillin resistant. This increased the rate of resistant isolates from 10.7 Treatment of ABM to 27.5%. The time to antibiotic administration is crucial for The optimal duration of antibiotic treatment prognosis, and delayed treatment is the most im- remains uncertain. The EFNS taskforce guide- portant cause of morbidity and mortality. Case- lines found highly variable durations of treatment control studies have not confirmed a benefit for in their data and recommended 10–14 days prehospital antibiotic treatment, possibly due to of antibiotic treatment for pneumococcal and sample composition (i.e. earlier recognition in unspecified bacterial meningitis; 5–7 days more severe cases), but a significant increase of for meningococcal meningitis; 7–14 days for 128 . Infections of the Nervous System

Figure 14.3. (A and B) Acute hydrocephalus causing secondary obtundation in a patient with acute meningitis. (Courtesy of Dr. John Morlese, Department of Radiology, University Hospitals of Leicester, UK.)

H. influenzae; 21 days for Listeria meningitis; and pressure in meningitis and is currently the subject up to 28 days for Gram-negative bacilli and pseu- of further investigation (IHPOTOTAM: Induced domonal meningitis. HyPOthermia TO Treat Adult Meningitis trial). Dexamethasone has gained a role in the ad- Neuroimaging is needed to exclude obstructive junctive treatment of pneumococcal ABM. hydrocephalus requiring CSF drainage (Figure There have been several randomized trials in 14.3A and B). Seizures need to be treated with IV different clinical settings in children and adults anticonvulsant drugs; phenytoin or fosphenytoin over the last 20 years, generally showing im- are the conventional choices, but levetiracetam is proved mortality and neurological residua. Cur- increasingly used due to its favorable side-effect rent recommendations are to institute 10 mg profile. Nonconvulsive status epilepticus has been dexamethasone qid for 4 days. Therapy is increasingly recognized as a cause of persistent initiated with the first dose of antibiotics in coma in patients on ICU and can be identified by immunocompetent patients with suspected EEG monitoring. S. pneumoniae or H. influenzae meningitis. Late complications can include stroke second- Note that this may reduce CSF penetration of ary to vasculitis or embolic complications from some antibiotics, e.g. vancomycin in penicillin- endocardial vegetations. CT or MR angiography resistant meningitis. is necessary to exclude vasoconstriction, vascu- Patients with severe ABM should be treated in a litic stenosis, or mycotic aneurysms, which are neurological intensive care unit (ICU). Early com- typically located in distal branches of the circle of plications include septic shock and circulatory Willis and may be the cause of secondary intra- collapse. This can occur with or without adreno- cerebral or subarachnoid hemorrhage. A progres- cortical necrosis (Waterhouse-Friderichsen syn- sive focal deficit may be due to brain or subdural drome in meningococcal meningitis). Brain swell- abscess and empyemas (Figure 14.4). Intraspinal ing (Figures 14.1A and 14.1B) may cause progres- abscesses may cause myelopathy and parapar- sive impairment of consciousness and is treated esis. Meningitis may cause severe deficits of cra- with standard measures including head elevation, nial nerves, most commonly deafness or visual osmotic substances, temperature control, and impairment, as well as spinal radiculopathies. avoidance of hypercapnia; mild hypothermia may Long-term sequelae are reported in 30–50% of be useful for the control of raised intracranial survivors. 14 Diagnosis and Management of Bacterial and Viral Meningitis . 129

geographical location, and estimates are difficult through lack of reporting. In the USA, the overall annual incidence has been estimated at 5–10 per 100,000 and more recently the annual rate has been estimated at more than 36,000 cases per year. The condition is significantly more com- mon in children, with an incidence in Finland of 209 per 100,000 infants and 27.8 per 100,000 in children aged under 14 years. Variation in im- munization patterns lead to further differences, with prevalence of mumps, measles, and being much lower in western countries with robust vaccination practices than in the devel- oping world. There are also differences in incidence according to gender, with mumps occurring 3 times more frequently in males. Figure 14.4. Post contrast T1-w MRI in bacterial Enteroviruses, spread by fecal–hand–oral con- meningitis showing subtentorial subdural empyema, tamination, are overall the most common cause sulcal effacement, obstructive hydrocephalus and of viral meningitis, and are responsible for over cerebral edema, and generalized leptomeningeal 80% of cases. This most likely accounts for the enhancement. peak incidence in summer and autumn. Lym- phocytic choriomeningitis virus was the first vi- rus to be recognized to cause meningitis and is TIPS & TRICKS transmitted by mouse excreta; it is now rarely found but is associated with severe disease in . Acute bacterial meningitis (ABM) is a immunocompromised patients. West Nile virus neurological emergency which must be is an arthropod-born flavivirus which was first correctly diagnosed and treated without recognized in the USA in 1999; by 2008 it had delay. caused over 28,961 cases, of which 11,822 were . The most important cause of morbidity considered neuroinvasive, with 33% reported as and mortality is late or inadequate meningitis (versus 63% encephalitis); its inci- administration of antibiotics. dence is greatest from July through September. . Antibiotic susceptibility can be highly Toscanavirus is a further arbovirus that common- variable according to local patterns. ly causes viral meningitis in Europe. Recognizing infection patterns is crucial for effective prevention strategies. These include vaccination programs (effective in mumps and Viral Meningitis measles, newly available for varicella zoster vi- Viral meningitis shares the meningitic triad of rus), personal and food hygiene (enteroviruses), fever, nuchal rigidity, and headache with bacte- and home hygiene (lymphocytic choriomeningi- rial meningeal infection, but in most cases is a tis), control of animal and insect vectors (arbo- relatively mild and self-limiting condition. viruses), and safe sexual practices (HIV). Nevertheless, lumbar puncture is necessary to Pathophysiology reliably differentiate the two, and to exclude other infectious agents and noninfectious After entering the body through the percutane- etiologies. ous, gastrointestinal, respiratory, or urogenital sources, replication and viremia develop prior to Epidemiology and Etiology CNS penetration. Neural penetration and, more The frequency of viral meningitis in the popula- often, hematogenous spread through the choroid tion varies significantly according to age and plexus or endothelium, are the two routes of viral 130 . Infections of the Nervous System access to the CNS. In meningitis, the endothelial Partially treated bacterial meningitis due to and meningeal cells are the initial sites of damage antibiotic use must be excluded. Obtaining CSF and viral replication. This results in inflamma- is essential. The CSF profile typically reveals an tion. Superficial cortical inflammation is com- asepticmeningitis with lymphocytic pleocytosis mon, but deeper brain structures are not affected of up to 1000 cells/mL. A neutrophilic pleocytosis in uncomplicated disease. may be seen early in the course and cause con- fusion with bacterial infection. Protein is only Clinical Features moderately elevated. Glucose is normal in CSF The onset of viral meningitis may be sudden, or in most cases of viral meningitis. This is in con- follow a flu-like viral prodrome of up to 48 hours trast to fungal meningitis, parasites, or tubercu- with low grade fever, myalgia, and upper respi- losis that will generally lower the CSF glucose. ratory symptoms. Symptoms sometimes exhibit a The Pediatric Emergency Medicine Collabora- biphasic course. Patients seldom appear as un- tive has published a Bacterial Meningitis Score well or toxic as with bacterial meningitis, but predicting the risk of bacterial meningitis. Risk is extraneurological manifestations may indicate considered very low if pleocytosis does not ex- the causative virus. Rashes are common with ceed 1000 cells/mL, protein is less than 0.8 g/L, the enteroviruses. Other skin manifestations include cell count in blood does not exceed 10,000, and zoster in varicella zoster infection, or herpangina there is no Gram-positive stain. PCR testing is in coxsackievirus A. Group B coxsackieviruses selected according to the likely viral infection commonly cause cardiac manifestations (myo- suggested by history and clinical features. Other carditis/pericarditis). Pharyngitis as well as nonviral infections with a similar inflammatory lymphadenopathy are common with Epstein– CSF profile include Lyme disease, listeriosis, or Barr virus infection. rickettsial disease. The history must cover potential exposure and Noninfectious etiologies causing aseptic men- include the patient’s travel history and outdoor ingitis include connective tissue diseases (Lupus activities, vaccination history, use of medication erythematosus, Sjogren syndrome, mixed connec- and drugs, and sexual history. tive tissue disease), drugs (nonsteroidal anti- An acute retroviral syndrome can occur at inflammatories, antibiotics), and by chemicals se- seroconversion in up to 50% of HIV infections. creted by dermoid or neuroepithelial cysts. Acute This syndrome can include fever and nuchal disseminated encephalomyelitis (ADEM) can rigidity and can manifest as an aseptic meningitis initially present with a meningitis syndrome, al- with CSF lymphocytic pleocytosis. Some cases though focal neurological deficits rapidly predom- with a normal CSF cell count have also been inate. Meningeal infiltration secondary to malig- reported. Therefore, HIV testing should be in- nancies can also present with aseptic meningitis. A cluded in the initial work-up. prolonged course or cranial nerve involvement can be indications for more extensive investigation. Differential Diagnosis Management and Prognosis The clinical triad is, in most cases, easily recog- nized. The clinical picture differs from bacterial Management is typically supportive, involving meningitis mostly, through the absence of signif- hydration, antipyretic, and analgesic medication. icant systemic illness. However, viral meningitis Antibiotics may be indicated initially if bacterial can be confused with an early evolving bacterial meningitis is under consideration, and acyclovir meningitis. In these circumstances procalcitonin is advised if encephalitis is suspected. There levels may help differentiate viral from bacterial should be a low threshold for using either of meningitis. these if there is an initial clinical doubt. Patients who fail to improve within a few days Prognosis is mostly good with a self-limiting require a more extensive work-up. Tuberculosis, course and complete recovery in 1–2 weeks. fungal, and parasitic disease should be reconsid- Complications such as persistent lethargy, ered. EEG and MRI may be indicated if encepha- malaise, sleep disorders, and fatigue are seen in litis is suspected. up to 5% of cases. There may be a link with 14 Diagnosis and Management of Bacterial and Viral Meningitis . 131 learning difficulties and delayed language devel- Chaudhuri A. Adjuvant dexamethasone use in opment in some affected children. However, the acute bacterial meningitis. Lancet Neurol most severe complications are observed when 2004; 3:54–61. meningeal inflammation extends to the brain. De Gans J, van de Beek D. Dexamethasone in Some forms of viral meningitis may develop a adults with bacterial meningitis. New Engl J Med relapsing course and qualify as Mollaret relapsing 2002; 347:1549–1556. aseptic meningitis. This is a syndrome of benign Dubos F, Korczowski B, Aygun DA, et al. Serum recurrent meningitis for which multiple viruses procalcitonin level and other biological markers can be responsible, including Human herpes- to distinguish between bacterial and aseptic virus 6, Herpes simplex viruses 1 and 2, and meningitis in children: a European multicenter Epstein–Barr virus. case cohort study. Arch Pediat Adolesc Med 2008; 162:1157–1163. LepurD,KutlesˇaM,BarsˇicB.Hypothermiainadult CAUTION community-acquired bacterial meningitis – . Viral meningitis may be the initial morethanapromise?JInfect2010Oct13(Epub). manifestation of serious chronic viral Lindsey NP, Staples JE, Lehman JA, Fischer M. infection and work-up includes HIV testing. Centers for Disease Control and Prevention . A prolonged clinical course is an indication (CDC). Surveillance for human West Nile virus for more extensive diagnostic assessment. disease – United States, 1999–2008. MMWR Surveill Summ 2010 Apr; 59(2):1–17. Nigrovic LE, Kuppermann N, Macias CG, et al. Clinical prediction rule for identifying children Acknowledgment with cerebrospinal fluid pleocytosis at very low MRI and CT scans are courtesy of Dr. John risk of bacterial meningitis. J Am Med Assoc Morlese, Department of Radiology, University 2007; 297:52–60. Hospitals of Leicester, UK. Rantakallio P, Leskinen M, von Wendt L. Inci- dence and prognosis of central nervous system Bibliography infections in a birth cohort of 12, 000 children. Scand J Infect Dis 1986; 18:287–294. Anon, Centers for Disease Control and Preven- tion (CDC). Geographic variation in penicillin Scarborough M, Gordon SB, Whitty CJ, et al. resistance in Streptococcus pneumoniae – Corticosteroids for bacterial meningitis in selected sites, United States, 1997. Morb Mortal adults in sub-Saharan Africa. New Engl J Med Wkly Rep 1999; 48(30):656–661. 2007; 357(24):2441–2450. Anon: Centers for Disease Control and Preven- Seupaul RA. Evidence-based emergency tion (CDC). Effects of new penicillin suscepti- medicine/rational clinical examination ab- bility breakpoints for Streptococcus pneumo- stract. How do I perform a lumbar puncture niae – United States, 2006–2007. Morb Mortal and analyze the results to diagnose bacterial Wkly Rep 2008; 57(50):1353–1355. meningitis? Ann Emerg Med 2007; 50(1):85–87. Beghi A, Nicolosi A, Kurland LT, et al. Mulder Van de Beek D, de Gans J, Tunkel AR, Wijdicks EF. DW, Hauser WA, Shuster L. Encephalitis and Community-acquired bacterial meningitis in aseptic meningitis, Olmsted County, Minnesota, adults. New Engl J Med 2006; 354(1):44–53. 1950–1981. Ann Neurol 1984; 16:283–294. Vardakas KZ, Matthaiou DK, Falagas ME. Adjunc- Chaudhuri A, et al. EFNS guidelines on the tive dexamethasone therapy for bacterial men- management of community-acquire bacterial ingitis in adults: a meta-analysis of randomized meningitis: report of an EFNS Task Force on controlled trials. Eur J Neurol 2009 Jun; 16(6): acute bacterial meningitis in older children and 662–673. adults. Eur J Neurol 2008; 15:649–659. 15 Encephalitis: Presentation and Management Ali E. Elsayed1 and Barnett R. Nathan2

1Mountainside Hospital, Montclaire, NJ, USA 2Departments of Neurology and Internal Medicine, NeuroCritical Care and NeuroInfectious Disease, University of Virginia, Charlottesville, VA, USA

Introduction signs and symptoms of meningoencephalitis – a combination of both meningitis and encephalitis. Encephalitis is defined by the presence of an in- flammatory process of the brain in association with clinical evidence of neurologic dysfunction. The presence or absence of normal brain function is the important distinguishing feature between Etiology encephalitis and meningitis. Patients with menin- A wide variety of pathogens have been reported gitis may be uncomfortable, lethargic, or distract- to cause encephalitis, most of which are viruses. ed by headache, but their cerebral function re- The epidemiology of viral encephalitis in devel- mains normal or close to normal. The diagnosis of oped countries has changed significantly in the encephalitis is suspected in the context of a febrile last few decades as a result of the initiation of disease accompanied by headache, altered level of vaccination protocols (such as measles and ru- consciousness, and symptoms and signs of cere- bella vaccine). bral dysfunction which can be classified into four Noninfectious encephalitis, such as acute dis- distinct categories: seminated encephalomyelitis (ADEM), is more commonly seen in children and adolescents. It is 1. Cognitive dysfunction (acute memory, speech, a type of encephalitis most likely mediated by an and orientation disturbances). immunologic response to an antigenic stimulus 2. Behavioral changes (disorientation, hallucina- after infection with viruses such as measles, tions,psychosis,personalitychanges,agitation). mumps, rubella, herpes simplex, cytomegalovi- 3. Focal neurological abnormalities (such as rus, influenza, and hepatitis A. It may also occur anomia, dysphasia, hemiparesis). followingimmunization formeasles, anthrax,Jap- 4. Seizures. anese encephalitis, yellow fever, influenza, small- pox,andrubella.Inmanycasesofencephalitis,the Note that many patients with a primary diagnosis etiology remains unknown (32–75%) despite ex- of meningitis or encephalitis, frequently reflect tensive diagnostic evaluation.

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

132 15 Encephalitis: Presentation and Management . 133

Diagnosis status change. Flaccid paralysis that evolves into History an encephalitis strongly suggests the possibility of West Nile virus (WNV) infections, while gas- Information will most likely need to be obtained trointestinal signs are associated with enteroviral from an accompanying person since most pa- disease, and upper respiratory findings may tients with encephalitis will be encephalopathic. accompany influenza virus infection and HSV-1 Geographic location as well as travel history encephalitis. Tremors of the eyelids, tongue, lips, should be considered in identifying possible and extremities may suggest damage to the basal causative pathogens, such as malaria and avian ganglia or cerebellum and the possibility of H5N1 influenza virus, which are endemic to or St. Louis encephalitis or WNV encephalitis in the prevalent in certain geographic regions. Seasonal appropriate season, geographic location, or travel occurrence is important for other pathogens such history. Hydrophobia, aerophobia, pharyngeal as West Nile viral infection and polio viral infec- spasms, and hyperactivity are highly suggestive tion. Occupation or hobbies may be important of encephalitic rabies. (as in a case of a forestry worker or an outdoor enthusiast with Lyme disease). History of insect Diagnostic Studies or animal bites can be relevant for arbovirus infection, as well as rabies. Other important his- General torical features may include a history of contact Lymphocytosis is suggestive of a viral encephali- with diseased individuals and the underlying tis and is helpful in differentiating viral from immune system condition of the patient. An nonviral encephalitis. associated abnormality outside the nervous sys- A culture of body fluids other than cerebrospi- tem (bleeding tendency in hemorrhagic fever) nal fluid (CSF) may be useful in establishing the may also point to a specific pathogen. etiology of encephalitis. All patients should have blood cultures sent for bacterial and fungal or- ganisms. Positive cultures may be indicative of TIPS & TRICKS encephalopathy secondary to systemic infection rather than encephalitis. Specific clinical findings Seasonal incidence of some viral CNS should direct other sites for culture (e.g. stool, infections: nasopharynx). Summer/Fall: Enterovirus, West Nile virus, Scraping and biopsy of skin rashes to identify St. Louis encephalitis virus, Eastern equine viral antigens by direct fluorescent antibody in encephalitis virus, California encephalitis cases of varicella (herpes zoster encephalitis) viruses and Western equine encephalitis may be useful. viruses. Cerebrospinal Fluid Findings Winter/Spring: Mumps and measles. Any season: Herpes simplex virus (HSV) types 1 Examination of the CSF, although not diagnostic, and 2, HIV virus. will usually confirm the presence of inflammato- ry disease of the CNS. Red cells are usually ab- sent; their presence in the appropriate clinical setting suggests HSV-1 infection. General Examination Viral infection of the nervous system is almost always part of a generalized systemic infectious TIPS & TRICKS disease. Other organs may be involved prior to In a CSF analysis for viral infection, the or in association with CNS manifestations. A peripheral white blood cell count is usually dermatomal pattern or a vesicular skin rash may less than 250/mm3, with a lymphocyte be indicative of herpes zoster virus. Parotitis predominance. A very early infection may strongly suggests the diagnosis of mumps en- show a neutrophilic predominance. CSF cephalitis in an unvaccinated patient with mental 134 . Infections of the Nervous System

protein is elevated but is usually less than The identification of HSV-1 in the CSF is a rapid, 150 mg/dL. CSF glucose concentration sensitive, and specific diagnostic test for HSV-1 (e.g. >50% of blood value) is typically normal, encephalitis. PCR testing for other viruses will but moderately reduced values are depend on the clinical situation, epidemiology, occasionally seen with HSV, mumps, and and availability. some enteroviruses. Serology Serologic testing is most important for patients These findings are generally quite different who are not improving and who do not have a from those associated with bacterial meningitis, diagnosis based upon CSF analysis, culture, and which include a higher white blood cell count in PCR. Most viral etiologies require paired sera for the CSF (>2000/mm3) with neutrophil predomi- diagnosis; thus, in the setting of acute illness, it is nance, a higher protein concentration (>200 prudent to save serum that can later be used mg/dL), and usually hypoglycorrhachia. if necessary. Convalescent serology should be The exclusion of bacterial meningitis based obtained no sooner than 3 weeks after the onset only upon individual CSF parameters can be of the clinical illness. As an example, the presence difficult, since the spectrum of CSF values in of IgM antibodies in a single serum sample pro- bacterial meningitis is so wide that the absence vides presumptive evidence of St. Louis encepha- of one of more of these findings is of little value. litis; however, a significant rise or fall between This was illustrated in a review of 296 episodes appropriately timed acute-convalescent or early– of community-acquired bacterial meningitis; late convalescent sera is diagnostic. 50% had a CSF glucose above 40 mg/dL, 44% West Nile virus has emerged as the most com- had a CSF protein below 200 mg/dL, and mon cause of viral encephalitis in the USA. 13% had a CSF white cell count below 100/mL A single specimen looking for IgM antibodies on (see Duran et al., 1993). the serum or CSF is sufficient for diagnosis. A single serum specimen can also be used to Culture diagnose mumps. Serology may also be helpful in obtaining evidence for primary EBV infection, Viral culture has been routinely ordered by most a rare cause of meningoencephalitis. physicians after obtaining CSF samples. Howev- er, one review demonstrated that viruses were Brain Biopsy recovered from only 6% of 22,394 viral cultures of A brain biopsy to establish the etiology of en- CSF samples. In subset analysis of the same cephalitis is rarely used today and is not routinely study, 1290 CSF samples were evaluated for HSV recommended. A biopsy should only be consid- by polymerase chain reaction (PCR) and culture. ered in patients with encephalitis of unknown Of these, only nine samples were positive for HSV etiology, or patients who deteriorate clinically and all were identified only by PCR testing (see despite treatment. Polage and Petti, 2006). Therefore, in most cir- cumstances, PCR testing of the CSF has replaced Neuroimaging viral culture for the common viral encephalitides. CT and MRI are most frequently used to evaluate Culture may still be important when rare causes patients with encephalitis. MRI is more sensitive of encephalitis are being considered (e.g. para- and specific, and CT with or without contrast influenza, measles, mumps) for which PCR should only be done if MRI is unavailable, im- testing is unavailable. practical, or cannot be performed. Diffusion- weighted imaging is superior to conventional Polymerase Chain Reaction MRI for the detection of early signal abnormali- With the advent of PCR technology, significant ties in viral encephalitis. advances have been made in the ability to diag- In certain patients with herpes encephalitis, nose viral infections of the CNS. CSF PCR can be some characteristic neuroimaging patterns have performed for HSV-1, HSV-2, and enteroviruses. been observed. There may be significant edema 15 Encephalitis: Presentation and Management . 135 and hemorrhage in the temporal lobes as well as Diagnosis hypodense areas on T1-weighted images. Many Examination of the CSF is indicated. In patients of these abnormalities can be found in 90% of with HSE, both CSF white cells (lymphocyte patients with herpes simplex encephalitis docu- predominance) and CSF protein levels are mented by CSF PCR. elevated. In cases of suspected ADEM, MRI is the The gold standard for establishing the diagno- diagnostic neuroimage of choice, often reveal- sis is the detection of herpes simplex virus DNA ing multiple focal or confluent areas of signal in the CSF by polymerase chain reaction (PCR). abnormalities in the subcortical white matter and, sometimes, subcortical gray matter on T2 and flair sequences. MRI can be negative early TIPS & TRICKS in the clinical course of suspected ADEM. Repeat imaging should occur if clinically PCR testing of CSF is the gold standard in the indicated. detection of HSV with 98% sensitivity and 94 to 100% specificity and is positive early in the Electroencephalogram (EEG) disease. An EEG is generally considered to be a nonspe- cific investigation. The main benefit of obtaining an EEG is to demonstrate cerebral involvement CSF serologic testing for HSV antigen and during the early stage of the disease. It can be antibody detection is not helpful in the early used as an indicator of cerebral involvement and diagnosis of HSV encephalitis. The use of puri- usually shows a background abnormality prior to fied HSV glycoprotein B to detect CSF antibodies evidence of parenchymal involvement on neu- has a sensitivity of 97% and a specificity of 100%. roimaging. Although an EEG is rarely useful in However, viral antibody titers, which rise four- identifying the pathogen, it has a role in identi- fold over the course of the illness, are first posi- fying patients with nonconvulsive seizures. tive after 10 days to 2 weeks of illness and are thus only helpful retrospectively. HSV antigen can Specific Organisms also be detected in the CSF, but as sensitivity Herpes Simplex Viruses Types 1 and 2 and specificity of this test is lower than PCR assays, there are very few situations in which HSV represents 5–10% of all cases of encephali- serology is preferred over PCR. tis. It is the most common cause of fatal sporadic A viral culture of CSF is rarely positive in the encephalitis in the USA and affects all age groups early stages of infection and is only positive later (HSV-1 infection is more common in adult and in about 4 to 5% of patients with brain biopsy- HSV-2 infection is more common in neonates) proven HSV encephalitis. and can occur in all seasons. Noninvasive neuroimaging studies support a Herpes simplex encephalitis (HSE) arises via presumptive diagnosis of HSE. Focal changes of one of three routes: (1) direct CNS invasion via the EEG are characterized by spike and slow the trigeminal nerve or olfactory tract following wave activity and periodic lateralized epilepti- an infection of oropharynx (most ot these pa- form discharges (PLEDs) which arise from the tients are younger than 18 years of age); (2) CNS temporal lobe. invasion after an episode of recurrent HSV-1 infection, which is believed to represent viral reactivation with subsequent spread; (3) CNS TIPS & TRICKS infection without primary or recurrent HSV-1 infection, which is felt to represent reactivation MRI usually detects changes earlier than a of latent HSV in situ within the CNS. CT scan in temporal and/or inferior frontal Patients usually present with headache, fever, lobe. Bilateral temporal lobe involvement is personality changes, memory problems, and nearly pathognomonic. commonly seizures. 136 . Infections of the Nervous System

Figure 15.1. Top row: T2 MRI sequence demonstrating bilateral (R>L) temporal lobe increased signal intensity consistent with Herpes simplex encephalitis. Bottom row: Same patient with T1 post-contrast imaging demonstrating bilateral (R>L) enhancement of temporal lobes.

Treatment um, WNV has been epidemic in the USA with over Acyclovir is the treatment of choice for patients 12,000 cases of meningoencephalitis. Nearly all with HSE, but morbidity and mortality remain human infections of WNV are due to mosquito high. Predictors of an adverse outcome include bites. Peak transmission occurs between July and age older than 30 years, a GCS level of conscious- October, reflecting the seasonal activity cycle of ness <6, and duration of symptoms before start- the mosquito vectors. Persons of all ages are ing acyclovir therapy >4 days. Dosage of acyclovir susceptible to WNV infection, though older and/ in normal renal function is 10 mg/kg intrave- or immunecompromised patients develop a more nously every 8 hours for 14–21 days. Therapy severe disease. Transmission has also been may continue beyond that if patients have not described via blood transfusion, organ transplant, had the appropriate clinical response and the and through transplacental transmission. repeated PCR for CSF is still positive. Most persons infected with WNV are asymp- tomatic, as symptoms are seen in only about 20 to West Nile Virus Infections 40% of infected patients. The illness is character- West Nile virus (WNV) was first isolated in 1937 ized by a flu-like illness with fever, headache, from the blood of a woman with a febrile illness malaise, back pain, myalgias, and anorexia. About who lived in the West Nile region of Uganda. 35% of infected patients develop meningoenceph- Until relatively recently, it was not considered to alitis. Additionally, cranial nerve palsies and an be a significant human pathogen. The virus acute flaccid paralysis, secondary to the infection historically was endemic throughout Africa, the of anterior horn cells, can complicate the disease. Middle East, west and central Asia, and the Medi- The cerebrospinal fluid usually demonstrates a terranean. WNV infection first appeared in North pleocytosis often with a predominance of lym- America in 1999 when an outbreak in New York phocytes as well as an elevated protein concen- City resulted in encephalitis in 62 patients and 7 tration. CSF for IgM is the preferred test with deaths. Since the beginning of the new millenni- positive PCR in less than 60%. 15 Encephalitis: Presentation and Management . 137

Neuroimagings are usually nonspecific, but usually sporadic and small outbreaks occur each MRI may reveal hyperintense T2/FLAIR lesions summer, mostly along the Atlantic and Gulf in the thalamus, substantia nigra and basal gan- coasts. Peak incidence is in August and Septem- glia, spinal cord, and cortical structures. ber. EEE mainly affects children and elderly Treatment persons. The illness usually begins with constitutional Treatment is supportive. symptoms lasting for several days, with fever, headache, nausea, and vomiting. About 8% of St. Louis Encephalitis (SLE) Virus infected people develop encephalitis. Neurologi- SLE virus is widely distributed in the USA and is cal symptoms usually occur abruptly with a ful- the second leading cause of epidemic viral en- minant course. Seizures and focal neurological cephalitis after West Nile virus. The original epi- deficits occur in approximately 90% of patients. demic of the virus occurred in St. Louis, Missouri, Many will become comatose or stuporous. EEE is in 1933 causing 1095 clinical cases. The disease is one of the most severe mosquito-transmitted endemic in the western United States with occa- diseases in the USA with approximately 33% sional large periodic outbreaks in the eastern mortality and significant brain damage in most states, and Central and South America. Trans- survivors. mission is by Culex vector mosquitoes with birds The diagnosis of EEE infections is generally as the intermediate host. SLE occurs during the accomplished by testing serum or CSF to detect summer months and peaks during August and virus-specific IgM and neutralizing antibodies. September. Infection with SLE virus only rarely results in Treatment clinical illness. Age is the most important risk Treatment is supportive factor for symptomatic encephalitis, with elderly persons at higher risk. The disease rarely affects Western Equine Encephalitis (WEE) Virus children. WEE disease is found in North America (west of Prodromal symptoms of a flu-like illness usu- the Mississippi) and South America. Transmis- ally precede the neurological symptoms. Patients sion occurs through mosquito vectors with always experience fever, malaise, myalgia, and birds acting as the reservoir. WEE mainly typically a severe headache. Some patients de- affects children and adults (age >50 years). The velop a cough and a sore throat, while others incidence of the disease is markedly reduced develop dysuria and urgency. Neurological intheUSAsecondarytoequinevaccination, symptoms usually occur rapidly, with tremors of vector control, and the decreased number of eyelids, tongue, lips, and extremities. These may horses. persist for weeks after recovery from the acute Clinical symptoms usually are headache, back- illness. Cranial nerve dysfunction as unilateral ache, altered consciousness, and seizures. facial motor weakness may be present. Motor Diagnosis is by serologic testing with detection and sensory deficits are rare. of IgM in serum and the CSF. The diagnosis of SLE is generally made by serology, particularly the IgM enzyme-linked im- Treatment munosorbent assay (ELISA). Treatment is supportive. Treatment Rocky Mountain Spotted Fever (RMSF) Treatment is supportive. Encephalitis RMSF is a tick-borne disease, and is the most Eastern Equine Encephalitis (EEE) Virus common rickettsial infection in the USA. It is EEE is widely distributed throughout North, Cen- caused by Rickettsia rickettsii, an obligate intracel- tral, and South America and the Caribbean. lular bacterium. RMSF occurs throughout North Transmission is through mosquitoes with birds America, Central, and South America. In the as the reservoir. In the USA, human infections are USA the disease is prevalent in the southeastern 138 . Infections of the Nervous System and south central states. Most cases occur in the Ehrlichiae are obligate intracellular bacteria spring and early summer. Transmission usually that grow within membrane-bound vacuoles in occurs after a tick bite. It may rarely occur after human and animal leukocytes. Transmission is exposure to infective tick tissues or feces, conjunc- through a tick bite with the white-tailed deer tival contamination, transcutaneous transmis- acting as the mammalian reservoir. Other modes sion, or inhalation. Clinical symptoms in the of transmission have been suggested, such as early phase of the disease consist of nonspecific blood transfusion, maternal–child transmission, symptoms like malaise, severe headache, and through direct contact with slaughtered deer. arthralgia. A rash usually develops between the Most cases occur in the summer and the spring. third and fifth day of illness. The rash begins as Common presenting symptoms are fever, maculopapular and becomes petechial. It starts headache, nausea, malaise, anorexia, and, rarely, on the ankles and wrists and spreads centrally a skin rash. CNS involvement is common, to the palms and soles. Neurological symptoms patients may develop confusion, stupor, halluci- occur late in the disease and are often the nation, cranial nerve palsies, and eventually cause of death. A wide variety of neurological seizures and coma. complications has been described, including Peripheral blood counts show leucopenia. cranial nerve palsies, complete paralysis, seizures, Thrombocytopenia and an elevated level of and coma. transaminases are also seen. CSF examination Diagnosis is made usually through clinical fea- often reveals elevated protein and a moderate tures in the appropriate epidemiologic setting. pleocytosis with lymphocytic or neurtrophilic Most patients have normal white blood cell predominance. counts at presentation. As the disease progresses, A diagnosis can be made on finding intraleu- thrombocytopenia becomes more prevalent and kocytic morulae in the peripheral blood or buffy may be severe. CSF analysis usually shows a high coat. Serology can be tested using the indirect white blood cell count with a neutrophilic or fluorescent antibody (IFA) test and reagents spe- lymphocytic predominance, moderately elevated cific for HME and HGA or enzyme-linked immu- protein, and normal glucose levels. The diagnosis nosorbent assays (ELISA). The PCR for HME and is best confirmed using serum for serological HGA is also widely used currently. testing. The indirect fluorescent antibody test has a sensitivity of 95%. Treatment Treatment Treatment should be initiated in all patients suspected of having ehrlichiosis.The drug of As diagnosis of RMSF can rarely be confirmed in choice is doxycycline and treatment should be the early stage, the corner stone of management is continued for 10 days. Patients with a doxycy- empiric antibiotic treatment. Oral or intravenous cline allergy should be treated with Rifampin for doxycycline is the drug of choice, though pregnant 7–10 days. Pregnant women with severe infection women should be treated with chloramphenicol. should be treated with doxycycline, otherwise Treatment should be continued at least for 3 days they can be treated with Rifampin. after the patient has become a febrile.

Human Ehrlichiosis Listeria Monocytogenes Ehrlichiosis is another tick-borne disease, and Listeria monocytogenes is an uncommon cause of the first case of human ehrlichosis was described encephalitis in the general population but is an in 1986. This etiologic agent, which was identi- important pathogen in pregnant patients, neo- fied as Ehrlichia chafeenesis, causes human nates <1 month, elderly individuals greater than monocytic ehrlichiosis (HME). Another agent, 50 years old, and immunocompromised Anaplasma phagocytophilum, which was identi- individuals. fied in 1994, causes human granulocytic anaplas- L. monocytogenes is a motile, nonspore-form- mosis (HGA). ing bacillus that has aerobic and anaerobic 15 Encephalitis: Presentation and Management . 139 characteristics. It is typically a food-borne organ- Noninfectious Causes ism mostly from ingestion of unpasteurized milk Acute Disseminated Encephalomyelitis and can also be found in water and soil. (ADEM) Listeriosis symptoms include fever, headache, ADEM is an inflammatory demyelinating disease nausea, or diarrhea. Infected pregnant women of the CNS which presents with a monophasic may experience only a mild, flu-like illness; how- course associated with multifocal neurologic ever, infections during pregnancy can lead to symptoms and encephalopathy. It usually occurs miscarriage or stillbirth, premature delivery, or after bacterial or viral infection or immunization. infection of the newborn. The most common organisms associated with CNS infection generally develops as a diffuse the ADEM prodrome are Corona virus, CMV, meningoencephalitis, usually associated with Epstein–Barr virus, and Herpes simplex. Neuro- bacteremia. In up to 24% of patients the enceph- logical symptoms typically present 1–3 days after alitis targets the brainstem (rhombencephalitis). infection or immunization and the clinical course Rhombencephalitis was first described in 1957 as can progress rapidly over a few days. Neurologi- an unusual form of listeriosis. It appears to occur cal symptoms vary with the location of the white predominantly in previously healthy patients matter lesions, which can arise anywhere in the without any predisposing conditions. The clinical CNS. The disease usually presents in children and course is usually biphasic, with a prodrome of young adults, occasionally affecting older adults. nonspecific symptoms consisting of headache, Presenting symptoms are frequently headache, malaise, nausea, vomiting, and fever, followed vomiting, change in consciousness and motor by progressive brainstem deficits with asymmet- deficits. Additionally, behavioral changes or psy- ric cranial nerve palsy, cerebellar dysfunctions, chosis can be seen on presentation. In older hemi- or tetraparesis, sensory deficits, respiratory patients, there may be no obvious preceding insufficiency, impairment of consciousness, and infection or vaccination. seizures. Blood and spinal fluid cultures are pos- There is a characteristic pattern of extensive itive in 60 and 40% of patients, respectively. and diffuse hyperintense T2/FLAIR lesions af- The condition is fatal unless treated early. Survi- fecting the brainstem and supratentorial regions vors commonly have significant neurological with relatively small mass effect. Lesions not only sequelae. affect the white matter but also gray matter and Diagnosis is always established by a culture of can cross the midline through the corpus organism from the blood or CSF. The analysis of callosum. CSF shows pleocytosis ranging from polymorph CSF findings are usually nonspecific and nuclear cells to mononuclear cells with a sub- include lymphocytic pleocytosis with elevated stantial number of lymphocytes seen in the CSF. protein levels and sterile cultures. CSF protein is elevated and CSF glucose is reduced. Treatment Treatment is usually with high-dose corticoster- Treatment oids, although no controlled trials have been Listeria is susceptible to common antimicrobial performed. Additionally, there are reports of effi- agents, such as ampicillin, penicillin, gentamicin, cacy of plasmapheresis as well as intravenous and trimethoprim-sulfamethoxazole. Ampicillin immunoglobulins. Mortality is higher in adults or penicillin G is the drug of choice. Gentamicin is than in children. In adults requiring ICU admis- also used to achieve synergy for Listeria CNS sion, mortality ranges between 8 and 25%. infection. The duration of therapy varies, immunocom- Bibliography petent patients with CNS infection are usually Durand ML, et al. Acute bacterial meningitis in treated for 2–4 weeks and immunocompromised adults. A review of 493 episodes. New Engl J patients for 3–6 weeks. Med 1993; 328(1):21–28. 140 . Infections of the Nervous System

McLauchlinJ.HumanlisteriosisinBritain,1967–85, Polage CR, Petti CA. Assessment of the utility of a summary of 722 cases. 2. Listeriosis in non- viral culture of cerebrospinal fluid. Clin Infect pregnant individuals, a changing pattern of Dis 2006; 43(12):1578–1579. infection and seasonal incidence. Epidemiol In- Siegman-Igra Y, et al. Listeria monocytogenes fect 1990; 104(2):191–201. infection in Israel and review of cases world- Mylonakis E, Hohmann EL, Calderwood SB. wide. Emerg Infect Dis 2002; 8(3): Central nervous system infection with Listeria 305–310. monocytogenes. 33 years’ experience at a gen- Tunkel AR, et al. The management of encephali- eral hospital and review of 776 episodes from tis: clinical practice guidelines by the Infectious the literature. Medicine (Baltimore), 1998; 77 Diseases Society of America. Clin Infect Dis (5):313–336. 2008; 47(3):303–327. Part IV Neuromuscular Complications Encountered in the Intensive Care Unit 16 Practical Management of Guillain–Barre Syndrome and Myasthenic Crisis Alejandro A. Rabinstein

Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA

Introduction bear in mind when faced with cases in which the respiratory failure appears to be out of proportion Guillain–Barre syndrome (GBS) and myasthenia to the severity of the systemic disease. gravis (MG) constitute the two most common Once neuromuscular respiratory failure is sus- causes of primary neuromuscular respiratory fail- pected, the next step is to confirm the primary ure in daily practice. They share some character- diagnosis. Characteristic features of GBS and MG istics, including their typically self-limited course will be discussed in the respective following sec- and response toimmune therapies. However,they tions of this chapter. Inability to determine the are also quite different in some important aspects. primary neuromuscular diagnosis is a very strong These differences have crucial practical implica- predictor of poor prognosis, probably because tionsand,therefore,shouldbeknownbyclinicians specific treatment cannot be provided in such caring for these patients. This chapter provides cases. The next step is to search for precipitants succinct and practical information to guide the (e.g. infections, medication changes in myasthe- managementofpatientswithGBSandmyasthenic nics), which should be addressed. These steps crisis in the intensive care unit (ICU). should be accomplished while assessing the ad- Basic Principles of Management equacy of airway safety, ventilation and oxygen- of Neuromuscular Respiratory ation. Systemic complications, such as aspiration Failure pneumonia, atelectasis, and cardiac arrhythmias can occur early and demand prompt diagnosis The diagnosis of primary neuromuscular respi- and treatment. ratory failure should be suspected in any patient presenting with mixed (hypoxic-hypercapneic) or predominantly hypercapneic respiratory fail- SCIENCE REVISITED ure and signs of muscle weakness (bulbar or appendicular). At times, this may be difficult in Neuromuscular respiratory failure can be patients presenting very acutely and in whom a precipitated by bulbar muscle weakness or recent history of progressive weakness is not respiratory muscle weakness. In fact, both available. GBS may be preceded by infections types of muscle weakness are most often and MG can be exacerbated by any acute system- combined. ic illness. These possibilities are important to

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

143 144 . Neuromuscular Complications Encountered in the Intensive Care Unit

Bulbar muscle weakness can lead to airway be regarded as a helpful complement to the obstruction by oral and respiratory secretions clinical examination and arterial blood gases. due to the inefficiency of protective mechanisms, most notably cough. Aspiration can rapidly ac- celerate the clinical decline. Respiratory muscle weakness first produces microatelectases in the Some caveats should be kept in mind when lung bases; the consequent shunting is responsi- performing and evaluating bedside respiratory ble for the mild hypoxia observed early in the tests in patients with acute neuromuscular weak- course of the disease. As weakness becomes more ness. The contributing role of pre-existent or severe due to worsening muscular fatigue, tidal intercurrent pulmonary disease should be con- volumes get progressively smaller and hypercap- sidered when interpreting the results. Tests are nia supervenes. Rapid and profound hypoxia strictly effort-dependent, thus it is crucial to develops shortly thereafter as the compensatory ensure that the patient is providing maximal action of accessory breathing muscles becomes effort during testing. The best of three consecu- overwhelmed. tive measurements should be used to optimize The clinical signs of neuromuscular respiratory reliability. Careful coaching by an experienced failure include dyspnea, tachypnea, restlessness, respiratory therapist is essential before com- tachycardia, diaphoresis (drops of sweat often mencing the test, since repeated suboptimal ef- seen on the forehead), staccato speech, recruit- forts may be misleading due to increasing fatigue. ment of accessory muscles (best objectified by Poor mouth sealing around the spirometer due to palpating the sternocleidomastoid muscles), and, facial weakness may be another cause of de- most importantly, paradoxical breathing pattern. ceivingly poor results and this problem should The paradoxical breathing pattern is character- be noted when present. Suctioning of respiratory ized by the inward (rather than the normal out- secretions should always precede these measure- ward) movement of the abdominal wall with each ments. Finally, any overt discrepancy among inspiration and it is a reliable marker of diaphrag- FVC, MIP, and MEP (e.g. preserved FVC and MEP matic failure. Its presence signifies impending with very poor MIP) measured at the same time respiratory failure and should prompt consider- should alert the physician about the possibility of ation of ventilatory assistance. a spurious result. Apart from the physical examination, the initial Arterial blood gases revealing hypoxia or hy- assessment of patients with acute neuromuscular percapnia should be considered an indication respiratory failure should include bedside testing for intubation in GBS. Myasthenic patients with of respiratory volumes and pressures by spirom- progressive exacerbations might present with etry, measurement of arterial blood gases, and mild hypoxia and compensated hypercapnia. performance of a chest X-ray to exclude pulmo- These patients must be admitted to the ICU and nary complications. often require ventilatory support. The presence of acidosis before the initiation of mechanical ventilation portends a poor prognosis regardless TIPS & TRICKS of the cause of acute neuromuscular respiratory failure. Bedside respiratory tests provide very useful GBS and MG respond to immune therapy with information to assess the initial severity and plasma exchange (PE) and intravenous immu- monitor the evolution of neuromuscular noglobulin (IVIg). In both conditions the early respiratory failure. Forced vital capacity initiation of therapy maximizes the benefit. It is (FVC), maximal inspiratory pressure (MIP, important to realize that the therapeutic effect also known as negative inspiratory force), of these interventions is not immediate when and maximal expiratory pressure (MEP) are discussing expectations with patients and fami- the most valuable and commonly employed lies. The mechanisms of action of PE and IVIg measures. However, they should never be are incompletely understood. Clearing of path- interpreted in isolation; instead, they should ogenic antibodies would be the most obvious 16 Practical Management of Guillain–Barre Syndrome and Myasthenic Crisis . 145

Table 16.1. Adverse events related to plasma exchange and intravenous immunoglobulin Plasma Exchange Intravenous Immunoglobulin Venous catheter-related Infusion-related Infection Headache Pneumothorax Shivering Local hematoma Myalgias Hemodynamic instability (hypotension) Chest pain Hemoconcentration Hyperviscosity (risk of thrombosis, including arterial events) Coagulopathy (mild) Aseptic meningitis Hypocalcemia Renal failure (tubular toxicity) Removal of highly protein-bound drugs Anaphylaxis (if IgA deficiency) property of PE; however, there is only a limited SCIENCE REVISITED correlation between the decrease in anti-acetyl- choline receptor antibody titers and the clinical GBS is typically caused by an autoimmune improvement after PE in MG patients, signaling demyelinating polyradiculoneuropathy (the that other mechanisms of action could also play nosological entity known as acute a role. GBS patients who respond less favorably inflammatory demyelinating to IVIg, however, have lower serum IgG titers polyradiculoneuropathy). A more severe 2 weeks after the infusion, which suggests that axonal form is often preceded by diarrhea the efficacy of IVIg may depend at least in part most frequently provoked by Campylobacter on its ability to achieve sustained elevations in jejuni (because this microorganism can serum IgG levels. trigger an antiganglioside response due to A treatment course of PE typically consists of molecular mimicry). exchanges of 1.5 to 2 liters per session on alter- nate days for a total of 5 exchanges. Lower volume exchanges can be safely performed on The first symptoms of GBS are often back pain consecutive days. The usual recommended and distal leg paresthesias, but the hallmark of dose of IVIg is 400 mg/kg per day for 5 days the syndrome is the rapid development of as- (i.e. total dose of 2 g/kg). However, in patients cending weakness associated with the loss of in whom the anticipated risk from increased deep tendon reflexes. Bulbar weakness usually serum viscosity is not high, administering occurs only after the weakness has progressed 1g/kgIVIgperdayfor2daysappearstobea from the legs to the arms. Yet, severe cases exhibit safe option. bilateral facial weakness, ptosis, ophthalmople- Given the lack of conclusive evidence that one gia, oropharyngeal muscle weakness, and respi- type of immune therapy is better that another for ratory failure. Diaphragmatic failure can develop either GBS or MG, the choice of PE or IVIg is often very suddenly, demanding emergency intuba- based on local preferences and experience and, tion. The other major characteristic of GBS is especially, on the anticipated risk of adverse autonomic dysfunction due to the involvement events in the individual case. Quantitatively, the of autonomic nerves. Cardiac arrhythmias, he- frequency of adverse events with PE is greater modynamic instability, gastroparesis, paralytic than with IVIg. However, this difference is relat- ileus, and bladder retention are the principal ed to complications from the placement of cen- manifestations. Clinical variants of GBS have tral venous catheters. The main adverse events been described; the best known is the Miller related to PE and IVIg are summarized in Fisher variant which features ataxia, arreflexia, Table 16.1. and ophthalmoparesis as its defining triad. 146 . Neuromuscular Complications Encountered in the Intensive Care Unit

The diagnosis of GBS relies on clinical criteria and MEP less than 40 H2O predict supported by electrophysiological and cerebro- requirement of mechanical ventilation spinal fluid changes. The criteria that support the (“20–30–40 rule”). diagnosis of GBS most strongly are progression of symptoms and signs over days to 4 weeks (fluc- tuations or decline after 8 weeks indicates the diagnosis of acute-onset chronic inflammatory Patients with electrophysiological signs of ax- demyelinating polyradiculoneuropathy), sym- onal dysfunction are more susceptible to devel- metric weakness affecting the legs more than the oping respiratory failure. Figure 16.1 delineates a arms (at least initially), mild or absent sensory decision tree for the initial assessment of respi- symptoms and signs, cranial nerve involvement ratory function in patients with GBS. (especially of both facial nerves), increased pro- Overall, one-third of patients hospitalized for tein content in the cerebrospinal fluid without GBS will require mechanical ventilation. In pa- associated cellular reaction (albumino-cytologi- tients with GBS, ventilatory assistance should cal dissociation), and electrophysiological signs always be invasive (i.e. delivered by means of an of impaired nerve conduction, including conduc- endotracheal tube). Noninvasive ventilation with tion blocks, F wave abnormalities, and prolonged a bilevel positive airway pressure (BiPAP) mask is distal latencies. not a safe option in GBS for several reasons: (1) patients who develop diaphragmatic failure usually remain extremely weak and require full CAUTION ventilatory assistance for many days (more than a Any patient suspected of having GBS who week); (2) diaphragmatic failure in GBS is due to presents with rapidly progressive weakness denervation, a situation completely different should be admitted to the ICU. As emergency from MG in which early respiratory insufficiency intubation can induce life-threatening due to fluctuating neuromuscular transmission complications from dysautonomia, it is failure produces a respiratory muscle fatigue that crucial to proceed with elective intubation in can be substantially helped by timely institution patients expected to require ventilatory of noninvasive ventilation; and (3) the manifes- assistance. tations of dysautonomia get worse as respiratory failure becomes more severe. Once patients are intubated, initial ventilation should be delivered using assist-control (AC) to The main clinical factors associated with high- rest the patient. However, switching promptly to er risk of requiring ventilatory assistance are a synchronized intermittent mandatory ventilation fast progression of weakness, the presence of (SIMV) is advisable to avoid diaphragmatic atro- facial and bulbar weakness, and a greater severity phy from disuse. When ventilating with SIMV, of generalized weakness. Serial bedside respira- adequate pressure support and positive end-ex- tory measurements also provide reliable infor- piratory pressure (PEEP) should be provided. mation to predict which patients with GBS will Daily bedside respiratory measurements may be require mechanical ventilation. useful to monitor the evolution of respiratory muscle weakness. It is crucial to ensure that the TIPS & TRICKS patient receives adequate chest physiotherapy to prevent pulmonary complications. Admission FVC or a decrease in FVC to less The main manifestations of dysautonomia in than 20 mL/kg, or a reduction in FVC, MIP, or GBS are listed in Table 16.2. It is very important to MEP greater than 30% from the baseline keep these in mind when prescribing medica- should be considered indications for ICU tions. Beta blockers should be used very cau- monitoring and possible elective intubation. tiously because they can provoke sudden hypo- In addition, the combination of FVC lower tension and bradycardia. When blood pressure is than 20 mL/kg, MIP worse than 30 cm H2O, very elevated, we prefer to use other options 16 Practical Management of Guillain–Barre Syndrome and Myasthenic Crisis . 147

Figure 16.1. Proposed algorithm for the initial evaluation of respiratory function in patients with GBS.

(such as hydralazine or nicardipine), always start- ferred. Treatment of gastroparesis and adynamic ing at low doses. Hypotensive spells frequently ileus is challenging because metoclopramide and respond to fluid boluses; when vasopressors are neostigmine can induce dangerous arrhythmias administered, low initial doses are again pre- in GBS patients. Unless it is unsafe because of very high gastric residuals and severe abdominal distension, enteral feeding should be continued. If enteral feeding needs to be decreased or Table 16.2. Main features of stopped, parenteral feeding should be started dysautonomia in GBS without delay to prevent malnutrition. We initi- Labile blood pressure ate antineuropathic pain medications early and . Hypertension prefer those with antidepressant action since . Hypotension depression is a very common complication in Cardiac arrhythmias these patients with severe weakness from GBS. . Tachycardia Immune therapy with PE or IVIg is considered . Bradycardia the standard of care in patients with GBS and it . AV blocks should be ideally initiated within 2 weeks of . Asystole symptom onset. Gastroparesis There is indirect evidence that higher doses of Adynamic ileus IVIg (i.e. more than the usual total dose of 2 g/kg) Bladder dysfunction could be justified in patients with severe GBS. . Retention Studies have shown that corticosteroids are not . Incontinence useful in GBS and the administration of high Neuropathic pain doses of intravenous corticosteroids is associated AV ¼ atrioventricular with increased systemic complications. 148 . Neuromuscular Complications Encountered in the Intensive Care Unit

The mortality rate of severe GBS causing neu- phonium). Decremental response with repetitive romuscular respiratory failure may still reach nerve stimulation is the electrophysiological hall- 5–10%. In addition, 20% of survivors may suffer mark of the disease. Increased jitter is seen in from long-term disability. Markers of poorer single-fiber electromyography. prognosis include older age, axonal changes on Although frequently used to monitor the pro- electrophysiological studies, diarrhea at onset gression of weakness in patients with myas- (seen commonly in axonal forms), and degree of thenic crisis, the value of pulmonary function disability at 2 weeks. However, young patients tests in MG is much less well established than in may recover fully even if they develop extremely GBS. The fluctuating nature of weakness in severe weakness with prolonged requirement patients with MG may render serial spirometric for mechanical ventilation. The most common measurements more variable and unpredict- residual symptoms are fatigue, mild distal able. In addition, the weakness of bulbar and paresthesias, and weakness. facial muscles is often a predominant feature early in the course of a myasthenic crisis. In these cases, testing may become impractica- Myasthenic Crisis ble because of insufficient mouth sealing. Fur- thermore, patients with impaired swallowing SCIENCE REVISITED and a weak cough may become unable to clear their secretions and require intubation for air- MG is a neuromuscular transmission way protection before they develop frank respi- disorder most often caused (except for some ratory muscle weakness. rare genetic forms) by an autoimmune reaction that interferes with the activation of the post-synaptic muscle fiber. TIPS & TRICKS

Prompt initiation of noninvasive ventilation In the majority of cases the mediators of this with the BiPAP mask may avert the need for autoimmune disease are antibodies against the endotracheal intubation in patients with acetylcholine receptors; when these antibodies respiratory insufficiency from MG. This is the are present the cases are categorized as seroposi- best strategy to treat failing MG patients and tive. Other autoantibodies can be observed in should be combined with administration of MG, most notably antimuscle specific tyrosine PE or IVIg very shortly after admission. kinase (MuSK) antibodies. Patients with anti- MuSK antibodies tend to have a more severe bulbar weakness and they appear to be at in- Even patients with severe bulbar weakness can creased risk of developing myasthenic crisis. tolerate noninvasive ventilation as long as they MG is clinically characterized by fluctuating receive diligent respiratory care with frequent weakness and fatigability with the early involve- suctioning of oral and respiratory secretions. In ment of facial and bulbar muscles. Consequently, fact, patients who are successfully treated with a worsening weakness in the late afternoon and BiPAP have less pulmonary complications (atel- evening, ptosis, diplopia, and nasal voice (from ectasis and pneumonia) than those who get di- oropharyngealmuscleweakness)areconspicuous rectly intubated. However, it is crucial to start features. Patients presenting with MG exacerba- noninvasive ventilation with BiPAP early; once tion or crisis typically have a history of worsening patients are already hypercapneic, the rate of weakness over the preceding days. Common trig- BiPAP success diminishes markedly. Figure 16.2 gers of these exacerbations include infections and illustrates a management strategy for patients medication changes. with MG exacerbation/crisis evaluated in the The diagnosis of MG can be confirmed by Emergency Department. serology, electrophysiology, or a therapeutic trial When patients are intubated, the general prin- with a cholinesterase inhibitor (most often edro- ciples of ventilation and chest physiotherapy 16 Practical Management of Guillain–Barre Syndrome and Myasthenic Crisis . 149

Figure 16.2. Proposed algorithm for the early management of patients with myasthenic exacerbation/crisis.

previously discussed for GBS also apply for MG. anti-inflammatory/immunosuppressant drugs, As gradual weaning proceeds, it is advisable to and cholinesterase inhibitors. avoid reaching muscle fatigue. Cholinesterase inhibitors (usually oral pyridos- tigmine, but parenteral neostigmine can be pre- scribed when the enteral route is not safe, such as CAUTION in the rare cases of concurrent gastrointestinal bleeding or recent abdominal surgery) can be Extubation may fail in up to one-quarter of transiently discontinued after intubation to min- MG patients. Presence of atelectasis is imize the production of respiratory secretions, strongly associated with extubation failure. but should never be stopped when the patient is being treated with noninvasive ventilation and should always be restarted in adequate doses Noninvasive support with BiPAP may be ex- before weaning is initiated. If oral and respiratory tremely useful to prevent reintubation. BiPAP secretions are excessive, low doses of atropine, should be initiated immediately if patients have glycopyrrolate, or scopolamine can be safely any signs of even mild respiratory insufficiency administered. shortly after extubation. Otherwise patients may The ideal form of administration of corticos- be closely watched, but it is prudent to have them teroids (oral versus intravenous, optimal dose) in wear the BiPAP mask the first night after extuba- myasthenic exacerbation/crisis is not well estab- tion as this is the critical time when most patients lished. As a principle, all these patients should fail – due to loss of muscle tone during REM sleep receive corticosteroids. However, caution should – and require reintubation. be exercised when considering the prescription The pharmacological treatment of myasthenic of high-dose intravenous methylprednisolone crisis should include immunomodulatory agents, in nonintubated patients because one-third to 150 . Neuromuscular Complications Encountered in the Intensive Care Unit one-half of patients will experience a clinically ed clinical course. The most common systemic meaningful exacerbation of weakness within complications are atelectasis, pneumonia, days of starting this treatment. Although daily diarrhea, and venous thromboembolism. Re- dosing of prednisone (with a usual initial dose current crises are not uncommon; close of 1 mg/kg of ideal body weight) is necessary at outpatient monitoring and adequate pharma- first, it is advisable to switch to alternate day cological management, including immunosup- dosing whenever feasible to reduce the risk of pressive therapy, are necessary to prevent their side effects. It is also reasonable to start a steroid- occurrence. sparing immunosuppressant (such as azathio- prine) during acute hospitalization to facilitate Bibliography an earlier reduction in steroid dose and to reduce Cabrera Serrano M, Rabinstein AA. Causes and the risk of recurrent crises. All patients receiving outcomes of acute neuromuscular respiratory high-dose corticosteroids should also receive failure. Arch Neurol 2010; 67(9):1089–1094. gastric protection to avoid peptic ulcers. Fletcher DD, Lawn ND, Wolter TD, Wijdicks EF. Long-term outcome in patients with Guillain– Barre syndrome requiring mechanical ventila- EVIDENCE AT A GLANCE tion. Neurology 2000; 54(12):2311–2315. Administration of PE or IVIg is considered Gajdos P, Chevret S, Toyka K. Plasma exchange standard of care for patients with myasthenic for myasthenia gravis. Cochrane Database Syst crisis. These immunomodulatory strategies Rev 2002; 4:CD002275. have been shown to improve the muscle Gajdos P, Chevret S, Toyka K. Intravenous im- strength in patients with MG exacerbations munoglobulin for myasthenia gravis. Cochrane and to reduce the risk of post-operative crisis Database Syst Rev 2008; 1:CD002277. when administered presurgically. However, Hiraga A, Mori M, Ogawara K, et al. Differences in they have never been specifically tested in patterns of progression in demyelinating and myasthenic crisis (i.e. not specifically in axonal Guillain–Barre syndromes. Neurology patients with neuromuscular respiratory 2003; 61(4):471–474. failure due to MG) and there is no proof that Hughes RA, Swan AV, van Doorn PA. Intravenous they shorten the duration of mechanical immunoglobulin for Guillain–Barre syndrome. ventilation. Cochrane Database Syst Rev 2010; 6:CD002063. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokinetics of intravenous immuno- In the only randomized-controlled trial that globulin and outcome in Guillain–Barre syn- compared PE versus IVIg in MG patients, the drome. Ann Neurol 2009; 66(5):597–603. efficacy of both treatments was similar and both Lawn ND, Fletcher DD, Henderson RD, et al. were safe, although IVIg was slightly better Anticipating mechanical ventilation in tolerated. The choice of immunomodulatory Guillain–Barre syndrome. Arch Neurol 2001; modality typically depends on local preference 58(6):893–898. and experience. There is a lack of evidence that Rabinstein AA, Wijdicks EF. Warning signs of combining PE and IVIg confers any additional imminent respiratory failure in neurological benefit. patients. Semin Neurol 2003; 23(1):97–104. The outcome of myasthenic crisis has im- € proved over the decades due to refinements in Raphael JC, Chevret S, Hughes RA, Annane D. critical care and, perhaps, the advent of better Plasma exchange for Guillain–Barre syn- immune therapies. Mortality in recent series is drome. Cochrane Database Syst Rev 2002; 2: lower than 5%. Still, ICU admissions spanning CD001798. 10–14 days are the norm if patients require Seneviratne J, Mandrekar J, Wijdicks EF, Rabin- intubation. Only those treated successfully stein AA. Noninvasive ventilation in myasthen- with BiPAP have a shorter and less complicat- ic crisis. Arch Neurol 2008; 65(1):54–58. 16 Practical Management of Guillain–Barre Syndrome and Myasthenic Crisis . 151

Seneviratne J, Mandrekar J, Wijdicks EF, Rabinstein van Koningsveld R, Steyerberg EW, Hughes RA, AA. Predictors of extubation failure in myasthenic et al. A clinical prognostic scoring system for crisis. Arch Neurol 2008; 65(7):929–933. Guillain–Barre syndrome. Lancet Neurol 2007; Thomas CE, Mayer SA, Gungor Y, et al. Myas- 6(7):589–594. thenic crisis: clinical features, mortality, com- Walgaard C, Lingsma HF, Ruts L, et al. Prediction plications, and risk factors for prolonged intu- of respiratory insufficiency in Guillain–Barre bation. Neurology 1997; 48(5):1253–1260. syndrome. Ann Neurol 2010; 67(6):781–787. Part V Neurological Complications and Consultations in General Intensive Care Units 17 Metabolic Encephalopathies Edward M. Manno

Neurological Intensive Care Unit, Cleveland Clinic, Cleveland, OH, USA

Introduction in the intensive care unit can be broad ranging from a mild delirium to coma. As this chapter is Metabolic encephalopathies are disorders of limited in context, the discussion will be limited brain function that do not have a structural to the description of delirium and the more com- source. They represent a group of entities that monly encountered encephalopathies attributed lead to neurological deterioration through a vari- to sepsis and hepatic failure. ety of mechanisms; however, their diagnosis is crucial in differentiating deterioration due to structural causes from more global disturbances Delirium seen with diffuse encephalopathies. Encephalop- Delirium is described as a fluctuating disturbance athies encountered in the intensive care unit are inconsciousnesscharacterizedbyimpairedatten- problematic and are associated with increased tion and disorganized thinking. The Diagnostic mortality and long-term cognitive deficits. The and Statistical Manual of Mental Disorders (DSM) terminology “metabolic encephalopathy” is anti- 4th edition of the American Psychiatric Associa- quated and probably too limited to encompass tion defines delirium as an acute disturbance of the scope of cognitive difficulties encountered in consciousness with an impairment in cognition, the modern-day intensive care unit. The syn- attention, or perception. The disturbance cannot dromes of acute cerebral dysfunction have been beaccounted forby ageneral medical condition or housed under a number of terminologies and a pre-existing dementia. include acute confusional state, ICU psychosis, Hyperactive, hypoactive, and the mixed forms organic brain syndrome or failure, and cerebral of delirium that have been described are based insufficiency. Newer terminologies have been on the behavioral pattern of psychomotor activi- proposed such as “critical illness brain ty. Hyperactive patients may be agitated and syndrome” or “critical illness associated cogni- combative while hypoactive patients may appear tive dysfunction”. All of these conditions have an calm and appropriate. The latter are subsequent- acute onset, deterioration in consciousness, and ly underdiagnosed unless a thorough mental cognitive function, and an underlying metabolic status examination is performed. The frequency or structural etiology that can distinguish these and significance of these subtypes is incomplete- disorders from psychiatric illness. Specific termi- ly characterized, however there is growing evi- nology such as “metabolic encephalopathy” pre- dence to suggest that patients with the hypoac- sumes a known etiology. The spectrum of cogni- tive form of delirium may have worse cognitive tive difficulties or encephalopathies encountered outcomes.

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

155 156 . Neurological Complications and Consultations in General Intensive Care Units

A number of clinical tools have been developed infecting organism. A more appropriate term to detect and monitor delirium in critical care may be sepsis-associated encephalopathy or de- patients. The Confusion Assessment Method for lirium. Since the encephalopathy is a conse- the Intensive Care Unit (CAM-ICU) and the Inten- quence of systemic inflammation, some authors sive Care Delirium Screening Checklist (ICDSC) have advocated the term “systemic inflammatory are the best validated against the DSM criteria. A response encephalopathy”. recentcomparisonsuggestedincreasedsensitivity Whatever terminology is used, acutely ill pa- and a negative predictive value of the CAM-ICU. tients with an encephalopathy have worse out- Delirium is reported in as many as 90% of comes. Outcome appears to parallel the severity critically ill patients, depending upon the clinical of the encephalopathy, which can be quantified assessment used. Most patients that are mechan- on EEG monitoring. Mild encephalopathies are ically ventilated will have some period of deliri- reversible but more recent findings of long-term um. The consequences of delirium in the ICU are neuropsychological changes after sepsis argue significant. It is associated with increased mor- for more permanent structural neuronal damage. tality, length of stay, and unplanned catheter Pathophysiology removal and extubation. Management focuses on the treatment of the The exact etiology of this sepsis or inflammatory- underlying diseases or physiological distur- associated encephalopathy remains speculative. bances, and treatment of symptoms. Prevention However, experimental evidence suggests that strategies have been developed in an attempt to inflammatory mediators, either directly or indi- minimize factors that appear to exacerbate the rectly, affect neurological function. Systemic and risk of worsening delirium. These include reori- visceral inflammation is detected by vagal affer- entation of the patient, early mobilization, re- ents through their axonal cytokine receptors. moval of catheters and physical restraints, sleep These afferents terminate in the nucleus tractus enhancement protocols, and the provision of solitarius which modulate baroreflexes and con- eyeglasses and hearing aids. These nonpharma- nect to the paraventricular nuclei of the hypo- cologic measures have proved useful in the short thalamus. The circumventricular organs lacking a term; however, the long-term impact on morbid- blood–brain barrier are similarly exposed to in- ity and mortality is unclear. flammatory cytokines. The response of these ex- Benzodiazepines and opioids are thought to posed centers is an induction and escalation of worsen delirium and are generally avoided or at other inflammatory mediators, including inter- best minimized during sedation of the critically ill leukins 2, 1b, 6, and tumor necrosis factors. patient. The exception is obviously benzodiaze- Inflammatory mediators can directly affect pinewithdrawal.Thepreferredagentsareantipsy- neurological function. Prostaglandins released chotic agents: Haldol has been advocated for its during this process can directly interfere with efficacy and safety profile, and magnesium re- neurotransmission and decrease the release of placement should be adequate in patients receiv- neurohormones. Specifically, prostaglandins, cy- ing Haldol. Serial electrocardiograms monitoring tokines, and nitric oxide can directly modulate the QT interval should be followed. Torsades de cholinergic transmission and the secretion of pointes has been reported with higher doses of corticotrophic-releasing hormone, ACTH, and Haldolandasmallbutgrowingbodyofliteratureis vasopressin. suggesting that continuous sedation with dexeto- Inflammatory mediators will greatly increase midate may be preferable to benzodiazepines or the oxidative stress encountered by neurons dur- propofol in the prevention of delirium. ing sepsis and can lead to apotosis. This has been documented in the highly metabolic brain regions Septic Encephalopathy of the hippocampus and cortex in septic rats. Septic encephalopathy refers to the encephalop- Similarly, mitochondrial dysfunction through im- athy encountered in the acutely ill or septic pa- pairment of mitochondrial respiratory chain en- tient. The terminology is imprecise since less zymes has been induced by nitric oxide in the than half of patients will have an identifiable medullary autonomic centers of a septic rat. 17 Metabolic Encephalopathies . 157

The escalation of inflammatory mediators can Magnetic resonance imaging of the brain is the also lead to the disruption of the blood–brain most useful imaging modality in sepsis. Case barrier, subsequently exposing the internal milli- reports have documented subtle infarctions in eu of the brain to neurotoxic substances. In a rat the basal ganglia and other highly metabolic and pig model of sepsis, microvessel edema re- brain regions. Diffusion imaging has been used sulted in the displacement of astrocytic foot pro- to detect cerebritis and early changes for the cesses from the vasculature. This can possibly posterior reversible encephalopathy syndrome. account for the development of the cerebral ede- Treatment ma commonly found in the septic patient. Blood– brain barrier disruption and alterations in the No specific treatment exists for the encephalop- astrocytic foot process may account for the path- athy associated with critical illness. The treat- ological findings of microhemorrhages and the ment for this inflammatory mediated encepha- clinical presentation of posterior reversible lopathy is treatment of the underlying illness. encephalopathies. Inhibition of nitric oxide reduces lipopolysaccha- The encephalopathy encountered during sep- ride-induced neuronal apotosis in a rat model of sis rarely occurs in isolation. Multi-organ dys- sepsis. Calcium channel blockers and the remov- function is common and an alteration in other al of circulating cytokines through plasma filtra- organ functions can lead to electrolyte distur- tion have been proposed. Various antioxidants bances and hypoglycemia. Ischemia secondary have been used in experimental models to reduce to hypotension is common. Cerebral autoregula- the cerebral edema associated with sepsis. tion can be maintained or can be severely affect- All treatments, however, remain experimental. ed. PET studies, however, suggest that decreased cerebral perfusion is matched to decreased cere- Hepatic Encephalopathy bral metabolism. Hepatic encephalopathy refers to the neuropsy- chiatric abnormalities that develop in chronic Clinical Features liver disease. It is also the principal feature of The encephalopathy attributed to inflammation fulminant hepatic failure. The encephalopathy appears to affect the cerebral hemispheres bilat- can be classified on the basis of the underlying erally. This nonfocal encephalopathy can range etiology of the hepatic failure. The World Con- from mild agitation and/or delirium to coma. gress of classified type A as Cranial nerve examination reveals small mini- being attributed to acute liver failure, type B to mally reactive pupils. Brainstem reflexes remain portosystemic bypass, and type C as chronic or largely intact. Roving conjugate eye movements persistent due to cirrhosis or portal hypertension. are common. Neurological findings are symmet- The encephalopathy can be further categorized rical and focal findings should prompt an inves- by the severity of the encephalopathy and neu- tigation for a structural cause. rological findings. Morbidity and mortality are EEG findings parallel the depth of the enceph- directly related to the severity of the encephalop- alopathy. Mild slowing is followed by progression athy. The West Haven criteria for classification of to theta and delta waves; and burst suppression the encephalopathy attributed to hepatic failure patterns have an ominous prognosis. Somato- is listed in Table 17.1. sensory-evoked potentials are not affected by Pathophysiology sedation but have limited utility in the septic patient. The pathologic changes in hepatic encephalopa- The plasma levels of biomarkers (neuron-spe- thy have been well described. Pathologically, cific enolase, S-100B) have been studied in sepsis there is a direct increase in the number and size but the sensitivity and specificity for detecting of protoplasmic astrocytes found predominantly brain dysfunction and morbidity are poorly char- in the deep layers of the cortex, thalamus, sub- acterized. Cerebral spinal fluid analysis is re- stantia nigra, and pontine nuclei. The degree of served for patients where meningitis is a glial abnormalities appears to parallel the inten- consideration. sity and duration of the illness. These swollen 158 . Neurological Complications and Consultations in General Intensive Care Units

Table 17.1. West Haven criteria for ing the effects of diets rich in branched chain altered mental status in hepatic amino acids on hepatic encephalopathy have encephalopathy been inconsistent. The GABA benzodiazepine Grade 0 Minimal hepatic encephalopathy, theory suggests that endogenously produced lack of detectable changes in per- benzodiazepines (probably from gut microor- sonality or behavior; no asterixis. ganisms) during liver failure account for the Grade 1 Trivial lack of awareness, short- encephalopathy. Pathologically, serum and CSF ened attention span, sleep distur- from animals with liver failure inhibit binding of bance, altered mood, and slowing benzodiazepines in cortical preparations. Simi- the ability to perform mental tasks; larly, human CSF chromatography and postmor- asterixis may be present. tem brain samples have revealed several benzo- Grade 2 Lethargy or apathy, disorientation diazepine-like substances that act as ligands. to time, amnesia of recent events, These are markedly increased in autopsied sam- impaired simple computations, ples of patients with hepatic encephalopathy. inappropriate behavior, and The ability of benzodiazepine antagonists to slurred speech; asterixis is present. reverse the encephalopathy has also been Grade 3 Somnolence, confusion, disorien- inconsistent. tation to place, bizarre behavior, The most recent theory suggests that that in- clonus, nystagmus, and positive tracytoplasmic glutamine is necessary for the Babinski sign; asterixis usually development of cerebral edema and the subse- absent. quent encephalopathy. Glutamine synthetase Grade 4 Coma, lack of verbal, eye, and oral has a high affinity for ammonia and is found response to stimuli. almost exclusively in astrocytes. Glutamine is subsequently formed from glutamate and am- monia. Intracellular concentration directly cor- astrocytes display enlarged nuclei with displaced relates with intracranial hypertension and CSF chromatin and are labeled Alzheimer type II glutamine levels highly correlate with the degree astrocytes. of the encephalopathy. Intracellular glutamine is There have been many theories to explain the believed to affect the brain glucose metabolism encephalopathy encountered with hepatic fail- and lead to the development of intracellular os- ure. The direct neurotoxic role of ammonia was moles. In vitro studies have also revealed that forwarded in the 1950s when patients using am- elevated intracellular ammonia can increase the monia-cation resins exchange resins as diuretics mitochondrial membrane permeability. Gluta- were found to develop an encephalopathy and mine can subsequently enter the mitochondria EEG changes that were remarkably similar to and disassociate into glutamate and ammonia. those seen in patients with hepatic failure. Evi- Intramitochondrial ammonia will then directly dence supporting this contention has been sub- increase the production of free radicals and im- stantial but this theory fell into disfavor as direct pair the oxidative energy production. This correlation of the encephalopathy with ammonia “Trojan horse” hypothesis speculates that intra- levels were lacking. The observation of increased cytoplasmic glutamine allows the entry of am- production aromatic amino acids in liver disease monia into the mitochondria. raised speculation that the formation of false Other theories that may be involved with neurotransmitters may account for the encepha- the development of the encephalopathy include lopathy. This theory has been supported by the alterations in brain proteins, increases in inflam- finding of increased levels of octopamine – an matory mediators, and increases in the blood– end product of aromatic amino acid metabolism brain barrier permeability attributed to ammonia. – in the CSF of patients with hepatic encepha- Clinical Presentation lopathy. However, octopamine directly injected into the CSF of animals does not produce an The majority of patients in fulminant hepatic encephalopathy. Similarly, clinical trials evaluat- failure will be unconscious and display evidence 17 Metabolic Encephalopathies . 159 for cerebral edema. The progression from a grade and loss of oculomotor reflexes is a late and I to a grade IV encephalopathy may be rapid in ominous sign. the fulminant form of hepatic failure, however Evaluation and Testing more chronic conditions will present with a slower and fluctuating course. Systemic findings in hepatic failure include spi- The encephalopathy due to chronic hepatic der nevi, signs of portal hypertension, enlarged or failure is variable and relapsing. Initially, patients shrunken livers, fetor hepaticus, and palmar ery- present with mild disturbances in consciousness thema. An evaluation for the source of hepatic manifested by subtle changes in cognitive func- failure should be undertaken if the underlying tions, and personality. Worsening delirium and etiology for this is unknown. lethargy occur as the encephalopathy progresses. Laboratory studies in liver failure reveal an Interestingly, the irritability and restlessness seen increase in serum bilirubin, and transaminases in the early stages of fulminant hepatic encepha- (although the latter may not be elevated in severe lopathy is not seen in the more chronic condition. cirrhosis). A chronic respiratory alkalosis pre- Repeated bouts of hepatic failure can lead to sumably from the direct effect of gut peptides dementia. Seizures are rare. Fluctuating neuro- on the medullary respiratory centers is also com- logical signs are common in acute liver failure. mon. The most sensitive measure to assess the Asterixis, an intermittent relaxation of increased functional degree of hepatic disturbance is the extensor tone, is a common sign. Historically, this coagulation profile. In liver failure the prothrom- was believed to be pathopneumonic for hepatic bin time, thrombin time, and partial thrombo- failure but is now known to be a relatively non- plastin times are elevated due to inadequate specific sign. Frontal release signs are common. synthesis of several coagulation factors. Platelet Parkinsonian rigidity may be seen but paratonia counts are typically under 100,000 and display is more common. The cranial nerves are gener- impaired function. In fulminant hepatic failure ally spared. Cerebellar signs, such as ataxia cere- the serum glucose can drop precipitously. bellar speech, dysarthria, ocular bobbing and In these circumstances renal failure can occur. dysconjugate gaze, are not uncommon. Clinical outcome in hepatic failure correlates highly with the depth of the encephalopathy. An EEG is capable of monitoring the progression TIPS & TRICKS of mental status changes although a quantitative EEG may be more sensitive. EEG findings mirror Metabolic encephalopathies generally the encephalopathy with the EEG initially dis- present with evidence for global cerebral playing mild diffuse slowing. As the encephalop- hemispheric dysfunction. Focal athy progresses, triphasic waves appear which neurological signs are not found with are followed by diffuse delta wave activity. Burst most encephalopathies. Hepatic suppression is seen in coma. encephalopathies are the exception, where The P300 response to an auditory stimulus is focal signs may be present perhaps due to the helpful in detecting early changes in mental sta- involvement of cerebellar or deep gray tus although other brainstem- and somatosenso- matter.These findings, however, should ry-evoked responses are less helpful. prompt an investigation for a structural Computed tomography (CT) can evaluate for source. intracerebral or subdural hemorrhages. A grading system has been developed to evaluate the degree of cerebral edema detected on CT that occurs in Fulminant liver failure presents with an agitat- fulminant hepatic failure but direct correlation to ed delirium that can progress rapidly to coma. intracranial pressure has failed. The globus pal- Seizures can occur in this syndrome, but may be lidus in cirrhosis can show a reversible signal related to hypoglycemia. Early coma is generally change on the T1-weighted MRI. The significance accompanied by hyperreflexia, which may disap- of this remains questionable, as this does not pear as the coma deepens. Decerebrate posturing appear to correlate with the encephalopathy. 160 . Neurological Complications and Consultations in General Intensive Care Units

Similarly, increased changes in cerebral white an improvement in the mental status is seen. matter can be detected with FLAIR imaging. This Electrolyte changes will need to be followed and may reflect the early development of cerebral corrected. Use can be limited by abdominal edema. These changes are reversible with im- symptoms. provement in liver failure. MR spectroscopy and Antibiotics reduce the intestinal production of other MR techniques are active areas of research ammonia by decreasing the urase-producing in the evaluation of acute liver failure. bacteria. Neomycin and metronidazole are the main treatments despite little evidence to sup- Treatment port any long-term improvement with their use. The initial treatment for neurological worsening Neomycin is given orally 1–4 g daily for chronic in liver failure is to identify and correct any hepatic encephalopathy. Dosing for acute liver precipitating factors. This may include new in- failure is 1–2 g every 4–6 hours. Its long-term use fections, medical noncompliance with medica- is limited by renal and ototoxicity. Metronidazole tions or dietary restrictions, gastrointestinal dosing is 250 mg orally every 12 hours. bleeding, the use of sedative of analgesic medica- The use of Rifaximin has increased in recent tions or electrolyte disturbances. years. It may be as effective as other antibiotics with a better safety profile. It is a nonabsorbable derivative of rifamycin with antimicrobial activity TIPS & TRICKS against aerobic and anaerobic Gram-negative and positive bacteria. It appears to be as effective Even very small doses of benzodiazepines can as lactulose and other antibiotics. Combined have a profound and prolonged effect in treatment has not been effectively studied. patients with hepatic failure. This may be L-ornithine and L-aspartate are amino acid secondary to the prolonged clearance of supplements which may increase the conversion these medications, but endogenous of ammonia to urea and glutamine. A meta-anal- benzodiazepines may themselves partially ysis of three studies suggested an improvement account for the encephalopathy. If Flumazenil in the encephalopathy and ammonia levels in is used (a benzodiazepine antagonist) it patients treated with L-ornithine and L-aspar- should be used with EEG monitoring. Several tate. This treatment may be helpful in patients cases of subclinical status have been reported that do not respond to lactulose. with its use in hepatic encephalopathy. In Other treatments that have been studied have addition, subclinical improvement in EEG limited information as to their effectiveness. Zinc patterns may be detected. supplementation and probiotic diets may help in mild encephalopathies. Branched chain amino acids are best given enterally. Liver support de- The pharmacologic treatment for hepatic en- vices incorporating extracorporeal albumin dial- cephalopathy centers on decreasing the ammo- ysis, or molecular adsorbent recirculation sys- nia production and uptake as well as facilitating tems, are used as a bridge to transplantation. its elimination. Lactulose or lacitol are nonab- sorbable disaccharides which facilitate the Treatment of Cerebral Edema movement of ammonia from the portal circula- tion to the colon; they also interfere with the in Fulminant Hepatic Failure uptake of glutamine from the intestinal mucosa Cerebral edema occurs in approximately 75% of and lead to gut acidification which will result in patients with Grade 4 hepatic encephalopathy. the suppression of the formation of ammonia Complications secondary to intracranial hyper- from gut bacteria. The laxative effect will addi- tension and decreased cerebral perfusion ac- tionally lower gut ammonia levels. Dosing is 15– count for the significant morbidity and mortality 45 mL orally 2 to 4 times a day and is titrated to 3 encountered with this condition. or 4 bowel movements a day. Rectal administra- The treatment of elevated intracranial pressure tion (300 mL) can be given every few hours until canbeparticularly problematicinthis population. 17 Metabolic Encephalopathies . 161

Invasive monitoring of intracranial pressure has þ NH4 , however the unprotonated form of the become common practice despite little support- ion (NH3) is permeable to the blood–brain ing evidence barrier. The alkalosis induced by hyperventilation will favor the formation of the unprotonated form of the ion and thus CAUTION may facilitate ammonia entry into the brain.

The placement of intracranial pressure monitoring devices can be difficult in the The definitive treatment for cerebral edema is patient with hepatic failure. The international transplantation, where remarkable recoveries normalized ratio must be corrected and have been reported even in dire circumstances. platelets may need to be given prior to insertion. Even with these precautions, bleeding complications can develop. Bibliography Obviously, close monitoring of the patient is Iacobone EI, Bailly-Salin J, Polito A, et al. Sepsis- essential. associated encephalopathy and its differential diagnosis. Crit Care Med 2009; 37(Suppl): S331– S336. Hyperventilation has not proved to be an ef- Manno EM. Evaluation and treatment of the fective method to treat intracranial hypertension patient with toxic-metabolic encephalopa- in hepatic failure. The mainstay of treatment has thies. In: Textbook of Neurosurgery ( Batjer H, been osmotic therapy. Mannitol of hypertonic Loftus C, eds). Lippincott-Raven Publishers, saline solutions may be given to increase the 2002: pp. 259–267. serum osmolality of the patient. Mild hypother- Maramattom BV. Sepsis associated encephalop- mia has many theoretical benefits to treating athy. Neurol Res 2007; 29:643–646. intracranial hypertension in acute liver failure, Siami S, Annane D, Sharshar T. The encephalop- and preliminary data has been promising. Barbi- athy in sepsis. Crit Care Clin 2008; 24:67–82. turates have been used historically but can com- plicate the diagnosis of brain death should the Stevens RD, Pronovost PJ. The spectrum of en- patient deteriorate despite treatment. cephalopathy in critical illness. Semin Neurol 2006; 26:440–451. Sudaram V, Shaikh OS. Hepatic encephalopathy: SCIENCE REVISITED Pathophysiology and emerging therapies. Med Clin N Am 2009; 93:819–836. The failure of hyperventilation to lower Vaquero J, Butterworth RF. Mechanisms of brain intracranial pressure in hepatic failure may edema in acute liver failure and impact of novel be attributed to the state of the ammonia ion. therapeutic interventions. Neurol Res 2007; Ammonia circulates in the plasma as an ion 29:693–690. 18 Delirium and Sedation in the ICU Jennifer A. Frontera

Neuroscience Intensive Care Unit, Departments of Neurosurgery and Neurology, Mount Sinai School of Medicine, New York, NY, USA

Epidemiology of Delirium used interchangeably with “acute confusional state” or “encephalopathy” and represents a clus- Delirium is a descriptive term defined in DSM IV ter of different etiologies. Despite differing, or as a fluctuating level of attentiveness with a sometimes multifactorial, causes patients with reduced ability to focus, sustain, or shift atten- delirium all have a disruption in attention and tion. Fluctuations in levels of consciousness an- arousal centers of the brain. The ascending retic- d/or behavioral disturbances develop rapidly ular activating system (ARAS), stretching from (over hours to days) and are not accounted for the midpontine tegmentum to the anterior cin- by a pre-existing dementia. Additionally, there gulate, is primarily responsible for arousal and must be evidence that the disturbance is caused attentiveness. The ARAS receives widespread in- by a medical condition, substance intoxication, put from the spinal cord, visual and auditory or medication side effect. Delirium is common centers, thalamus, hypothalamus, and hippo- among hospitalized patients, particularly in the campus, as well as cortical feedback. Distur- ICU setting, where it has been reported to occur bances in any of these areas may lead to delirium. in up to 70% of patients, compared to 10% of Abnormalities in neurotransmitters (such as ace- emergency department patients, 16% of post- tylcholine, serotonin, dopamine, GABA, trypto- acute care patients, and 42% of hospice patients. phan, melatonin, and glutamate) and cytokines (Older patients are particularly susceptible to (such as interleukins and interferons), have been developing delirium, with up to 50% developing implicated in the pathogenesis of delirium. Since delirium at some point during their hospital stay. the pathophysiology of delirium is so complex, it Etiology and Pathophysiology is not surprising that it is often multifactorial in nature. Some common etiologies of delirium are of Delirium listed in Table 18.1. It is important to note that It is important to recognize that delirium is not a 50% of older patients with delirium have under- disease, but rather a symptom of underlying lying diagnoses of stroke, Parkinson disease or pathology. The term “delirium” is sometimes dementia (that is often undiagnosed).

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

162 18 Delirium and Sedation in the ICU . 163

Table 18.1. Etiologies of delirium Category Example

Drugs . Prescription: opiates, benzodiazepines, dexmedetomidine, barbiturates, antiepileptic medications, neuroleptics, antic- holinergics, antihistamines, dopamine agonists, steroids, antibiotics, histamine-2 receptor blockers, Baclofen, cyclo- benzepine, antidepressants, anti-arrhythmics, Beta-blockers, clonidine, digoxin . Illicit drugs . Seratonin syndrome . Neuroleptic malignant syndrome Endocrine . Hyper/hypothyroid . Hyper/hypoparathyroid . Hyper/hypoglycemia . Adrenal insufficiency Infection . Sepsis/SIRS . Hyperthermia . Hypothermia Metabolic Disarray . Hypoxia . Hypercapnia . Acidosis . Uremia . Acute liver failure (hyperammonemia) . Hyper/hypo Na, Ca, Mg, PO4 Neurological injury . Seizures/status epilepticus (convulsive, nonconvulsive) . Ischemic stroke/TIA . Hypoperfusion syndrome . Intracranial hemorrhage (subdural, subarachnoid, intraparenchymal . CNS infection (meningitis, encephalitis, abscess) . Traumatic brain injury . Posterior reversible encephalopathy syndrome (due to hy- pertension, medications) . CNS vasculitis . CNS inflammatory lesion (multiple sclerosis, ADEM, neuro- sarcoidosis, Lyme disease, drug effect) . CNS tumor (primary CNS malignancy, metastasis) . Paraneoplastic syndrome Nutritional . Acute thiamine deficiency (Wernike’s) . B12 deficiency . Niacin deficiency Toxins . Arsenic, lead, ethylene glycol, methanol, cyanide, carbon monoxide Withdrawal states . EtOH/benzodiazepine withdrawal . Opiate withdrawal Other . Poor pain control . Sleep deprivation . Sundowning . Sensory deprivation: low hearing, low vision, language barrier 164 . Neurological Complications and Consultations in General Intensive Care Units

TIPS & TRICKS Table 18.2. Confusion Assessment Method (CAM-ICU)21 Thirty percent of all delirium is due to 1 Acute onset and fluctuating course medications. Stop all sedation to remove the . Identify an acute change in mental drug effect from the equation. Simple status from the baseline exam OR laboratory tests can eliminate metabolic . Identify fluctuating changes in mental disarray and a focused neurological status or behavior over the past 24 examination off sedation has a 97% negative hours that may vary in severity predictive value for eliminating an AND underlying neurological etiology. 2 Inattention . Identify an inability to focus attention, easy distractibility or inability to pro- Evaluation of Delirium in the ICU cess components of conversation (e.g. count backwards, say months The CAM-ICU scale (used extensively in the trials backwards) mentioned above) was specifically developed to AND identify delirium as defined by DSM IV guidelines 3 Disorganized thinking (Table 18.2). In a study of 96 mechanically-venti- . If the patient is verbal (and not lated ICU patients, 471 CAM-ICU assessments aphasic): identify illogical or incoherent were performed in patients with a RASS of 3to thought processes, inability to under- þ 4 and compared with the gold standard DSM IV stand proverbs or inability to perform definition of delirium. The authors found that simple calculations (e.g. How many delirium, diagnosed by this tool, occurred in things are in a dozen? Where does a 83% of ICU patients for a mean of 2.4 days. The cactus grow?) CAM-ICU had a 93–100% sensitivity and a 98– . If the patient is intubated or nonverbal 100% specificity when compared with the DSM (and not aphasic): use yes/no questions IV guidelines. or letter board to identify illogical or A major limitation of the CAM-ICU scale is that incoherent thought processes (e.g. Can it allows for the determination of delirium in the a cat sing? Does wool come from an context of sedative use. In up to 30% of cases, the alligator?) cause of fluctuating mental status is the sedation OR medication itself. In fact, though the CAM-ICU 4 Altered level of consciousness scale is meant to be repetitively used, patients . Identify if the patient’s level of may receive varying amounts of sedation during consciousness is anything other than each evaluation. Though it is typical in a neuro- alert (i.e. drowsy, lethargic, stuporous, critical care setting for sedation to be held to comatose or agitated/combative) examine a patient, this practice is not consistent- ly applied in other specialty or mixed population ICUs. From a neurologist’s and neurointensivist’s Even in patients with no underlying neurological perspective, without eliminating the obvious diagnosis, it has been shown that 8–10% of med- confounder of sedation upon a patient’s mental ical ICU patients have seizures, the majority of status, it is impossible to: (1) identify if delirium which are nonconvulsive. Seizures in this popu- is present (or levels of sedation are simply differ- lation are particularly common in patients with ent), (2) determine the underlying cause of the sepsis. Similarly, stroke is not uncommon among delirium, and (3) address the underlying etiolo- ICU patients with a primary medical diagnoses. gy. Additionally, in the setting of sedation, serious In a study of 123 medical ICU patients with neurological events may be occurring and go “altered mental status,” new CT findings were undetected and untreated. For example, in a present in 26 (21%), including ischemic infarc- neuro-ICU setting, the rates of nonconvulsive tion in 13 (11%), intracerebral hemorrhage in status epilepticus are as high as 35%. 2 (2%), and tumor in 3 (2%). 18 Delirium and Sedation in the ICU . 165

TIPS & TRICKS physicians, and other healthcare staff can quickly become proficient at the CAM-ICU, an argument Subtle or nonconvulsive seizures are can be made that this time would be better impossible to diagnose without continuous spent learning a basic neurological examination EEG monitoring. Patients with an unexplained (Table 18.3). A neurological examination not altered mental status or coma should undergo only identifies fluctuations in attentiveness, but 24–48 hours of continuous EEG monitoring to also identifies, or rules out, acute neurological evaluate for seizures or status epilepticus since injury. In a retrospective study of 127 ICU this can be easily treated if diagnosed, but patients who received a neurological consult for catastrophic if missed. an isolated change in mental status, 7% had an ischemic stroke and 1% had a subarachnoid hemorrhage. In this study, the neurological ex- A solution to the problem of identifying deliri- amination had a 97% negative predictive value um, but missing a serious underlying neurologi- for ruling out acute neurological injury. Most cal condition, is to replace the CAM-ICU with neurointensivists and neurocritical care nurses serial neurological examinations performed off utilize an abbreviated neurological examination sedation. While it has been shown that nurses, on a serial basis to track a patient’s progress.

Table 18.3. Neurological assessment of delirium in the ICU Delirium is present when there is fluctuation in level of arousal, attentiveness and/or orientation. The cranial nerve and motor exam help to identify and localize an underlying neurological injury that may be contributing to delirium Step 1 Assess for fluctuations Mental status assessment* in mental status

Arousal . Spontaneously awake, eyes open and alert . Opens eyes to voice . Opens eyes to physical stimuli . No eye opening Attentiveness . Able to say months backwards from December to January . Able to count backwards from 20 to 1, but cannot do months backwards . Able to count from 1 to 10, but cannot do either of the above . Able to follow complex 2–3 step verbal commands, but cannot do any of the above . Able only to follow simple verbal commands . Able only to follow mimicked commands . Cannot follow commands, but can track visual stimuli . Cannot track visual stimuli, but saccades to voice . Does not saccade to voice, but saccades to physical stimuli . No response to examiner Orientation . Oriented to person, place and time . Oriented 2 . Oriented to self only 166 . Neurological Complications and Consultations in General Intensive Care Units

Step 2 Identify localizing abnormalities in the neurological exam Cranial nerve exam

CN II/III . Pupil symmetry and reactivity to light . Visual field assessment, blink to threat (II, VII, visual pathways) CN III/IV/VI/VIII . Extraocular movements . If patient cannot track test Oculocephalic reflex (Doll’s eyes maneuver) . Vesibulo-ocular reflex, hearing CN V/VII . Corneal response, facial sensation, facial movement CN IX/X/XII . Gag, tongue movement

Motor exam*

Strength Test all 4 limbs: . No drift holding arm or leg out for 10 seconds . Drift; limb moves before 10 seconds, but does not hit bed or support . Able to move limb against gravity (MRC60 3/5) . Unable to move limb against gravity, but some movement if force of gravity eliminated (MRC60 2/5) . No movement to command Response to physical If patient cannot comply with above motor exam, stimuli test response to physical stimulia: . Localizes to physical stimuli . Withdraws from physical stimuli . Flexor posturing (decorticate) . Extensor posturing (decerebrate) . Plegia (no movement to physical stimuli) or triple flexion (stereotyped flexion at hip, knee and ankle)

Exam should be performed in patient’s native language after sedation has been discontinued for a reasonable amount of time *Within each category responses are listed from best to worst. **Patient can have mixed responses.

In patients who are other than neurologically attentiveness as “delirium,” but irrespective of intact, a leading indicator can be identified, the label applied, the cause of the alteration which demonstrates the patient’s best examina- must be identified and treated. tion (i.e. the patient can reliably count from 20 to The following is a rational approach to evalu- 1). If the patient becomes unable to perform ating delirium in the ICU. First, sedating and this task, then efforts should be mounted to toxic medications should be discontinued, if pos- determine why the patient has changed neuro- sible. After an appropriate washout period, a logically. It is possible to label this fluctuation in neurological examination should be performed 18 Delirium and Sedation in the ICU . 167 to identify any focal features that might lead to ICU þ (Table 18.2) for delirium. Coma was de- localization or etiology. Basic laboratory tests to fined as response to physical stimuli, but no eye evaluate for metabolic disarray (e.g. uremia, hy- opening, or no response to physical stimuli (RASS perammonemia, hypoxia, hypercarbia, hypogly- 4or5). There was no stipulation as to the cemia, endocrine dysfunction) should be sent. amount or type of sedation a patient could re- Based on the examination and laboratory results, ceive when evaluated. Delirium occurred in 82% imaging such as head CT or MRI and vascular of patients and was significantly associated with imaging, such as CT or MR angiography, should 6-month mortality (Hazard Ratio 3.2, 95% CI 1.4– be considered. Continuous EEG to evaluate for 7.7, p ¼ 0.008), hospital length of stay (Hazard seizures or nonconvulsive seizures should be Ratio 2.0, 95% CI 1.4–3.0, P < 0.001) and post-ICU entertained in all patients with unexplained de- length of stay (Hazard Ratio 1.6, 95% CI 1.1–2.3, lirium. For patients undergoing continuous EEG p ¼ 0.009). Each additional ICU day spent in de- monitoring who are able to follow commands, 24 lirium was associated with a 10% increased risk of hours of monitoring will capture 95% of seizures, death (Hazard Ratio 1.1, 95% CI 1.0–1.3, p ¼ 0.03). but only 80% of seizures were detected in coma- Being in a “coma” in addition to delirium further tose patients monitored for 24 hours. For this increased the mortality rates and prolonged the reason, 48 hours of continuous EEG may be length of stay. Indeed, 18.5% of the patients in required in comatose patients. New onset men- this study remained in a persistent “coma” and ingitis is exceedingly uncommon in hospitalized died, though neither the cause of “coma” nor the patients; however, lumbar puncture should be cause of death was reported. This study also considered in patients with fever and meningis- found that the use of lorazepam and the cumu- mus or patients who have had neurosurgical lative lorazepam dose was directly associated procedures that might predispose them to with the presence of delirium. This was not the CNS infection. case for propofol, fentanyl, or morphine. It re- mained unclear from this study whether delirium Impact of Delirium in the ICU was a marker for lorazepam use or if, indeed, The implications of delirium in the ICU were lorazepam was responsible for increased mortal- explored in a prospective study of 275 mechani- ity and prolonged length of stay, or even if loraz- cally-ventilated patients in a medical and cardiac epam was a causal factor in the development of ICU setting. Delirium was diagnosed in patients delirium. with a Richmond Agitation and Sedation Scale This question was addressed, in part, by the (RASS) of 3toþ4 (Table 18.4) who were CAM- MENDS trial. This randomized-controlled trial of

Table 18.4. Richmond Agitation and Sedation Scale (RASS)20 Score Rating Description

þ4 Combative Violent, immediate danger to self and staff þ3 Very agitated Aggressive, removes devices, tubes, catheters þ2 Agitated Ventilator dyssynchrony, frequent nonpurposeful movement þ1 Restless Anxious but no aggressive movements 0 Alert and calm 1 Drowsy Sustained eye opening and eye contact to voice (>10 seconds) but not fully alert 2 Light sedation Brief eye opening and eye contact to voice (<10 seconds) 3 Moderate sedation Movement or eye opening to voice but no eye contact 4 Deep sedation No response to voice, but movement or eye opening in response to physical stimulation 5 Unarousable No response to voice or physical stimulation 168 . Neurological Complications and Consultations in General Intensive Care Units

106 mechanically-ventilated medical/surgical This study found a lower prevalence of delirium ICU patients examined the impact of dexmede- in those receiving dexmedetomidine (54%) com- tomidine (up to 1.5 mg/kg/h) compared to loraz- pared to those receiving midazolam (76.6%, epam (up to 10 mg/h) during the first 120 hours of P < 0.001) and, similarly, increased delirium-free ICU stay on the development of delirium, diag- days (2.5 vs. 1.7, p ¼ 0.002) and shorter time to nosed by the CAM-ICU. Both medications could extubation (3.7 days vs. 5.6 days, p ¼ 0.01). be titrated to a RASS level dictated by the treating Though this trial found an association of in- physician and a sedation cessation period was creased delirium rates in midazolam compared not mandated. The addition of fentanyl to treat to dexmedetomidine, it did not control for other pain was allowed. This study excluded those with possible causes of delirium that may have dif- a history of neurological disease, learning disabil- fered between the two groups. Since patients ity, dementia, seizure, liver failure, alcohol abuse, were never examined off sedation, it is not clear MI, second- or third-degree heart block, as well as that acute neurological injury (stroke, seizure, moribund and pregnant patients. Compared to etc.) was excluded as an etiology of delirium. patients who received lorazepam, those random- In a substudy of SEDCOM, mortality was found ized to dexmedetomidine had significantly more to be significantly lower in patients without deliri- days without delirium and coma and a trend um (11.9% vs. 30.3% in those with delirium, toward shorter mechanical ventilation time, P < 0.001) and the median time to extubation and shorter length of stay (7.5 vs. 9 days, p ¼ 0.92) length of stay were shorter in those without and lower 28-day mortality (17% vs. 27%, delirium (P < 0.001). There was a dose response p ¼ 0.18). There was a lower prevalence of effect for the duration of time spent in delirium “coma” in the dexmedetomidine group (63% vs. and the risk of mortality, prolonged ventilation 92%, P < 0.001). Though patients on dexmedeto- time, and prolonged length of stay. Interestingly, midine spent less time delirious, there was no 30-day mortality did not differ between the dex- difference in the incidence of delirium between medetomidine and midazolam groups in the larg- the two groups (79% vs. 82%, p ¼ 0.65). Other er SEDCOM study (22.6% vs. 25.4%, p ¼ 0.60), factors that may have contributed to delirium in suggesting that the association of delirium and either group were not adjusted for in the analysis. mortality cannot be explained by a sedation effect The SEDCOM trial, published 2 years later, alone. This poses the tantalizing question: What randomized 375 medical/surgical ICU patients to was the etiology of delirium in these patients? dexmedetomidine (0.2–1.4 mg/kg/h) vs. midazo- Unfortunately, none of the trials mentioned thus lam (0.02–0.1 mg/kg/h) titrated to RASS 2toþ1 far addressed this crucial issue. Is delirium a from enrollment until extubation or 30 days. marker for undiagnosed acute neurological injury Patients with acute stroke, uncontrolled seizures, (stroke, seizure, etc.), sepsis, or something else? liver failure, dementia, renal insufficiency In ICU survivors, delirium in the ICU has requiring dialysis, acute MI, second- or third- been associated with long-term cognitive dys- degree heart block, EF < 30%, bradycardia, or function. In a prospective cohort study of 99 hypotension were excluded. Though the primary mechanically-ventilated ICU patients surviving outcome measure was the percentage of time 3 months enrolled in the Awakening and within the target sedation range (RASS 2to Breathing Controlled trial, cognitive outcomes þ1), delirium was examined as a secondary end- were assessed at 3 and 12 months by a blinded point using the CAM-ICU. A “daily arousal neuropsychologist administering a battery of assessment” was performed during which RASS nine neuropsychological tests measuring: atten- 2toþ1 patients were asked to open their eyes tion and concentration, information processing to voice, track the examiner, squeeze the exam- speed, verbal memory, visual-spatial construc- iner’s hand or stick out their tongue and were tion and delayed visual memory, executive graded as “awake” if they could perform 3 of the 4 function, language and global mental status. tasks. There was no mandated sedation vacation Cognitive impairment occurred in 79% of pa- time and CAM-ICU assessments could be per- tients at 3 months and 71% at 12 months. After formed while the patient was receiving sedation. adjusting for age, education, baseline cognitive 18 Delirium and Sedation in the ICU . 169 status, APACHE II scores, severe sepsis and ex- TIPS & TRICKS posure to sedative medications in the ICU, in- creasing days of delirium was associated with Delirium is a descriptive diagnosis and gives worse age-adjusted cognitive scores at 3 months no information about the underlying (p ¼ 0.02) and 12 months (p ¼ 0.03). Duration of etiology. General ICU patients (even those mechanical ventilation, however, was not signif- that do not have a primary neurological icantly associated with cognitive scores. This diagnosis) are at risk of neurological study is unique because after adjusting for causes complications that may manifest as delirium. of delirium such as sepsis, exposure to sedative Stroke and seizure are particularly common medication, and severity of illness, the duration comorbidities of critical illness. of time with delirium was significantly associated with worse cognitive outcomes. Though this study excluded patients with cardiac arrest and The Argument for Limiting Sedation neurological deficits that prevented them from in the ICU living independently (e.g. large stroke, severe dementia), it did not account for any new neu- Though evidence suggests that delirium is associ- rological injury that may have occurred during ated with worse outcomes independent of the ICU stay. Since only 4% of patients in this sedative effect, the MENDS and SEDCOM trials cohort had the admission diagnoses of hepatic suggest that sedation can contribute to the preva- or renal failure or alcohol withdrawal, it is possi- lence of delirium and the duration of time spent ble that undiagnosed neurological injury was a delirious. Furthermore, in order to drill down on contributor to the development of delirium. the etiology of delirium, it is critical that the con- In fact, the patients enrolled in this study were tribution of sedation be eliminated from the equa- all at high risk for adverse neurological compli- tion. Frequent arguments for sedating patients cations of their primary illness. Fifty percent of include the concept that sedation prevents pa- patients in this study had severe sepsis, which is tients from accidentally harming themselves or a risk factor for seizures and status epilepticus. self-extubating, or that it is more “humane” to Additionally, 20% of patients had an admitting keep an intubated patient sedated. In fact, that diagnosis of myocardial infarction or CHF. literature does not support either of these con- The risk of ischemic stroke is increased 5-fold cepts. Daily interruption of sedation has been during the first month after diagnosis of CHF. shown not only to be safe, but to improve out- The risk of stroke after MI is 4.6% over 42 months comes and is now a routine component of most and the risk of seizure after MI is nearly ventilator weaning protocols. In a landmark trial of doubled compared to age- and gender-matched 128 mechanically-ventilated medical ICU patients controls. randomized to daily sedation interruption until The above literature has identified the fact that the patient awakens versus sedation interruption delirium is associated with an increased risk of at the discrepancy of the treating physician, those death and poor cognitive outcome. While seda- receiving a sedation vacation spent 2.4 fewer days tion use is associated with the development of on the ventilator (p ¼ 0.004) and had a significantly delirium, other unspecified factors are clearly shorter length of stay (6.4 days vs. 9.9, p ¼ 0.02) contributing. The diagnosis of delirium may, in Though this study included agitated and uncom- fact, be a marker for unrecognized neurological fortable patients, there was no difference in the events (i.e. stroke or seizure). Though it is possi- rates of accidental extubation. Stopping sedation ble that an entirely different or novel mechanism also allowed physicians to identify neurological for acute brain injury is occurring in delirious injury. Significantly more patients in the control ICU patients, common and treatable adverse group never awakened from a coma (20%) and neurological events should be evaluated. Deter- died in a coma (17%) compared to the sedation mining the underlying mechanism for delirium is interruption group (9 and 8%, respectively). This critical if adequate treatment strategies are to be may be because serious neurological illness went addressed. undiagnosed and untreated in the control group. 170 . Neurological Complications and Consultations in General Intensive Care Units

Conversely, more head CTs and MRIs were per- Awakening and Breathing Controlled trial, this formed on the control group than on the sedation study demonstrates that sedation interruption is interruption group, presumably because these not only safe, but also improves outcomes and studies were unnecessary in the context of a re- may ameliorate delirium. assuring, unsedated, neurological examination. Though continuous sedation has long been the This study was followed by the multicenter paradigm in most ICU settings, this concept was Awakening and Breathing Controlled trial, recently challenged in a single center randomized which randomized 336 mechanically-ventilated trial of 140 mechanically-ventilated patients patients to either sedation interruption followed who received either no continuous sedation, but by a spontaneous breathing trial or continued as-needed morphine or Haldol (which could be sedation with a spontaneous breathing trial. As in converted to a continuous infusion if necessary) or the Kress trial, those in the intervention group had continuous sedation with daily sedation interrup- significantly more ventilator-free days and a short- tion until awakening. Those not receiving contin- er ICU and hospital length of stay. In addition, 1 uous sedation had significantly more days off the year mortality rates were lower in the intervention ventilator, and a shorter ICU and hospital length of group (44% vs. 58%, p ¼ 0.01). The number of stay. Additionally, there was a trend toward lower patients needed to treat to prevent one mortality ICU mortality (22% vs. 38%, p ¼ 0.06), though was only 7. Though there were more self-extuba- there was no difference in hospital mortality rates. tions in the treatment group (10% vs. 4%, p ¼ 0.03), Although data was analyzed on an intention to there was no difference in re-intubation rates, and treat basis, 18% of patients in the noncontinuous the rate of tracheostomy was lower in the inter- sedation group required a continuous infusion at vention group (13% vs. 20%, p ¼ 0.06). some point during the study. Agitated delirium Aside from improved performance during occurred in 20% of the nonsedation group and 7% spontaneous breathing trials, sedation interrup- in the continuous sedation group (p ¼ 0.04), but tion can allow patients to participate in other there may be a diagnosis bias reflecting the diffi- tasks, such as . In a randomized culty of diagnosing delirium in sedated patients. It trial of 104 mechanically-ventilated ICU patients, is important to note that this study was conducted 49 received sedation interruption followed by a with 1:1 nurse to patient staffing. Since using as- standardized physical therapy protocol (which needed medication dosing is labor intensive, included an escalating pathway of passive ROM the results of this study may not be generalizable followed by active supine activities, followed to ICUs with less generous staffing models. by transfers, and finally performance of routing Nevertheless, the cost savings in shorter length of activities of daily living), while 55 patients stay and fewer mechanical ventilation days may underwent sedation interruption and physical offset the expense of higher staffing ratios. therapy at the discretion of the treating Overall, limiting sedation allows for faster lib- physician. Significantly more patients in the in- eration from mechanical ventilation, shorter tervention group had a return to independent length of stay, better functional outcome at dis- functional status at hospital discharge (59% charge, lower mortality rates, and possibly less vs. 35%, p ¼ 0.02). The time from intubation to delirium. Use of intermittent, as-needed sedation achieving ADL milestones such as getting out of appears to be efficacious and may further bed, standing, marching in place, transferring to a limit the total duration of exposure to sedation chair, and walking, were also significantly shorter compared to continuous infusions. in the intervention group. Similarly, patients who received the physical therapy protocol had higher Treatment of Delirium Barthel index scores (measure of activities of daily living), shorter duration of mechanical ventilation in the ICU Setting and a trend toward a shorter ICU length of stay. Delirium has traditionally been treated with sed- This study was also able to demonstrate signifi- ative medications; however, as mentioned above, cantly less delirium in the ICU and hospital in the these same medications may induce or worsen intervention group. Along with the Kress and delirium. Old paradigms for treating delirium 18 Delirium and Sedation in the ICU . 171 have promulgated the use of lorazepam infu- Typical and atypical neuroleptic use for the sions, though more recent data from the MENDS treatment of delirium has been compared in an and SEDCOM trials would suggest that this is an ICU setting in two small well-designed studies; outdated approach. In fact, a prospective study of however, the utility of these agents remains ICU patients found that lorazepam increased the unclear. When Haldol and ziprasidone were risk of incident delirium by 20%. It should be compared to placebo in a randomized-controlled mentioned, however, that benzodiazepines are trial of 100 mechanically-ventilated ICU patients, the most appropriate treatment for alcohol or there was no difference in the number of days benzodiazepine withdrawal. spent in delirium or coma, nor was there a dif- First-generation antipsychotics, such as Hal- ference in mechanical ventilation days, ICU dol, have also been commonly used to treat length of stay, or mortality. In this study, the delirium in doses that are alarmingly high. Some average daily doses of Haldol and ziprasidone studies have advocated Haldol 5 mg IV followed were 15 and 113 mg/day, respectively. At by doubling of the dose every 20 minutes. Others these doses, there was no difference in the inci- have suggested infusion rates of 10 mg/h with dence of akathesia or extrapyramidal syndrome increases of 5 mg/h every 30 minutes as needed. compared to placebo. In another randomized, In fact, Haldol doses of 1200 mg/day and placebo-controlled study, 36 patients with deliri- >200 mg/day for 15 days have been reported. um in the ICU received either quetiapine at Safety data for these doses of typical neuroleptics escalating doses up to 200 mg every 12 hours, or is based on only a handful of case reports. In one placebo. Patients receiving quetiapine (median case series, 8 patients with agitation refractory to daily dose of 110 mg) spent significantly less time benzodiazepines and narcotics were treated with delirious or agitated and had a trend toward 3–25 mg/h of Haldol. Of this group, 5 patients better functional status at discharge. More som- survived, 2 developed a tremor, 1 developed nolence was observed in the quetiapine group. third-degree heart block, and 1 developed ven- Interestingly, it is not uncommon for physicians tricular tachycardia. Adverse reactions to anti- to use quetiapine in low doses (below antipsy- psychotics include extrapyramidal movement chotic thresholds, such as 25–50 mg) to promote disorders, neuroleptic malignant syndrome, and restoration of normal sleep–wake cycles. It is sudden death. Extrapyramidal side effects are possible that simply restoring normal sleep may higher with high-dose typical neuroleptics attenuate delirium. and include akathesia, acute dystonic reaction While benzodiazepines may induce or (more common in young men), Parkinsonism worsen delirium (except in the case of alcohol (more common in older women), and tardive or benzodiazepine withdrawal), and the role of dyskinesia (more common in older patients antipsychotics in treating ICU delirium is un- receiving first-generation antipsychotics for a clear, pharmacologic pain control is an important prolonged period of time). Additionally, antipsy- component of managing delirium. It has been chotic medications carry a black box warning of long recognized that inadequate analgesia is a sudden death. In a study of 90,000 Medicaid strong risk factor for delirium. In one study, patients, both typical and atypical antipsychotics severe pain increased the risk of delirium nine- were found to double the rate of sudden death fold. Pain control is also important for limiting compared to non-use. This study also found a post-ICU conditions such as post-traumatic dose-related effect on the risk of death, presum- stress disorder (PTSD). In a study of 696 ICU ably due to the cardiac repolarization effects, military patients without serious traumatic prolonged QTc, and risk of arrhythmia. Other brain injury, 35% developed PTSD. In a multivar- studies have found an increased risk of mortality iate analysis, adequate pain control with mor- in elderly and demented patients when antipsy- phine significantly reduced the risk of developing chotics are used to treat delirium. In these stud- PTSD. ies, risk seems to be greater soon after initiation Nonpharmacologic strategies can also be ef- of antipsychotics and more pronounced with fective in limiting the incidence of delirium. conventional neuroleptics. Sleep deprivation may contribute significantly to 172 . Neurological Complications and Consultations in General Intensive Care Units delirium. Not only do ICU patients spend fewer incumbent upon the scientific community to hours sleeping, but sleep quality, architecture, adequately investigate the causes of delirium in and circadian rhythms are also altered. Since up the ICU and characterize the neurological and to 40% of ICU patients are sleep deprived, simple cognitive risks of ICU care. Limiting sedation strategies to increase sleep include keeping and/or using dexmedetomidine, rather than mid- shades open and the lights on during the day azolam or lorazepam, may help to attenuate the and off at night, and limiting night-time exam- risk of developing delirium and allow for the inations and interruptions in sleep. These strate- identification of an acute neurological injury, as gies are also helpful to reduce sundowning. well as shorten mechanical ventilation time, im- Limiting sensory deprivation by providing pa- prove length of stay, reduce mortality rates and tients with glasses, hearing aids, calendars, and improve functional outcome. clocks can also mitigate against delirium. In non- English speaking patients, having ready access to Bibliography staff or family members for translation can be important for reorientation. In a study of 852 Ely EW, Shintani A, Truman B, et al. Delirium as a elderly hospitalized patients, a protocol of orien- predictor of mortality in mechanically-venti- tation, cognitive stimuli, nonpharmacologic lated patients in the intensive care unit. JAm sleep aids, early mobilization, minimization of Med Aassoc 2004; 291:1753–1762. restraints, visual and hearing aids, and preven- Ely EW, Inouye SK, Bernard GR, et al. Delirium in tion of dehydration resulted in a significant re- mechanically-ventilated patients: validity and duction in the number of delirium episodes and reliability of the confusion assessment method the number of days spent in delirium compared for the intensive care unit (CAM-ICU). JAm to a control group. Med Assoc 2001; 286:2703–2710. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs TIPS & TRICKS lorazepam on acute brain dysfunction in me- chanically-ventilated patients: the MENDS Agitated delirium can be initially addressed randomized controlled trial. J Am Med Assoc using nonpharmacologic methods such as 2007; 298:2644–2653. restoring sleep–wake cycles, or by providing Riker RR, Shehabi Y, Bokesch PM, et al. Dexme- vision and hearing augmentation to the detomidine vs midazolam for sedation of criti- impaired. Restraints and chemical sedation cally ill patients: a randomized trial. J Am Med can often worsen agitation. If continuous Assoc 2009; 301:489–499. intravenous sedation is necessary, Shehabi Y, Riker RR, Bokesch PM, et al. Delirium dexmedetomidine is a superior choice to duration and mortality in lightly sedated, me- benzodiazepines (except in the circumstance chanically-ventilated intensive care patients. of alcohol withdrawal). Antipsychotics Crit Care Med 2010; 38:2311–2318. should be used with caution, due to side effects. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator wean- ing protocol for mechanically-ventilated Conclusions patients in intensive care (Awakening and Fluctuating attentiveness, or delirium, is com- Breathing Controlled trial): a randomised con- mon in ICU patients. Delirium has been associ- trolled trial. Lancet 2008; 371:126–134. ated with increased mortality and poor cognitive Girard TD, Jackson JC, Pandharipande PP, et al. outcome but, unfortunately, the etiology of delir- Delirium as a predictor of long-term cognitive ium in the ICU has not been well characterized in impairment in survivors of critical illness. Crit major studies. Serious neurological insults, such Care Med 2010; 38:1513–1520. as stroke or seizure, may be underdiagnosed or Kress JP, Pohlman AS, O’Connor MF, Hall JB. labeled as delirium in the general ICU setting. It is Daily interruption of sedative infusions in 18 Delirium and Sedation in the ICU . 173

critically ill patients undergoing mechanical tients: a randomised controlled trial. Lancet ventilation. New Engl J Med 2000; 342:1471– 2009; 373:1874–1882. 2477. Strom T, Martinussen T, Toft P. A protocol of no Schweickert WD, Pohlman MC, Pohlman AS, sedation for critically ill patients receiving me- et al. Early physical and occupational therapy chanical ventilation: a randomised trial. Lancet in mechanically-ventilated, critically ill pa- 2010; 375:475–480. 19 Neurologic Complications of Cathy Sila

Department of Neurology, Case Western Reserve University School of Medicine, and Stroke & Cerebrovascular Center, Neurological Institute, University Hospitals–Case Medical Center, Cleveland, OH, USA

Neurological Complications 11 performance measures endorsed by the National of Cardiac Surgery Quality Forum. Public reporting of these risk- adjusted outcomes for approximately 20% of the Coronary artery bypass graft (CABG) surgery for US cardiac surgery programs is currently available myocardial revascularization is the most frequently at: http://www.comsumerreportshealth.org. performed cardiac surgery with more than 500,000 The spectrum of neurologic complications in- procedures performed in the USA and 800,000 cludes encephalopathy, ischemic stroke, cogni- procedures world wide. Although percutaneous tive decline, coma, peripheral nerve injuries, coronary revascularization procedures outnumber optic neuropathy, and pituitary apoplexy. Post- CABG surgery by at least three-fold, CABG remains operative neurologic complications may be clas- the preferred therapy approach for left main or sified by the clinical manifestation of the injury severe triple vessel disease, concomitant valvular, (e.g. stroke, encephalopathy, coma, etc.) or by the or aortic arch disease, and may be the only option proposed mechanism of the injury (e.g. macroem- for patients who have failed endovascular proce- bolism, microembolism, hypoperfusion, hypoxic- dures. Neurologic complications of cardiac surgery ischemic injury, hemorrhage, etc.) but for many and interventional procedures for cardiac disease cases the relationship between the clinical picture are important determinants of patient outcome. and the presumed mechanism is either multifacto- Ischemic stroke following cardiac surgery increases rial or uncertain. mortality by three- to five-fold, increases critical care days and hospital length of stay, and increases the likelihood of discharge to a care facility. Since CAUTION 1989, the Society of Thoracic Surgeons has spon- sored a registry to collect key outcomes data on Don’t be too quick to attribute a patient’s patients undergoing cardiac surgery and now more delay from awakening from anesthesia to a than 90% of US programs participate. Stroke, de- medication or metabolic effect. This is often fined as a new post-operative neurologic deficit the first clue to a perioperative neurologic persisting for more than 24 hours, is one of the complication. registry outcomes measures and is also one of the

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

174 19 Neurologic Complications of Cardiac Surgery . 175

Encephalopathy and hypertension, diabetes, excessive alcohol con- Neurocognitive Deficits sumption, post–operative atrial fibrillation, a history of peripheral vascular disease or prior The most common neurologic complication of CABG (Table 19.1). Patients with post–operative cardiac surgery is a neurocognitive deficit rang- encephalopathy or cognitive decline are also ing from post-operative encephalopathy to a more likely to have pre-operative cerebral atro- more subtle cognitive decline noted by family phy or white matter changes on baseline neuro- members and confirmed by neuropsychometric imaging. In one longitudinal neurocognitive testing. In prospective studies of patients under- study, 42% of patients developed progressive going CABG, post-operative encephalopathy cognitive decline at 5 years, which was attributed was recognized in 3% of patients by ICU staff to an underlying vascular or degenerative demen- but diagnosed in up to 12% by neurologists. The tia. As post-operative cognitive decline is also majority of patients will improve during hospi- a risk factor for late cognitive deterioration – talization, and 80% will recover to be able to particularly in patients who are older and with perform normally on a bedside neurocognitive lower levels of education – it may be an unmask- tests by the time of discharge. However, when ing of a pre-existing vascular or degenerative more extensive neuropsychological test batter- dementia. ies are employed, 35–75% of patients have docu- mented impairments in cognitive function with- in the first 7–10 days after surgery and 20% of Stroke these are rather severe. Deficits in attention, Stroke following cardiac surgery is almost invari- concentration, memory, and processing speed ably ischemic in nature. The risk of ischemic persist in 10–30% at 3–6 months. Risk factors for stroke following CABG is 2–5% but can be as high post-operative encephalopathy include post- as 5–15% following more complex cardiac sur- operative intra-aortic balloon pump support or geries, such as valvular replacement or repair, use of pressor agents, which are markers of ventricular aneurysm resection, or aortic arch systemic hypotension, as well as advanced age, reconstruction. Neuroimaging patterns include

Table 19.1. Risk factors for neurologic deficit after coronary artery bypass surgery Encephalopathy Stroke Medical History Hypertension Hypertension Diabetes Diabetes History of Alcohol abuse Prior stroke Peripheral artery disease Recent MI Prior CABG Left ventricular dysfunction Chronic renal insufficiency Patient Features Older age Older age Cognitive impairment Carotid stenosis Cerebral atrophy Cerebrovascular disease Intraoperative/Post-operative IABP support Aortic arch atheroma factors Pressor support Atrial fibrillation Atrial fibrillation Prolonged cross-clamp time Circulatory arrest Prolonged CBP time Low cardiac output Complex cardiac surgery 176 . Neurological Complications and Consultations in General Intensive Care Units

Figure 19.3. Neuroimaging patterns of stroke-MRI diffusion-weighted image of a bilateral border zone Figure 19.1. Neuroimaging patterns of stroke- pattern of infarction. Whether this indicates poor MRI diffusion-weighted image of a major territory clearance of emboli or hypoperfusion, this pattern is embolism in a patient with post-operative coma. associated with a poor prognosis for survival.

major territory embolism, multifocal embolism characteristic of a proximal source of embolism, and a multifocal border zone pattern best de- tected with MRI diffusion imaging (see Fig- ures 19.1–19.3). Risk factors for stroke after CABG include advanced age, aortic arch atheromatous disease, prior stroke or documented cerebrovas- cular disease, recent myocardial infarction, left ventricular dysfunction, hypertension, diabe- tes, chronic renal insufficiency, and post-opera- tive atrial fibrillation (Table 19.1). Patients with post-operative stroke were also more likely to have longer cross-clamp times, total cardiopul- monary bypass (CPB) time and post-operative low cardiac output. An important cue to a post- operative neurologic deficit is a delay in awaken- ing from anesthesia. Intracranial hemorrhage within one week of cardiac surgery is rare and results from hemor- rhagic transformation of bland infarcts or coa- Figure 19.2. Neuroimaging patterns of stroke-MRI gulopathies in the critically ill or after cardiac diffusion-weighted image of multifocal embolism in a transplantation. Subdural hematomas have also patient with post-operative confusion. This pattern, been described, presenting as post-operative sei- characteristic of a proximal source of embolism, is zures or focal neurologic deficit. Neuroimaging best detected with MRI diffusion imaging and was not features include both acute bleeding as well as evident on CT. acute chronic features and are likely related to 19 Neurologic Complications of Cardiac Surgery . 177 the anticoagulation required by the cardiopul- injury to the phrenic nerve, most commonly the monary bypass circuit. left, could be demonstrated in up to 70% of pa- tients. As an elevated left hemidiaphragm is a Coma common and nonspecific radiographic finding in Although many patients with a neurologic com- the post-operative period, addition testing with plication are slow to awaken from anesthesia, fluoroscopy or ultrasound is often required to true post-operative coma or “failure to awaken” establish the diagnosis of a phrenic neuropathy. is uncommon, occurring in less than 1% of pa- Minor injuries resolve during hospitalization al- tients. For these patients, neuroimaging is essen- though more significant injuries require 3–6 tial as many are due to major territory cerebral months. The orthopnea and reduced ventilation infarction with a risk of life-threatening brain of a unilateral phrenic neuropathy may be well swelling that may warrant surgical intervention. tolerated in patients with otherwise normal pul- Other causes include smaller territory but multi- monary function, but in the setting of underlying focal cerebral infarction affecting brainstem or chronic obstructive pulmonary disease, it is asso- thalamic nuclei, bilateral border zone patterns, or ciated with significant prolongation of ICU and a diffuse global hypoxic–ischemic insult. The hospital stay, rehospitalizations, and reduced sur- sensitivity of MRI diffusion-weighted imaging in vival. Injury to the recurrent laryngeal nerve may identifying cerebral infarction is at least twice also occur during intubation and central venous that of CT. The prognosis of post-operative non- line placement. Presenting as hoarseness and a metabolic coma is extremely poor with an 85% weak cough, it may also cause dysphagia, increas- mortality and a < 5% chance of useful neurologic ing the risk of aspiration pneumonia. recovery. Local injury to the saphenous and radial nerves during the harvesting of veins and arteries for the Seizures bypass grafts range from the common, localized Seizures occur in about 3% of patients following neuralgia and peri-incisional sensory deficit to cardiac surgery and are often indicative of an rare severe injuries from traction and laceration. underlying ischemic injury. Lastly, positional compression neuropathies affecting the peroneal and ulnar nerves can affect Peripheral nerve injuries any patient with prolonged immobility and bedr- Peripheral nerve injuries following CABG occur in est, weight loss, and nutritional deficits. 2–13%. Injury to the brachial plexus is probably the best known and the most problematic. Lower Other Rare Complications trunk injuries are the most common and present Ischemic optic neuropathy following cardiopul- with weakness and sensory loss in the ulnar-C8- monary bypass is rare, reported to occur in 0.01– T1 distribution. Causalgic pain is often a major 0.1%. The proposed mechanism is reduced pos- presenting feature and although many improve terior ciliary artery blood flow in the setting of during hospitalization, 0.8% are chronic. Involve- hypotension, and some case-control studies have ment of the overlying sympathetic chain pro- also suggested post-operative anemia as a risk duces a Horner syndrome with miosis, ptosis, factor. Pituitary apoplexy is a rare complication and anhidrosis. Injury to the lower trunk plexus of pituitary adenomas but its occurrence, precip- and the sympathetic chain are attributed to itated by recent cardiopulmonary bypass surgery, stretch injuries related to chest wall retraction or is recognized by multiple case series in the fracture or dislocation of the first or second ribs. literature. Upper trunk brachial plexus injures are uncom- Presentations include ptosis, mydriasis, multi- mon and there is controversy whether these re- ple oculomotor nerve palsies and visual loss, sult from jugular vein cannulation. but the presentation can be less obvious with Myocardial cooling techniques employing ice headache, malaise, unexplained hyponatremia. slush or cold saline solutions in the pericardium Less severe cases missed in the post-operative can result in thermal injuries to the phrenic and period may present later with malaise and pitui- recurrent laryngeal nerves. In a prospective study, tary insufficiency. Off-pump surgery has been 178 . Neurological Complications and Consultations in General Intensive Care Units proposed as a superior alternative for patients geal echocardiography (TEE) monitoring of mi- with a known untreated pituitary adenoma war- croemboli during cardiac surgery. Several pro- ranting CABG surgery. spective studies have correlated the burden of HITS on TCD during CPB with cognitive deficits on neuropsychological testing. The majority of Mechanisms of Neurologic Injury HITS occur during aortic arch cross-clamping In most institutions, cardiac surgery is performed and other manipulation, and at the initiation of with CPB or the “heart-lung machine.” The car- bypass. These studies have also been instrumen- diopulmonary bypass circuit can contribute to tal in guiding technologic improvements to limit cerebral injury by a variety of potential mechan- embolization from the CPB circuit. In-line filtra- isms: cerebral embolization of atheromatous ma- tion with 40 micron filters and membrane oxyge- terial and other debris, cerebral hypoperfusion, nators were introduced to filter such macroem- or from cerebral edema resulting from a systemic boli as air, fat, glove powder, PVC tubing debris, inflammatory response. The CPB circuit con- and silicone antifoaming agents. Heparin-bond- structs an extracorporeal course encompassing ed and closed circuits have been developed to cannulation of the proximal ascending aorta and reduce activation of the inflammatory and coag- the right atrium through a median sternotomy ulation system while on bypass. exposure. Cardiac arrest is achieved after system- Around 1995, “off-pump” coronary artery by- ic heparinization and occlusion of the ascending pass surgery was introduced in an effort to reduce aorta either by external cross-clamping or inter- the risk of embolization from the CPB circuit or nal balloon occlusion, and systemic blood flow is from the aortic arch. Performed on the “beating then supported by the CPB pump. Oxygenated heart” using specialized stabilizers that limit cor- blood is supplied to the body though approxi- onary vessel motion, off-pump surgery does not mately 6 feet of tubing and adjusted for target require aortic cross-clamping and does not use pump flows, perfusion pressure, temperature, CPB. However, off-pump techniques are often and in-line venous saturation. which performed under induced bradycardia and rela- require opening of the cardiac chambers, such as tive hypotension, and although flow is pulsatile, valvular repair or replacement or resection of a relative hypotension may increase the risk of ventricular aneurysm, are associated with a sig- cerebral hypoperfusion in patients with a poor nificant increase in the risk of stroke. This in- vascular reserve or an underlying small vessel creased risk is related to prolongation of the disease. To test the relative efficacy of these new cross-clamp time and total bypass time, reflect- techniques, investigators have employed neuro- ing the complexity of the case, potential for em- cognitive testing results as a primary endpoint bolism of valve debris, and embolism of air since the incidence of stroke is too infrequent to and particulates during mechanical de-airing of reasonably power a trial. Although off-pump sur- the heart. gery has demonstrated a substantial reduction in Combining clinical information with neuroim- the number of cerebral microemboli as well as a aging data, the proposed mechanism of ischemic reduced severity of the inflammatory response stroke after cardiac surgery performed with car- compared to surgery performed with CPB, diopulmonary bypass is largely embolic; nearly there has been no significant impact on neuro- half are attributed to emboli from atheromatous cognitive testing results or composite endpoints debris from the aortic arch, from the heart, or that include stroke events. The topic remains from the bypass pump. Less than one-third are controversial among experts and institutions, attributed to hypoperfusion with or without con- and studies continue to investigate the subsets comitant cerebrovascular disease with the re- and evolution of hybrid PCI-CABG surgery, mainder cryptogenic. Much of the data support- endovascular and robotic procedures. ing the major role of aortic arch atheromatous Cardiopulmonary bypass is performed under disease as a source of cerebral embolism comes mild hypothermia at 32 C, which provides a from transcranial Doppler (TCD) monitoring of neuroprotective state by lowering the cerebral high-intensity signals (HITS) and transesopha- neuronal metabolism. At this temperature, 19 Neurologic Complications of Cardiac Surgery . 179 autoregulation is preserved and cerebral blood of 3–19%. A meta-analysis of 16 nonrandomized flowismorethanadequatetomeetdemands; studies comparing combined versus staged this state is proposed as the major contributor to CABG and carotid endarterectomy (CE) re- the good neurologic outcome of the majority of ported a significantly higher risk of stroke, patients undergoing these complex surgeries. death, and stroke or death when the surgeries Cerebral autoregulation remains preserved until werecombined(6.0,4.7,and9.5%)comparedto the temperature drops to less than 22 Cor staged surgery (3.2, 2.9, and 5.7%), respectively. when mean arterial pressures are less than Several nonrandomized studies analyzing the 20 mmHg or greater than 100 mmHg, particular- neuroimaging features of post-CABG ischemic ly in patients with diabetes. When the aortic stroke indicate that approximately 5% are con- arch is too diseased to permit cross-clamping, sistent with a large-artery mechanism, but 60% or when the aorta itself requires repair or recon- are not confined to a single carotid territory and struction, circulatory arrest with deeper hypo- at least 75% occur in the absence of significant thermia at 18 C is employed, which carries a carotid stenosis. In one retrospective single- higher risk, 20% risk, of neurocognitive im- center cohort study, the perioperative stroke pairment. Various studies have demonstrated risk with CE þ CABG was 15% and determined that cognitive deficits increase with older age to be in excess of the risk of stroke experienced and circulatory arrest time over 25 minutes with by patients with a similar degree of carotid sten- up to one-third demonstrating significant defi- osis who underwent CABG alone. After this cits with circulatory arrest times of 50 minutes study was reviewed, their institution abolished or longer. When prolonged circulatory arrest is routine pre-operative carotid ultrasound scre- anticipated, cerebral circulation can be sup- ening of patients anticipating CABG surgery. ported by selective antegrade or retrograde ce- rebral perfusion. The benefits of these techni- ques are offset by the risks associated with EVIDENCE AT A GLANCE cannulation of the great vessels, including dis- section, vessel occlusion, distal atheroembo- Meta-analysis of nonrandomized studies lism, and delayed stenosis. indicate a significantly higher risk of poor Many neuroprotective agents, efficacious in outcomes with combined CABG þ CE when animal models when administered prior to an compared to staged surgeries. ischemic insult, were not demonstrated to have any clinical benefit in the treatment of acute ischemic stroke. Several of these have been stud- Clinical trials of carotid angioplasty and stent- ied as a prophylactic therapy prior to cardiac ing (CAS) have demonstrated a lower risk of surgery and have not shown promise although periprocedural myocardial ischemia than CE. the small trials and low risk of stroke overall make CAS is approved for patients with symptomatic the results difficult to interpret. carotid stenosis with high-risk criteria, such as coronary heart disease. A single-center experi- Concomitant Carotid Stenosis ence, comparing combined coronary and carotid revascularization with either CAS or CE, reported and Cerebrovascular Disease a significantly lower risk of stroke or myocardial Carotid stenosis is an important risk factor for infarction at 30 days in those managed with CAS stroke during CABG. Patients at highest risk in- þ CABG compared to CE þ CABG (5% vs. 19%, clude those with symptomatic and severe steno- p ¼ 0.01). However, the majority in both groups sis of the extracranial or intracranial cerebral had asymptomatic carotid stenoses, 54% vs. 77% arteries, carotid occlusion bilateral greater than and as there was no control group without carotid 50% carotid stenosis, and significant intracranial revascularization, it is uncertain whether this stenosis. Despite this, there is no evidence that a strategy would reduce stroke risk compared to routine protocol of prophylactic carotid revascu- CABG alone. Until the requisite data is available, larization reduces the perioperative stroke risk a reasonable approach to patients with carotid 180 . Neurological Complications and Consultations in General Intensive Care Units and coronary disease using existing clinical Table 19.2. Bleeding complications of trials results is to attempt to view the carotid intra-arterial thrombolytic therapy for disease independently. Patients with asymptom- acute ischemic stroke complicating atic carotid stenosis should undergo CABG alone cardiac surgery (aggregate data, less but be followed carefully in the post-operative than 100 cases in the literature) period as symptoms related to a perioperative 17% Bleeding requiring transfusion carotid plaque rupture can occur. For patients 12% Perivascular or catheter intervention with recently symptomatic 70% carotid steno- site sis, CAS would be the preferred revascularization 6–10% Symptomatic hemorrhagic trans- strategy prior to CABG based on the single-center formation of the cerebral infarct study. Aggressive medical risk factor manage- 5% Tamponade from hemopericardium ment is also warranted, as the long-term prog- 5% Operative site hemorrhage-thoracic nosis of patients with symptomatic carotid and or mediastinal coronary disease is poor, with 36% mortality 5% Nasal, pharyngeal, or esophageal at 3.4 years. hemorrhage Evaluating an Acute Neurologic Deficit in a Cardiac Surgical Patient care is then on the appropriate diagnosis, evalua- tion for potential life-threatening brain swelling, The evaluation and management of a suspected supportive care, prevention of medical complica- acute ischemic stroke in the setting of a recent tions, assessment for rehabilitation therapies, and cardiac surgery is not fundamentally different neuroprognostication. The remainder of post- from other situations, but this situation poses operative strokes have their onset rather equally several challenges that warrant a tailored ap- distributed throughout the post-operative period proach. The first challenge is establishing the and should be evaluated aggressively for potential time of onset or when the patient was last known revascularization options. The ideal patient is one to be neurologically at the baseline. If the consult recovering from successful cardiac surgery with an is requested when the patient is slow to awaken acute deficit witnessed by their healthcare team from anesthesia, the time last known well was who is otherwise hemodynamically stable and off prior to the induction of anesthesia. Determining anticoagulants. whether a stroke has occurred or whether a Thrombolytic therapy options are still limited by revascularization strategy is an option will re- thepost-operativestateorpresenceofconcomitant quire more sophisticated imaging than the usual antithrombotic therapies which increase the risk of CT scan without contrast. In the setting of non- bleeding. Limited case series of patients with acute transplant cardiac surgery, stroke is almost ex- focal ischemic stroke treated with mechanical clusively ischemic in nature. The most useful revascularization, intra-arterial thrombolysis and imaging modality is MRI with diffusion-weighted combined therapies have suggested similar revas- imaging to establish the presence and distribu- cularization outcomes with somewhat increased tion of infarction, MR angiography to evaluate for risks of systemic bleeding (Table 19.2). arterial occlusion, and MR perfusion to evaluate the tissue at risk. If MR imaging is contraindi- cated due to the presence of a permanent pace- maker or temporary pacing wires, the alternative TIPS &TRICKS is to combine CT with CT angiography and CT The majority of strokes noted in the first post- perfusion to evaluate for a substantial mismatch operative days are complete at the time of in the cerebral blood flow deficit from the cere- evaluation but the remaining 40% that occur bral blood volume imaging. in the post-operative period should be The majority (as much as 60%) of strokes noted evaluated aggressively for potential in the first post-operative days are complete at the revascularization options. time of evaluation and are not eligible for revas- cularization strategies. The focus of neurologic 19 Neurologic Complications of Cardiac Surgery . 181

Bibliography Murkin JM, Newman SP, Stump DA, Blu- Barbut D, Yao FS, Hager DN, et al. Comparison of menthal JA. Statement of consensus on as- transcranial Doppler ultrasonography and sessment of neurobehavioral outcomes after transesophageal echocardiography to monitor cardiac surgery. Ann Thorac Surg 1995; emboli during cardiopulmonary bypass. Stroke 59:1289–1295. 1996; 27:87–90. Newman MF, Grocott HP, Stanley TO, et al. Lon- Borger MA, Fremes SE, Weisel RD, et al. Coronary gitudinal assessment of neurocognitive func- bypass and carotid endarterectomy: does a tion after coronary artery bypass surgery. New combined approach increase risk? A meta- Engl J Med 2001; 344:451–452. analysis. Ann Thorac Surg 1999; 68:14–20. Roach GW, Kanchuger M, Mangano CM, et al. Breuer AC, Furlan AJ, Hanson MR, et al. Central Adverse cerebral outcomes after coronary nervous system complications of coronary ar- bypass surgery. New Engl J Med 1996; tery bypass graft surgery: prospective analysis 335:1857–1863. of 421 patients. Stroke 1983; 14:682–687. Stamou SC, Hill PC, Dangas G, et al. Stroke Diegler A, Hirsch R, Schneider F, et al. Neuromo- after coronary artery bypass: incidence, pre- nitoring and neurocognitive outcome in off- dictors, and clinical outcome. Stroke 2001; pump versus conventional coronary bypass op- 32:1508–1513. eration. Ann Thorac Surg 2000; 69:1162–1166. Svensson LG, Crawford ES, Hess KR, et al. Deep Katzan I, Masaryk TJ, Furlan AJ, et al. Intra-arte- hypothermia with circulatory arrest. Determi- rial thrombolysis for perioperative stroke after nants of stroke and early mortality in 656 open heart surgery. Neurology 1999; 52: patients. i 1993; 106:19–28. 1081–1084. Wolman RL, Nussmeier NA, Aggarwal A, et al. Lederman RJ, Breuer AC, Hanson MR, et al. Pe- Cerebral injury after cardiac surgery: identifica- ripheral nervous system complications of cor- tion of a group at extraordinary risk. Multicenter onary artery bypass graft surgery. Ann Neurol Study of Perioperative Ischemia Research 1982; 12:297–301. Group (McSPI) and the Ischemia Research Ed- ucation Foundation (IREF) Investigators. Stroke Li Y, Walicki D, Mathiesen C, et al. Strokes after 1999; 30(3):514–522. cardiac surgery and relationship to carotid ste- nosis. Arch Neurol 2009; 66:1091–1096. Ziada KM, Yadav JS, Mukherjee D, et al. Compar- ison of results of carotid stenting followed by Moody DM, Brown WR, Challa VR, et al. Brain open heart surgery versus combined carotid microemboli associated with cardiopulmonary endarterectomy and open heart surgery (coro- bypass: a histologic and magnetic resonance nary bypass with or without another proce- imaging study. Ann Thorac Surg 1995; 59: dure). Am J Cardiol 2005; 96:519–523. 1304–1307. 20 Neurological Complications of Medical Illness: Critical illness Neuropathy and Myopathy Edward M. Manno

Neurological Intensive Care Unit, Cleveland Clinic, Cleveland, OH, USA

Introduction pharmacologically paralyzed. Thus, the terminol- ogy of critical illness neuropathy and myopathy Technological advancements and improvements were used to describe the clinical, electrophysio- in the management of critically ill patients have logical and pathological findings of critically ill increased patient survival after prolonged bouts patients. However, the neuropathy rarely occurs of critical illness. This has led to the recognition without simultaneous involvement of the mus- of limb and respiratory weakness that can com- cle. Most authors now prefer the term “critical monly occur after a bout of sepsis. These neuro- illness neuromyopathy” to describe the clinical muscular complications of severe illness have features encountered after severe critical illness. been recognized for a long time but were poorly characterized. Osler (1892) described a catabolic myopathy and diaphragmatic weakness that Clinical Presentation occurred in patients after a bout of sepsis. Patients with critical illness neuropathy and my- Mertens (1961) described a group of polyneuro- opathy typically present with flaccid areflexic pathies that occurred in patients that had been in limbs, with intact sensation, and a normal cranial a prolonged coma. Bolton and colleagues, how- nerve examination. Neurological consultation ever, provided the best characterization of this usually occurs for failure to wean from the venti- illness. From 1977 to 1983 Bolton and colleagues lator long after cardiopulmonary conditions have described 19 cases of a polyneuropathy that they resolved. The patient may grimace to noxious attributed to the mediators of sepsis. This neu- stimuli but will be unable to withdraw the in- ropathy accounted for the difficulties in weaning volved extremity. The exam may be difficult to from mechanical ventilation. interpret since most patients will have a concur- It became immediately apparent that this rent septic encephalopathy (see Chapter 17) and neuropathy was not an isolated phenomenon. may be sedated. Around the same time Zochodne et al. (1994) The neuropathy is primarily axonal. It involves described the first cases of a necrotizing myopa- the motor axons to a greater degree than the thy that occurred in patients that had been trea- sensory axons, but with advancement of the dis- ted with large doses of corticosteroids and were ease the sensory nerves will become progressively

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

182 20 Neurological Complications of Medical Illness: Critical illness Neuropathy and Myopathy . 183 involved. The neuropathy also progresses distally Predominant muscle involvement occurs in to more proximally over time. Subsequently, about a third of patients treated for status asth- muscle weakness and areflexia will progress maticus and 40% of critically ill patients. Over from distally to more proximal. two-thirds are patients that are in an intensive Muscle atrophy will develop as the neuropathy care unit for greater than 1 week have some progresses and leads to denervation of involved evidence of muscle involvement. muscles. The atrophy is often more severe than can be accounted for by immobilization alone Electrophysiologic Studies and most likely represents the simultaneous in- Conventional electrophysiological studies are volvement of a critical illness myopathy. Cranial the mainstay for identifying the presence of nerve and facial muscle involvement can occur a neuropathy or myopathy. The predominant late in the process but early involvement should electrophysiological abnormality encountered in prompt an investigation into other possible neu- the critically ill patient is a reduction in ampli- romuscular etiologies such as Guillian–Barre or tude of the compound muscle and sensory nerve myasthenia. action potentials. These findings are consistent Critical illness myopathy may occur simulta- with a progressive axonal sensorimotor degener- neously or independently of the neuropathy. The ation of the peripheral nerves and represent a exact onset may be difficult to determine because decrease in the total number of nerve fibers that of a concurrent neuropathy or encephalopathy, or can be stimulated. Conduction velocities are the use of neuromuscular blockade. A diffuse flac- largely unaffected since the peripheral nerve cid weakness involves the limbs, neck flexors, and myelin is spared until late in the course of diaphragm. Unlike the neuropathy, facial muscles the process. Needle electromyography typically are not spared. Reflexes become depressed as the will reveal fibrillation potentials or sharp waves myopathy worsens. Myalgias are uncommon. indicative of muscle involvement. The acute quadriplegic myopathy was original- Phrenic nerve conduction studies and electro- ly described in young patients that were treated myography of the diaphragm and the respiratory for a severe bout of status asthmaticus. Patients muscles can reveal respiratory muscle and nerve were treated with high-dose corticosteroids and involvement which may account for the difficulty were pharmacologically paralyzed to facilitate in weaning from mechanical ventilation. Phrenic mechanical ventilation. As the patients improved nerve conduction velocities usually reveal nor- and the paralysis was reversed, an acute quad- mal latencies but diaphragmatic muscle action riplegia was discovered. Initial concerns for potentials may be reduced. Amplitudes increase cervical injury during intubation prompted as recovery ensues. Motor units in the diaphragm radiological evaluation but the diagnosis was may reveal a myopathic appearance. made electrophysiologically, which revealed a Differentiating involvement of the peripheral diffuse myopathic process. nerves found in critical illness neuropathy from the muscle involvement in critical illness myop- Incidence athy can be challenging. Critical illness neuropa- Both the neuropathy and myopathy due to criti- thy and myopathy can both lead to a decrease in cal illness are common to patients in the inten- compound action muscle potentials. As men- sive care unit. The incidence is related to the tioned, fibrillation potential and sharp waves are severity of illness and time spent in the intensive commonly found during needle examination. care unit. About a third of all patients on me- This, however, may represent denervation of the chanical ventilation will exhibit electrophysiolog- involved muscle. In the cooperative patient, low ical evidence for a neuropathy. Approximately amplitude motor unit potentials with early re- 60% of patients in an intensive care unit will cruitment is suggestive of direct muscle involve- develop evidence for a neuropathy after one ment. Bolton (2005) has suggested a set of criteria week. 75% of septic patients will develop a neu- for diagnosis which is listed in Table 20.1. ropathy and this will increase to almost all pa- However, in many cases the patient may not be tients that develop multiorgan failure. able to cooperate with the examination, and in 184 . Neurological Complications and Consultations in General Intensive Care Units

Table 20.1. Diagnostic criteria of critical illness myopathy. For a definitive diagnosis, patients should have the first five features . Sensory nerve action potential amplitudes >80% of the lower limit of normal. . Needle EMG with short-duration, low amplitude muscle unit potentials with early or normal full recruitment, with or without fibrillation potentials. . Absence of a decremental response on repetitive nerve stimulation; and . Muscle histopathologic findings of a myopathy with myosin loss. . Compound muscle action potential amplitudes <80% of the lower limit of normal in two or more nerves without conduction block; . elevated serum creatine kinase and . Demonstration of muscle inexcitability.

Source: Bolton 2005.

these circumstances direct muscle stimulation than the muscle action potential that is may be required. In direct muscle stimulation, directly stimulated. If a myopathy exists, the compound muscle action potentials are mea- nerve-stimulated compound muscle potential sured after nerve stimulation and compared to will be the same or greater than the direct compound muscle action potentials of direct muscle-stimulated action potential. In situations stimulation of the muscle (Figure 20.1). If the where both a neuropathy and a myopathy muscle is relatively unaffected, nerve-stimulated exist, the ratio of nerve to muscle stimulation is compound muscle action potentials will be less usually greater than 0.5.

Figure 20.1. Determining muscle involvement with critical illness may require direct muscle stimulation. In this testing compound action muscle potentials are recorded at a site distal to stimulation. Stimulation occurs at the nerve and subsequently directly on the muscle proximal to the recording site. Compound muscle action potentials are recorded and compared. (Adapted from Zink et al. 2009; with permission from Nature.) 20 Neurological Complications of Medical Illness: Critical illness Neuropathy and Myopathy . 185

Histopathology tizing myopathy has also been characterized by Nerve biopsy samples were performed by the phagocytosis of myocytes. Selective muscle Bolton (2005), and colleagues, of patients with changes secondary to denervation (either func- electrophysiological documented critical illness tionally from pharmacological paralysis or polyneuropathy. Samples revealed fiber loss and physically due to critical illness neuropathy) are axonal degeneration. The distal nerve segments commonly encountered and can complicate the were more severely involved. No inflammation interpretation of the muscle biopsy. was noted. Muscle changes showed acute and Pathophysiology chronic denervation. In a small number of cases nerve biopsies were normal despite electrophys- The pathophysiologic mechanism involved in iological evidence for a neuropathy. This was the development of critical illness polyneuropa- believed to reflect either the limitations of the thy is complex and incompletely understood. biopsy itself or that functional change may pre- The severity of the neuropathy, quantified by cede pathological alterations. electrophysiological studies, correlates directly There are a wide range of myopathic changes with intensive care length of stay, glucose levels, that can be found with muscle biopsy. Findings and hypoalbuminemia. can range from normal to diffuse and severe Sepsis itself is believed to directly affect the muscle necrosis. This may represent a spectrum peripheral nerve function. Since blood vessels to of pathology that exists from muscle inexcitabil- peripheral nerves lack autoregulation, mediators ity to necrosis. of sepsis may gain direct access to the Several subtypes of critical illness myopathies peripheral nerves. Cytokines exhibit histamine- have been described, but are now generally type qualities and can increase the microvascular grouped into three categories. The most common permeability to the nerves. Endovascular edema type of myopathy described is attributed to is increased in hyperglycemia and hypoalbumi- thick filament myelin loss. This is most common- nemia, which may account for the decreased ly encountered after pharmacological paralysis peripheral neuropathies reported in critically ill and high-dose corticosteroids. A muscle patients with tight glucose control. Endoneural biopsy reveals the loss of all fiber types; electron edema also is believed to increase the intercapil- microscopy reveals the complete loss of myosin lary distance. Capillary leakage is facilitated (Figure 20.2). Cachetic myopathies histologically through the passage of neurotoxic substances reveal internalized nuclei, rimmed vacuoles, into the endoneurium. Increased E selectin and fatty degeneration, and fibrosis. A severe necro- leukocyte adhesion molecules found in sepsis have been documented in the endothelium of peripheral nerves. Both are known to increase permeability. Similarly, metabolites of pharma- cologic paralytics known to be neurotoxic may gain access to the peripheral nerves with increased permeability. Bioenergetic studies of muscle have revealed an impaired mitochondrial function in muscle in sepsis. It is speculated that bioenergetic failure would lead to a decrease in energy-dependent ATP-ase necessary for axonal transport of nutri- tional substances and structural proteins. This may account for the distal to proximal involve- ment of the peripheral nerves. The processes involved with the development Figure 20.2. Electronmicrography of a biopsy in a of the myopathy are multifactorial. Proteolytic patient with acute quadriplegic myopathy. Note the pathways are activated by proinflammatory complete loss of myosin filaments. cytokines (interleukin 1 and 6, tumor necrosis 186 . Neurological Complications and Consultations in General Intensive Care Units factor, interferon g) and are released during judicious use of pharmacologic paralysis may systemic inflammation or sepsis. Degradation decrease the incidence of the myopathy. targets the myosin heavy chains. Proteins are There are no specific treatments for either the also degraded by a proteosome, apoptosis is myopathy or neuropathy secondary to critical increased, and intrinsic anabolic processes are illness, and there have been several attempts to impaired through the interleukin suppression specifically treat or prevent the development of of myosin repair genes. Similarly anabolic hor- the neuropathy. Trials of corticosteroids, plasma mones are decreased during critical illness. exchange, and intravenous immunoglobulin have A channelopathy has been speculated to devel- all been unsuccessful in arresting or slowing the op during sepsis which could inhibit muscle development of the neuromyopathy. Nutritional membrane excitability. An overall drop in cortisol supplements and antioxidants have similarly not levels may lead to an inactivation of sodium been helpful. Patients treated with testosterone or channels. Nitric oxide is crucial to maintaining growth hormone supplementation actually did muscle membrane excitability; and an impaired worse than their respective placebo arms, pre- gene expression of nitric oxide synthetase is sumably due to increased hyperglycemia. reported in sepsis. Calcium entry into the sarco- Tight glucose control, however, may have a role plasmic reticulum necessary for muscle con- in preventing the development of the neuropa- traction is also decreased in critical illness. An thy. A planned subanalysis of an intensive insulin unidentified myotoxic substance is also believed trial in critically ill patients (Van den Berghe to be released in critical illness. et al., 2005) was suggestive of a decrease in both Changes in metabolic pathways may account critical illness neuropathy and myopathy in pa- for bioenergetic failure determined by nuclear tients with tight glucose control. For patients in magnetic resonance studies. During sepsis, glu- the intensive care unit longer than 1 week, the coneogenesis is increased and muscle develops a incidence of the neuromyopathy was 39% for relative resistance to insulin. Subsequently, mus- tight glucose control group compared to 50% of cle can become relatively starved of metabolic the nonintensive insulin group (p >0.02). There substances and will initiate processes that will was also an improved 3-month mortality (but not lead to intrinsic muscle breakdown. 1 month) in the intensive insulin group. This has Infiltration of the muscle with activated leuko- been attributed to the better rehabilitation po- cytes has been well documented and strongly tential of patients that survived a bout of sepsis. suggests a role for inflammation in the develop- Concerns have been raised about the safety of ment of the myopathy. intensive insulin treatment due to an increase in The reason for the preferential degradation of the number of hypoglycemic episodes. Thus myosin is unknown; however, the role of phar- the decision to initiate tight glucose control macologic or functional denervation has been remains a clinical one. Future studies focusing implied. Denervated rat muscle myosin rapidly on patients projected to have a prolonged bout develops increased corticosteroid receptors. with sepsis may be warranted. High doses of corticosteroid could subsequently There is a growing body of evidence to suggest lead to severe preferential catabolism of myosin. that exercise and early mobilization can decrease Similarly, a neuromuscular blockade increases both the incidence and severity of the neuromyo- the corticosteroid receptors in muscle cytoplasm. pathy. Prospective clinical trials are currently A direct myotoxic effect of neuromuscular under debate. blockers themselves has been speculated. An increased capillary permeability during sepsis Prognosis may allow direct access to muscle membranes. The prognosis for critical illness neuropathy is dependent upon the length and degree of axonal Treatment loss. The severity of the illness can range from The best treatment is the aggressive treatment mild, with recovery within weeks, to significant of sepsis. Limiting the systemic inflammatory re- permanent functional loss. Recovery has been sponse to sepsis is the highest priority. Similarly, a reported in about 50% of patients although 20 Neurological Complications of Medical Illness: Critical illness Neuropathy and Myopathy . 187 rehabilitation may be extended for patients that severity of the neuropathy. Early mobilization is have been in the intensive care unit longer than hoped to improve rehabilitation. 1 month. In more severe (about a third) cases patients may be para- or tetraplegic and experi- Bibliography ence severe impairment in their quality of life. Bolton CF. Neuromuscular manifestations of critical illness. Muscle Nerve 2005; 32: 140–163. TIPS & TRICKS Hermans G, De Jonghe B, Bruuyninckx F, Van den Berghe G. Interventions for preventing Serial electrophysiological studies can be critical illness polyneuropathy and critical ill- performed and used to assess prognosis. The ness neuropathy. Cochrane Database Syst Rev length of the neuropathy and the muscles 2009; Issue 1: Art.No. CD006832.doi:10.1002/ involved can be determined. Also which 14651858.CD006832.pub2(2009). muscles are denervated can be determined. Hermans G, Wilmer A, Meersseman W, et al. Impact of intensive insulin therapy on neuromuscular complications and ventilator- Patients with an isolated myopathy may have a dependency in MICU. Am J Resp Crit Care Med better prognosis; however, little data exists to 2007; 175: 480–489. support this supposition. Lacomis D, Giuliani MJ, Van Cott A, Kramer DJ. Acute myopathy of intensive care: clinical, electromyographic, and pathological aspects. TIPS & TRICKS Ann Neurol 1996; 40: 645–654. An important differentiation, that will affect Latronico N, Shehu I, Guarneri B. Use of electro- both recovery and weaning from mechanical physiologic testing. Crit Care Med 2009; ventilation, is determining if muscle is 37(Suppl): S316–S320. primarily affected or secondarily from disuse. Maramattom BV, Wijdicks EFM. Acute neuro- For patients with a functional denervation muscular weakness in the intensive care unit. due to complete axonal loss there will be little Crit Care Med 2006; 34: 2835–2841. reason to attempt weaning from mechanical Mertens HG. Disseminated neuropathy following ventilation until the nerves are reconnected coma. On the differentiation of so-called to muscle. Disuse atrophy can benefit from toxic polyneuropathy. Nerve-nartz 1961; 32: weaning trials. 71–79. Needham DM. Mobilizing patients in the inten- sive care unit: improving neuromuscular weak- Conclusions ness and physical function. J Am Med Assoc 2008; 300: 1685–1690. Critical illness neuropathy and myopathy repre- Osler W. The Principles and Practices of Medicine. sent a spectrum of neuromuscular disorders af- D. Appleton: New York, 1892. fecting both peripheral nerve and muscle found Van den Berghe G, Schoonheydt K, Becx P, et al. in critically ill patients. The process appears to be Insulin therapy protects the central and mediated through inflammatory cytokines re- peripheral nervous system of intensive care leased during the systemic inflammatory syn- patients. Neurology 2005; 64: 1348–1353. drome or sepsis. The incidence and severity of the process is directly related to the severity of Zink W, Kollmar R, Schwab S. Critical illness illness and length of stay in the intensive care polyneuropathy and myopathy in the intensive unit. Treatment focuses on early recognition and care unit. Nat Rev Neurol 2009; 5: 372–379. treatment of sepsis. A limited use of neuromus- Zochodne DW, Ramsey DW, Saly V, et al. Acute cular blockade may also prove useful. Prognosis necrotizing myopathy of intensive care: is related to the degree of axonal loss and muscle electrophysiological studies. Muscle Nerve involvement. Tight glucose control may limit the 1994; 17: 285–292. 21 Hypothermia: Application and Use in Neurocritical Care Edward M. Manno

Neurological Intensive Care Unit, Cleveland Clinic, Cleveland, OH, USA

Introduction and low flow states began to show significant neurological benefit. These results, coupled with Reducing core body temperature to treat neuro- several reports of excellent neurological out- logical injury is not a new concept. The observa- comes after prolonged submersion in ice water tion that hypothermia could be beneficial after in children playing ice hockey, invigorated the neurological injury was initially described in the search for the clinical application of therapeutic 1940s. Intraoperative hypothermia was applied hypothermia. during cardiac and neurological surgery in the 1950s and Peter Safar’s initial description of car- diac resuscitation included hypothermia as one Hypothermia: Mechanisms of its treatment modalities. Development and of Action and Therapeutic Targets widespead use did not occur primarily because A complex series of events occur after neurologi- of the intensity of care needed to manage patients cal injury and have been the source of a number on the hospital floors and the multiple complica- of reviews. In brief, cerebral ischemia leads to the tions encountered with moderate to deep hypo- development of cellular energy failure at the level thermia (26–32 C). of the mitochondria. The loss of ATP production In the 1990s several factors converged to sup- inhibits the activity of Na-K membrane pumps. port the application of hypothermia. One was the Loss of cellular integrity occurs as increases in development and refinement of intensive care extracellular glutamate leads to NMDA receptor- which could allow for resources to manage these mediated calcium entry into the cell. Intracellular complex patients. Similarly, preclinical research mediated excitotoxicity leads directly to cell suggested that the use of mild hypothermia could death through the production of free radicals accomplish the beneficial effects of hypothermia with subsequent membrane peroxidation and while avoiding many of the deleterious side ef- DNA fragmentation. fects of more aggressive hypothermia. Basic sci- Reperfusion prior to cell death can also lead to ence work from Myron Ginsberg’s laboratory and the production of free radicals which can worsen others began to outline the deleterious effects of neurological injury. Many cells that are initially fever and the therapeutic benefits of mild hypo- viable will also suffer subsequent death due to thermia on ischemic neurons. Animal models apoptotic mechanisms. Secondary injury is com- utilizing mild hypothermia during cardiac arrest mon in many types of neurological injury beyond

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

188 21 Hypothermia: Application and Use in Neurocritical Care . 189 cerebral ischemia and may include direct trau- (33 C) for 12 hours or normothermia. Cooling ma, cerebral edema, diffuse axonal injury, and was initiated immediately by paramedics apply- continued seizure activity. ing cold packs to the head and torso. Midazolam Hypothermia affects several areas not only in and vecuronium were used to prevent shivering the ischemic cascade of events but in multiple and aid temperature modulation. This study did other secondary events (Table 21.1). Cellular ox- not exclude older patients or those with pro- ygen and glucose requirements are uniformly longed hypoxia. The primary outcome variable lowered with decreased temperature. Blood– of favorable outcome (defined as hospital dis- brain barrier permeability is reduced with charge to home or a rehabilitation facility) was hypothermia, as is reperfusion injury. Epileptic improved from 26 to 49% (p < 0.05) After adjust- activity, microthrombus formation, and post- ments for age, baseline characteristics, and time injury inflammation is similarly reduced with for return of spontaneous circulation, the odds decreasing temperature. ratio for good outcome improved to 5.25 (CI: 1.47–18.76, p ¼ 0.011). Induced Hypothermia After Cardiac On the basis of these studies the American Arrest Heart Association and the Task force of the In- In 2002, two randomized-controlled trials con- ternational Liaison Committee on Resuscitation firmed the benefit of therapeutic hypothermia (ILCOR) recommended therapeutic hypothermia after cardiac arrest. All of the patients enrolled (33 C) for 12–24 hours post-cardiac resuscitation had witnessed events, with initiation of resusci- in patients with a presenting cardiac arrhythmia tation within 15 minutes and the return of spon- of ventricular fibrillation or ventricular tachycar- taneous circulation within 1 hour. Patients dia. A meta-analysis concluded that 6 patients needed to have a GCS score < 8 after the return would need to be treated to allow for 1 patient to of spontaneous circulation and the initial leave the hospital in good condition. rhythm had to be either ventricular fibrillation or ventricular tachycardia. On average, approxi- Therapeutic Hypothermia in Hospital mately 10% of patients screened were eligible for Arrest and for Nonventricular study. Fibrillation Arrest The largest study included 275 patients from Given the success of these studies, there is nine European hospitals; the patients were ran- considerable interest in expanding the use of domized to therapeutic hypothermia (defined as hypothermia after cardiac arrest beyond the in- 32–34 C) or normothermia after resuscitation clusion criteria of the initial studies. The majority from cardiac arrest. The trial excluded patients of patients after cardiac arrest present in either older than 75, presenting cardiac arrhythmia of asystole or PEA. There is increased risk of neuro- asytole and pulseless electrical activity (PEA), and logical injury in patients presenting with asytole patients with prolonged periods of post-resusci- or PEA since these rhythms most likely degener- tation hypoxia or hypotension. ated from preceding ventricular tachycardia The protocol initiated hypothermia upon ar- or fibrillation. Thus, asytole or PEA in these cir- rival to the hospital and used refrigerated cooling cumstances will represent an agonal end stage blankets to induce (goal within 4 hours) and arrhythmia with a longer period of cerebral is- maintain hypothermia for 24 hours. This was chemia or anoxia. In addition, asytole and PEA followed by a slow rewarming period over 12 will most likely represent a no-flow condition hours. Midazolam and vecuronium were used while ventricular tachycardia and fibrillation may for sedation and paralysis to prevent shivering. represent a persistent low-flow state. The results were impressive with an improve- Small pilot trials appear to confirm these sus- ment in 6 month mortality from 55 to 41% (RR, picions with only 7% of patients surviving after 0.74; CI: 0.58–0.95) and favorable neurological the return of spontaneous circulation in patients outcome from 39 to 55% (RR 1.4; CI: 1.08–1.81). presenting with either asystole or PEA. Given the The second study randomized 77 patients from low survival rate and poor outcome in this popu- four Australian hospitals to either hypothermia lation, the number of patients needed to achieve 190 . Neurological Complications and Consultations in General Intensive Care Units

Table 21.1. Potential mechanisms for the beneficial effect of hypothermia

Prevention of Ischaemia can induce apoptosis and Hours to many apoptosis* calpain-mediated proteolysis Hypothermia days or even can prevent or reduce this process weeks Reduced mitochondrial Mitochondrial dysfunction is a frequent Hours to days dysfunction, improved occurrence in the hours to days after an energy homoeostasis† episode of ischaemia, and might be linked to apoptosis Hypothermia reduces metabolic demands and might improve mitochondrial function Reduction of excessive Production of free radicals such as Hours to days free radical production† superoxide, peroxynitrite, hydrogen peroxide, and hydroxyl radicals is typical in ischaemia Mild-to-moderate hypothermia (30–35) is able to reduce this event Mitigation of Cascade of reactions following reperfusion, Hours to days reperfusion injury† partly mediated by free radicals but with distinctive and a range of features Suppressed by hypothermia Reduced permeability Blood-brain barrier disruptions induced Hours to days of the blood-brain by trauma or ischaemia are moderated by barrier and the hypothermia. The same effect occurs with vascular wall; reduced vascular permeability and capillary oedema formation* leakage Reduced permeability Decreased leakage of cellular membranes, Hours to days of cellular membranes with associated improvements in cell (including membranes function and cellular homoeostasis, of the cell nucleus)† including decrease of intracellular acidosis and mitigation of DNA injury Improved ion Ischaemia induces accumulation of First minutes homoeostasis† excitatory neurotransmitters such as to 72 h glutamate and prolonged excessive influx þ of Ca2 into the cell. This activates numerous enzyme systems (kinases) and induces a state of permanent hyperexcitability (exitotoxic cascade), which can be moderated by hypothermia Reduction of Cellular oxygen and glucose requirements Hours to days metabolism* decrease by an average of 5–8% per degree Celsius decrease in temperature Depression of the Sustained destructive inflammatory First hour immune response reactions and secretion of proinflammatory to 5 days and various cytokines after ischaemia can be blocked potentially harmful or mitigated by hypothermia proinflammatory reactions* 21 Hypothermia: Application and Use in Neurocritical Care . 191

Table 21.1. (Continued ) Reduction in cerebral Some areas in the brain have significantly Minutes to thermopooling* higher temperatures than the surrounding many days areas and measured core temperature. These differences can increase dramatically during injury, with up to 2–3C higher temperatures in injured areas of the brain. Hyperthermia can increase the damage to injured brain cells; this is mitigated by hypothermia Anticoagulant Microthrombus formation might add to Minutes to days effects* brain injury after CPR. Anticoagulant effects of hypothermia might protect against thrombus formation. Thrombolytic therapy has been shown to improve outcome after CPR7 Suppression of Many patients experience seizures after Hours to days epileptic activity ischaemic episodes or trauma, or both, and seizures* which might add to injury. Hypothermia has been shown to mitigate epileptic activity

On the basis of observations in animal studies, with some support from clinical observations (e.g., reduction in inflammatory response and pro-inflammatory cytokine levels associated with hypothermia after traumatic brain injury and CPR: decrease in excitatory transmitters measured using microdialysis probes in human beings; decrease in local brain hyperthermia). CPR-cardiopulmonary resuscitation. *Some supporting clinical evidence. †Animal studies only. Reproduced from Polderman KH, 2008 with permission from Elsevier.

statistical significance in a randomized trial trolled trial is unlikely. However, in selected pa- would be unfeasible. Nevertheless, given the tients where neurological injury is probable, the safety of therapeutic hypothermia there appears use of therapeutic hypothermia seems warranted. little reason not to consider initiating a protocol. The Post Cardiac Arrest Care Section of the 2010 An in-hospital cardiac arrest differs from an American Heart Association Guideline for Cardio- out-of-hospital arrest in several features. The pulmonary Resuscitation and Emergency Cardio- response time and return of spontaneous circu- vascular Care suggests that induced hypothermia lation may be faster during in-house resuscita- may be considered for comatose patients with a tion. Patients in cardiac care units can often have return of spontaneous circulation after in-house their circulation restored immediately with little cardiac arrest or out-of-house cardiac arrest with neurological effect. Out-of-hospital cardiac arrest an initial rhythm of asytole or PEA. is primarily attributed to underlying cardiac dis- Application of Therapeutic ease, while in-hospital cardiac arrest can be secondary to a number of factors, including re- Hypothermia: Technical Aspects spiratory insufficiency, sepsis, pulmonary embo- The optimal timing, technique, and duration of lism, electrolyte abnormalities, etc. therapeutic hypothermia are currently unknown. The rate of survival to hospital discharge after Animal studies suggest that hypothermia should in-hospital cardiac arrest is only 18% according be initiated as soon as possible post-cardiac ar- to data obtained from the National Registry of rest. Better neurological outcomes are achieved Cardiopulmonary Resuscitation. Given this poor in laboratory animals if cooling is initiated during survival rate, the feasibility of performing a con- resuscitation; however, clinical studies have yet 192 . Neurological Complications and Consultations in General Intensive Care Units to verify this observation. In fact, even delayed Another question not addressed by the current hypothermia may provide some benefit. In the state of the literature is whether noncomatose European study, the target temperature was not survivors of cardiac arrest may benefit from ther- attained for 16 hours in many patients. Various apeutic hypothermia. These studies will require a methods to achieve hypothermia have, however, long-term follow up and more sensitive measures been developed since the initial studies. The of cognitive outcome. European study applied forced-air-cooling blan- Shivering will greatly increase the cerebral kets upon arrival at the hospital. The Australian metabolic rate and can actually impair the neu- study applied ice packs to the head and torso. roprotective effects of therapeutic hypothermia. Cooling was initiated by emergency personnel Care to prevent and manage shivering is crucial during transport to the hospital. Each technique for the induction and maintenance of hypother- has selected advantages and disadvantages: cool- mia. In the European and Australian studies, ing blankets took longer to achieve therapeutic patient shivering was prevented through heavy target temperatures, however ice packs may be sedation and paralysis, using both midazolam more cumbersome and make the titration of and vecuronium. Sedation and paralysis were exact temperatures difficult. continued during the rewarming phase. Newer cooling devices applied directly to the In practice, a series of medications and man- limbs and torso have been developed. The tem- euvers can be used to prevent shivering. The perature can be closely regulated through a feed- highest number and density of skin temperature back mechanism from bladder thermometers. receptors are found on the face, hands, and feet. These devices are noninvasive and can be applied Surface counter rewarming with attention to the by nursing or auxiliary personnel. Skin care is also hand, feet, and face can provide sufficient hypo- important since devices left in place for extended thalamic feedback in many instances to prevent periods can lead to burns. shivering. This approach may seem counterintu- Invasive cooling devices that have also been itive since surface or intravascular cooling may developed are placed in a central vein using the occur with surface warming of the hands and same technique for central line placement. Tem- face. Rewarming of these thermoregulators can perature control is modulated through iced saline suppress shivering while allowing the mainte- infused into a bladder which is in contact with nance of hypothermia. venous blood. The procedure is invasive, requires A number of medications are also used to physician placement, and carries all the risks of suppress shivering. Traditional measures using an invasive line. The technique, however, may acetaminophen and/or ibuprofen are largely in- achieve faster times to target temperatures and effective in temperature control and the preven- can be placed during other procedures such as tion of shivering in the brain-injured patient. The cardiac catheterization. most effective medication to prevent shivering is Other methods currently being studied are meperedine; however, it must be used judici- nasopharyngeal cooling through the use of ously, given its multiple metabolites and poor perfluorochemical evaporation administered via side effect profile (most notably, lowering the nasal prongs. This is effective in decreasing seizure threshold). Intravenous magnesium low- forebrain temperature in animal studies and is ers the shivering threshold and may provide currently being investigated in clinical trials. The some neuroprotective effects. Some authors sug- infusion of large volumes of intravenous iced gest maintaining magnesium levels between 3 crystalloids is also effective in lowering the body and 4 mg/dL. Buspirone is a serotonin 1A partial temperature quickly. Clinical trials to date sug- agonist often used to prevent shivering. It is less gest that pulmonary edema has not been prob- sedating than many of the other medications lematic with the use of iced crystalloids. listed and can be used in combination with other The optimal duration of hypothermia is also agents. Dexetomidate used as a drip or in com- unknown. Preclinical studies suggest that longer bination with meperidine or buspirone can be hypothermic time may improve outcome but will particularly effective in controlling shivering. A need further study for clinical verification. stepwise protocol with increasing measures to 21 Hypothermia: Application and Use in Neurocritical Care . 193 decrease shivering can also be employed. Shiver- metabolism and drug disposition. These studies ing management is reviewed in Mahmood (2007). suggested that the clearance of medications me- There are many potential complications that tabolized by the enzyme cytochrome P450 can develop with the use of therapeutic hypo- were decreased 7–22% for each change in degree thermia. The most worrisome are bleeding and Celsius. This would have considerable influence sepsis. Multiple metabolic derangements are also on many sedative medications commonly used in common with induced hypothermia and can patients’ post-cardiac arrest. include the development of a metabolic acidosis, The prognostic significance of biochemical hyperglycemia, and hypokalemia. Lactate levels markers and physiological studies in cardiac are commonly elevated during hypothermia, arrest patients treated with therapeutic hypo- however levels above 5–6 mmol/L should raise thermia has also been studied in small series. In concern for sepsis or worsening cardiac function. one study a decrease in neuron-specific enolase Rewarming is performed slowly to avoid obtained 24–48 hours post event was associated rapid electrolyte shifts (hyperkalemia can occur with good neurological outcome. This was in the rewarming stage as potassium shifts into more commonly found in patients treated with the extracellular space), vasodilation, shivering, therapeutic hypothermia. In another study a and potential worsening neurological injury. The neuron-specific enolase level of >33 mg/L had a European study allowed for passive rewarming false positive rate of 29%. over 8 hours while the Australian study initiated The utility of somatosensory-evoked potentials controlled rewarming over 6 hours. has also been questioned in the setting of thera- peutic hypothermia. Two out of 36 patients tested Neurological Prognostication with bilateral absence N20 responses had good outcomes. While the majority of patients had after Therapeutic Hypothermia poor outcomes, the authors concluded that ab- Determining neurological prognosis after cardiac sent N20 responses alone should not be used to arrest may be more difficult with the use of limit therapies. Similarly, 4 of 6 patients with therapeutic hypothermia. In 2006 the American post-anoxic status treated with therapeutic hy- Academy of Neurology developed practice pothermia had moderate recoveries. One patient parameters for the prediction of neurological was described as having a complete neurological outcome in comatose patients after cardiac ar- recovery. rest. Almost 400 publications were reviewed and The neurological examination continues to be recommendations were based and categorized the most useful for prognostic guidance in pa- on a progressive classification scheme. Clinical tients treated with therapeutic hypothermia after features that were predictive of poor outcome cardiac arrest. Rosetti et al. (2010) studied 111 included: myoclonic status epilepticus within patients treated with hypothermia post-cardiac the first 24 hours, absent pupillary or corneal arrest. The clinical findings of incomplete brain- responses within the first 3 days, or absent or stem reflexes, myoclonus, and absent motor re- extensor posturing after 3 days. The bilateral sponses obtained 3 days post-arrest individually absence of the N20 component of the somato- had a false positive rate that varied between 4 sensory-evoked potential recorded 1–3 days post and 24%. Interestingly, two of these findings in event was similarly predictive of poor outcome. combination continued to have prognostic sig- The biochemical marker, neuron-specific eno- nificance for poor outcome. A nonreactive EEG lase, was predictive of poor outcome if a level of was also incompatible with a good functional 33 mg/L or greater is recorded 1–3 days post event. outcome. A retrospective series from the Mayo Therapeutic hypothermia confounded normal Clinic compared neurological findings in 103 neurological prognosis after cardiac arrest from patients treated with hypothermia post-cardiac many potential mechanisms. One possible arrest and compared them with 89 patients mechanism is through the effect on drug metab- that were not treated with therapeutic hypother- olism. A systematic review of 21 studies evaluated mia. In this series the findings of absent pupillary, the effects of hypothermia and rewarming on corneal, or motor responses 3 days post-cardiac 194 . Neurological Complications and Consultations in General Intensive Care Units arrest remained predictive of poor neurological A subsequent trial of hypothermia initiated outcome. More work will need to be done in soon after injury also failed to show any benefit this area. of therapeutic hypothermia. A subset analysis of this study, however, revealed that patients who The Use of Therapeutic were randomized to hypothermia and had had Hypothermia in other surgical evacuation of a subdural hematoma Neurological Diseases had a trend toward better outcomes that those Traumatic Brain Injury who were maintained at normal temperatures. Currently the 2007 Guidelines for Severe Trau- The application of therapeutic hypothermia has matic Brain Injury state that there is insufficient not been limited to cerebral anoxic damage. Over data to support the use of therapeutic hypother- the past 20 years several clinical studies have mia for traumatic brain injury. A review by the assessed the efficacy of therapeutic hypothermia Cochrane data group in 2009 made similar after traumatic brain injury. There were signifi- recommendations. cant variations in trial design and treatment Despite the failure of large clinical trials to protocols. Although results varied, there were reveal any benefit for hypothermia in traumatic enough positive trends in outcomes to fund brain injury, some enthusiasm for this treatment larger clinical trials. remains. One possible explanation for the failure What appeared to be clear from these clinical of efficacy may be that the duration of treatment studies was that hypothermia was effective in was insufficient. There is some preliminary data lowering intracranial pressure. What was un- to suggest that maintaining hypothermia for known was whether the induction of hypothermia greater than 48 hours may improve the outcome. could improve long-term patient outcome. In A meta-analysis of several small series reported 2001 a controlled trial of 392 patients randomized an improved outcome when hypothermia is patients to therapeutic hypothermia or normo- continued for 2–5 days post-traumatic injury. thermia. The target goal was to reach, and main- The Eurotherm 3235 Trial is a multicenter tain, atemperatureof33 Cfor 48hours.Therewas randomized-controlled trial scheduled to enroll no improvement in mortality or functional out- 1800 patients over 41 months. In this trial come. However, on subset analysis there was a hypothermia will be maintained for an indefinite trend for patients that were younger than 40, and period to maintain an intracranial pressure below patients that were hypothermic on presentation 20 mm/Hg. (that were randomized to the hypothermia group), to show significant improvement. Ischemic Stroke SCIENCE REVISITED Therapeutic hypothermia has been investigated for the treatment of ischemic stroke. The appli- The decrease in intracranial pressure found cation of therapeutic hypothermia to noncoma- with hypothermia is most likely accounted tose patients may be difficult since conscious for by a decrease in cerebral metabolic rate. patients may require significant amounts of A decrease in cerebral metabolic rate will be sedation to induce hypothermia and prevent accompanied by a decrease in cerebral blood shivering. flow and subsequent cerebral blood volume. The feasibility of inducing hypothermia in Since the brain is enclosed within a fixed conscious patients with an ischemic stroke was space (the skull), a decrease in blood volume initially tested in a phase I trial and was subse- will result in a decrease in pressure. Long- quently followed by a phase II study. In the term benefits of hypothermia may be Cooling for Acute Ischemic Brain Damage II secondary to decreases in the formation study, 18 patients were randomized to a target of cerebral edema. temperature of 33 C within 12 hours of onset and were compared to 22 patients with standard 21 Hypothermia: Application and Use in Neurocritical Care . 195 medical therapy. The target temperature was Subarachnoid Hemorrhage maintained for 24 hours. In the hypothermic A single study assessed the feasibility of applying group, mean diffusion-weighted imaging lesion and maintaining therapeutic hypothermia after growth was lower than in the nontreated group subarachnoid hemorrhage for the treatment of but the results were statistically insignificant. recalcitrant cerebral edema. Twenty-one high- There was also no difference in the long-term grade patients after subarachnoid hemorrhage outcome between treatment and control groups. (SAH) were treated with therapeutic hypother- Approximately 40% of the patients treated with mia. One group was treated for less than 72 hours hypothermia required endotracheal intubation. and another for greater than 72 hours. No differ- While these trials demonstrated the feasibility of ence was noted on functional independence after applying hypothermia to this population, they 3 months. were not powered sufficiently to address ques- The success of intraoperative hypothermia in tions of efficacy. patients undergoing cardiopulmonary bypass or A similar study analyzing CSF volumes on temporary circulatory arrest has led to an interest computed tomography scans as a surrogate for in expanding this modality to other neurosurgical cerebral edema, demonstrated a tendency for procedures. The Intraoperative Hypothermia for decreased amounts of post-stroke cerebral Aneurysm Surgery Trial randomized 1001 good edema in 18 patients treated with therapeutic grade SAH patients to an intraoperative temper- hypothermia as compared to a control group. In ature of 33 C or to a normothermia group with a this study, however, CSF volumes normalized temperature of 36.5 C. No statistical difference within 30 days and infarct volumes and func- was noted in ICU or hospital length of stay or tional outcomes were no different. 6-month functional outcome. The lack of differ- Therapeutic hypothermia has been evaluated ence in functional outcome may be attributed for the management of malignant cerebral edema to the overall good clinical condition of these in large hemispheric infarcts. Reported mortality patients. rates were better than historical controls but worse than those reported with hemicraniec- tomy. These trials were hindered by medical Intracerebral Hemorrhage complications and difficulties with managing No study to date has assessed therapeutic hypo- rebound intracranial hypertension during the thermia in the treatment of intracerebral rewarming phase. Therapeutic hypothermia hemorrhage. combined with hemicraniectomy was studied and 25 patients randomized to either hemicra- Status Epilepticus niectomy alone or in combination with hypother- One small case series reported control of refrac- mia. Mortality was 12% in both groups and there tory status epilepticus when therapeutic hypo- was a trend for improved NIH stroke scores for thermia was added as an adjuvant therapy. No the hypothermia group. systematic trials have been studied. The above studies appear to suggest that hy- pothermia alone may be ineffective in ischemic stroke; however, it may serve as an effective Spinal Cord Injury adjuvant treatment. To that end trials are Animal models evaluating cooling strategies in currently underway, including hypothermia cou- thoracic and cervical contusions have reported pled with IV thrombolytic therapy (in an attempt improved locomotive function and forelimb to extend the window for administration of tPA) grip strength after treatment with therapeutic hy- and other pharmacologic agent such as caffeine pothermia. To date no clinical studies have been and ethanol. To date, however, the American undertaken. The American Association of Neuro- Heart Association guidelines for the treatment of logical Surgeons/Neurological and Spinal Surgery acute ischemic stroke cannot recommend the use Joint Sections of the Disorders of the Spine and the of therapeutic hypothermia. Joint Section of Trauma state that there is no 196 . Neurological Complications and Consultations in General Intensive Care Units evidence to recommend either for or against the Bernard SA, Gray T, Buist MD, et al. Treatment of practice of therapeutic hypothermia as a treat- comatose survivors of out of hospital cardiac ment for acute spinal cord injury. arrest with induced hypothermia. New Engl J Med 2002; 346: 557–563. Conclusions Clifton GL, Valadka A, Zygun D, et al. Very early Significant preclinical and basic science work hypothermia induction in patients with sever supporting the use of therapeutic hypothermia brain injury (the National Acute Brain Injury to treat neurological injury was verified in two Study: Hypothermia II): a randomized trial. studies reporting improved neurological out- Lancet Neurol 2011; 10: 131–139. comes after cardiac arrest with the use of induced Fugate JE, Wijdicks EFM, Mandreker J, et al. Pre- mild hypothermia. dictors of outcome and patient surviving car- While the exact mechanism of action is un- diac arrest. Ann Neurol 2010; 68: 907–914. known, therapeutic cooling is known to affect Ginsberg MD, Sternau LL, Globus MY, et al. Ther- several steps in the ischemic cascade of neuro- apeutic modulation of brain temperature: rel- logical injury. evance to ischemic brain injury. Cerebrovasc The implementation of therapeutic hypother- Brain Metab Rev 1992; 4: 189–225. mia requires initiation soon after resuscitation, Holzer M, Bernard SA, Hachimi-Idrissi S, et al. and preclinical models suggest that cooling (on behalf of the Collaborative Group in Induce should start during resuscitation. The questions Hypothermia for Neuroprotection after Cardi- still remain as to the timing and duration of ac Arrest). Hypothermia for neuroprotection treatment and to whether this treatment can be after Cardiac arrest: Systematic review and extended to cardiac arrest if the initial discovered individual patient data meta-analysis. Crit Care rhythm is a systole or pulseless electrical activity. Med 2005; 33: 414–418. Clinical work evaluating the effects of hypother- Linares G, Mayer SA. Hypothermia for treatment mia on neurological prognostication after cardiac of ischemic and hemorrhagic stroke. Crit Care arrest is currently underway. The expansion of Med 2009; 37(Suppl): S243–S249. therapeutic hypothermia to other areas of neu- Mahmood MA, Zweifler RM. Progresss in shiver- rological injury has been less successful. Enthu- ing control. J Neurol Sci 2007; 261: 47–54. siasm continues for its use in traumatic brain injury, although clinical trials to date have not Polderman KH, Herold I. Therapeutic hypother- been able to provide evidence for a benefit. Fur- mia and controlled normothermia in the inten- ther work is needed in neurological ischemia sive care unit: Practical considerations, side from subarachnoid hemorrhage and intracere- effects, and cooling methods. Crit Care Med bral hemorrhage. Therapeutic hypothermia may 2009; 37: 1101–1120. prove beneficial as an adjuvant treatment for Polderman KH. Induced hypothermia and fever acute ischemic stroke. control for prevention and treatment of neu- rological injuries. Lancet 2008; 371: 1955–1969. Rosetti AO, Oddo M, Logroscino G, Kaplan PW. Bibliography Prognostication after cardiac arrest and hypo- Badjatia N. Hyperthermia and fever control in thermia. A postoperative study. Ann Neurol brain injury. Crit Care Med 2009; 37(Suppl): 2010; 67: 301–307. S250–S257. The Hypothermia After Cardiac Arrest Study Bernard S. Hypothermia after cardiac arrest: Ex- Group. Mild therapeutic hypothermia to im- panding the therapeutic scope. Crit Care Med prove the neurological outcome after cardiac 2009; 37: S227–S233. arrest. New Engl J Med 2002; 346: 549–556. 22 Etiologies of Posterior Reversible Encephalopathy Syndrome and Forms of Osmotic Demyelination Syndrome J. Javier Provencio

Cerebrovascular Center, Cleveland Clinic, Cleveland, OH, USA

Introduction (Bartynski, 2008). As this theory is still not well tested, I suggest that we stick with PRES at the Among the myriad of diseases that can cause moment. acute neurological dysfunction, two which are In the case of ODS, there have also been a commonly linked together, are the syndrome of number of names given to the syndrome, includ- posterior reversible encephalopathy (PRES) and osmotic demyelination syndrome (ODS). These ing central pontine myelinolysis and extrapon- two diseases have a number of things in com- tine myelinolysis. Again, when it was recognized mon, which make them natural partners for this that these were the same syndrome with different chapter. manifestations, the term “osmotic demylination” First, they are both poorly named. PRES and was adopted. Unlike PRES, however, this name its common subtypes have gone through a actually does represent what occurs in this number of name changes, including hypertensive disease. encephalopathy, eclampsia-associated encepha- Second, both of these syndromes reflect aber- lopathy, and transplant-associated encephalop- rations of control of water in the brain and both athy. It has been recognized that all of these lead to edema. In the case of PRES the problem syndromes are probably the same process man- seems to be in the control of the blood–brain ifesting in a number of different disease states. barrier leading to the development of vasogenic The term “PRES” has largely been settled on in edema; in ODS, the central aberration is the loss the literature despite the fact that the injury in of the ability to regulate the osmotic milieu of the PRES is not always (and not even commonly) brain parenchyma leading eventually to the de- posterior and is not always reversible. This velopment of cytotoxic edema. leaves only the words “encephalopathy” and In this chapter, we will take each syndrome in “syndrome” that are accurate, but they are so turn. We will discuss the prevailing theories vague that they are not useful. There has been at about their causes because they inform our least one call to change the name again to decisions for treatment. We will discuss the com- “neurotoxic vasogenic edema syndrome” based mon presentations in the patients, including sub- on a theory of the true cause of the edema groups, that are most affected. We will discuss

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

197 198 . Neurological Complications and Consultations in General Intensive Care Units

Figure 22.1. Neuroimages of 38 patients with reversible posterior leukocephalopathies. The top row represents the initial images while the bottom row represents repeat imaging at a later point. Note that not all leukoencephalopathies are posterior. (Reproduced from Lee et al., 2008. Copyright Ó (2008) American Medical Association. All rights reserved.)

imaging including the pitfalls to making the cor- where it was noticed that women with eclampsia rect diagnosis. Finally, we will discuss treatment occasionally developed an encephalopathic syn- algorithms based on the prevailing theories. drome that, on computer tomography (CT) scans It is important to note that as both of these of the head, showed hypodensities suggesting entities are less common and, therefore, do not edema in the occipital and parietal lobes. Not avail themselves to large clinical treatment long after, reports in patients with accelerated trials, the algorithms will be based on small hypertension surfaced. Because both of these trials, common practices, and the theory of the original entities shared hypertension as a cardi- cause of the insult. In addition, particularly in nal feature, it was assumed that the edema was regard to PRES, there is still controversy sur- due directly to the hypertension. The initial com- rounding the actual cause and, therefore, the mon theory was that the pressure induced locally treatment that should be implemented. The by the hypertension caused damage to the blood– chapter will include the common treatment al- brain barrier and water was forced into the brain. gorithm with the understanding that in the near This theory could be called into question for two future it may fall out of favor. An attempt will be reasons: (1) the amount of hypertension does made to highlight areas that are likely to change not predict who will develop PRES, or its severity in the future. (in fact, most patients with PRES do not have sufficiently high blood pressure to overcome ce- Posterior Reversible rebral autoregulation); and (2) clinical scenarios Encephalopathy would become apparent (including medication PRES has been recognized in one form or another toxicities) in which hypertension was not a prom- for decades but the initial published reports dealt inent feature. Despite the change in name and exclusively with patients with a single instigating understanding of the links to hypertension, anti- disease (reviewed in Hefzy et al., 2009). The hypertensive therapy remains an important pillar earliest reports were from the obstetric literature of therapy. 22 Etiologies of Posterior Reversible Encephalopathy Syndrome . 199

TIPS & TRICKS also has detrimental effects on the endothelium, as does cyclosporine and other chemotherapeu- PRES is not just a disease of hypertension. tic agents. The effects of autoimmune diseases on Thinking of the disorder as a toxic the endothelium are less well studied, and have phenomenon will help determine and conflicting findings. There is also the possibility ameliorate the cause. At risk populations that this syndrome develops either indepen- include chronic hypertension, pregnancy, dently or from the interplay between the above solid particularly mechanisms. those on cyclosporine and tacralimus. The implication of this non-hypertension me- diated alternative theory (that cyclosporine is directly toxic to blood vessels and is therefore the PRES has now been described in a multitude of cause of PRES) is that our current therapy of disease processes. The most common include lowering blood pressure may be detrimental. Hy- pre-eclampsia/eclampsia, accelerated hyperten- pertension and its associated vasoconstriction sion with no other cause, allogenic bone marrow may decrease the amount of blood that crosses transplantation (allo-BMT), in patients taking that damaged vasculature, subsequently decreas- cyclosporine (and occasionally tacrolimus), in ing the amount of edema (this may account for the patients with autoimmune diseases (with or finding in cyclosporine patients that hypertension without cyclosporine treatment), and in patients is associated with more limited disease). In addi- receiving chemotherapy. Interestingly, of the tion, hypertension may have the additional effect patients taking cyclosporine who develop PRES, of helping to perfuse distal arterial beds, limiting those with hypertension seem to have less severe damage to the blood vessels and preventing vasogenic edema than patients who do not further edema (similar to findings in stroke). have hypertension, calling into question whether Although water has previously been thought to hypertension is truly the cause of PRES. transit across the BBB easily, this is now known to If not hypertension, then it is clear that the be mediated by a specific channel, aquaporin-4. process leading to PRES must have the ability to Work in animals suggests that water transport affect both the brain and be associated with across the BBB is regulated in large part by hypertension in some patients. The obvious aquaporin-4, and recent work has identified body systems that have the potential to affect aquaporin-4 as a possible agent in the develop- the blood–brain barrier (BBB) integrity and lead ment of PRES. to hypertension are the kidneys and the endothe- lial cells of the vasculature. It is still not certain if either of these systems is the ultimate cause of SCIENCE REVISITED PRES but both deserve further discussion. Interestingly, eclampsia, accelerated hyperten- PRES has been thought of as hypertensive sion, cyclosporine, and autoimmune disorders all encephalopathy. There is considerable share renal failure as a common manifestation. evidence that PRES presents itself in patients The rennin angiotensin system is important in without hypertension or in patients in whom the regulation of blood pressure, and stenosis hypertension does not seem to be the culprit. of the renal artery clearly leads to accelerated Newer theories of PRES suggest that there are hypertension. How the renal system would affect multiple mechanisms that may injure brain the permeability of the cerebral vasculature to vascular endothelial cells. It is important to water is still not clear. The release of vascular take nonhypertensive causes of PRES, even in endothelial growth factor from the kidney is one patients with a history of hypertension. possible mechanism. In regard to the vascular endothelium, there are more mechanisms to consider. It is clear that Imaging eclampsia leads to endothelial dysfunction and The imaging of PRES can be difficult for the endothelial damage in some cases. Hypertension nonradiologist. The common, textbook images 200 . Neurological Complications and Consultations in General Intensive Care Units show patients with occipital and parietal bilateral CAUTION vasogenic edema affecting both the cortex and subcortical white matter on either CT or MRI Lowering blood pressure precipitously in of the brain. In fact, the other common sites for patients with chronic hypertension may PRES include the frontal lobes, the inferior lead to ischemia due to the shift of the temporal-occipital junction, and the cerebellum. autoregulation curve toward hypertension. Although bilateral lesions are the most common finding, there are reports of mostly unilateral or asymmetrical patterns. In some patients, the In the case of cyclosporine toxicity, stopping occipital and parietal lobes are not involved. the cyclosporine often helps to resolve the issue. Some authors have attempted to categorize the This may not be a simple decision since patients localization into three subtypes: holocerebral, often take cyclosporine to prevent organ rejec- superior frontal, and occipital-parietal. This clas- tion after solid organ transplant. The decision to sification, although tempting, has many excep- stop cyclosporine may risk failure of the trans- tions and may be an oversimplification. planted organ. Failure to stop the medicine, in our experience, has lead to a continuation of the edema. With the approval of tacrolimus, the de- TIPS & TRICKS cision whether to continue or stop cyclosporine PRES was originally thought to only present was made easier. In many cases, changing in the occipital lobes. Although a significant to tacrolimus has helped to resolve the PRES. number of patients have some occipital lobe Although there are case reports of tacrolimus- involvement, lesions can appear anywhere in induced PRES, they are less frequent. the white matter with edema extending to the cortex. CAUTION

The vasogenic edema in PRES usually resolves In patients with solid organ transplantation completely within a week. In some patients, where cyclosporine or tacralimus are thought however, intracerebral hemorrhage and stroke to be the culprit, stopping these drugs acutely have been noted in the areas of PRES. There are may lead to acute organ rejection and reports of permanent damage, particularly in death. Close consultation with the transplant patients with eclampsia. The one finding that is physicians is important. consistent in PRES is the presence of diffusion- weighted lesions without changes in the actual diffusion coefficient (ADC) suggesting vasogenic Autoimmune disorders pose a particular edema and not infarction. In less than classic problem. Many patients with autoimmune dis- cases, consultation with a radiologist with expe- orders take immunosuppressive medications rience in neurologic imaging can be very helpful. including cyclosporine. It can be a difficult to determine if the autoimmune disease or the Treatment treatment is the culprit. If the autoimmune dis- Because of the lack of conclusive evidence for ease is to blame, the rational treatment is to the causative agent for PRES, the treatment has intensify therapy. The converse would be true if centered on stopping the offending agent and the treatment is to blame. controlling the blood pressure. In the case of The second mainstay of therapy is hyperten- eclampsia, there is evidence that the placenta sion control. As mentioned earlier, this may be of may be the offending agent. If PRES occurs dur- benefit or may be detrimental. In patients with ing the pregnancy, delivery of the baby is almost accelerated hypertension as the cause of PRES, it always curative. If it occurs after the birth of the seems reasonable to lower the blood pressure child, retained placental products are often found cautiously. It is important to remember that and removal seems to be curative. patients with prolonged untreated hypertension 22 Etiologies of Posterior Reversible Encephalopathy Syndrome . 201 have a shifted cerebral autoregulation curve that other parts of the body. Sodium moves across may predispose them to ischemia at pressures the BBB through an energy-dependent channel that we would normally consider normotensive. (Na-K ATPase pump). When the blood becomes For this reason, in our institution, we lower mean hypo-osmolar, the oncotic pressure difference arterial blood pressure by about 15% from the favors entry of water into the brain (which moves highest recorded value. The exception to this rule freely across the BBB). This results in cerebral is in patients who have significant enough edema edema. The immediate response from the astro- to increase the intracranial pressure. In this situ- cytes and endothelial cells is to move the sodium ation, lowering the mean arterial pressure to a out of the brain, thereby decreasing the osmolar- pressure that will keep the cerebral perfusion ity of the brain interstitium and force water out of pressure (CPP) greater than 60 mm/Hg seems the brain. If the blood osmolarity increases acute- reasonable (although untested in this patient ly at this stage, the brain is usually capable of population). shifting sodium ions across the BBB quickly en- Because the science behind PRES is still un- ough to prevent damage to the myelin. clear, it is possible that the treatment strategy The risk of ODS increases the longer the hypo- may change with new studies. Ultimately, sup- osmolarity is present. The ability of the brain to portive care with careful attention to complicat- manage osmolarity with sodium efflux in the ing issues in the intensive care unit may offer the setting is limited and can be expended over time. most benefit. Renal failure seems to be associ- Once the ability of the brain to manage osmolar- ated with many of the processes that lead to ity changes (by moving sodium out of the brain) PRES. The monitoring of renal function and is expended, the brain resorts to moving proteins consultation with a nephrologist may be of par- and other complex chemicals, collectively called ticular benefit. organic osmoles (often referred to as idiopathic osmoles) across the BBB to prevent the brain Osmotic Demyelination swelling. Although this process is effective at normalizing the osmolar gradient between the Syndrome brain and the blood, the complex nature of ODS was first described in 1959 in 4 patients with the organic osmoles makes transport back to the myelin loss in the central pons. At the time, the brain slow. This increases the risk that if the blood syndrome was associated with poor nutrition osmolarity is rapidly corrected, the brain (need- (particularly in alcoholic patients). The asso- ing to reaccumulate organic osmoles) takes a ciation with sodium correction was made defini- long time to normalize the gradient. During tively in 1981. the time between the normalization of osmolarity The pathophysiology of ODS is not well un- of the blood and the slower process of re- derstood. Almost all physicians have had the establishing the organic osmoles, the concentra- experience of a patient who becomes hypona- tion of blood is higher than that of the brain, tremic in the hospital and is inadvertently cor- leading to water movement from the brain to the rected faster than expected by algorithms of blood. The ensuing change in water content sodium replacement. In these cases, ODS is un- causes demylination of susceptible brain tissues. common. The response of the clinician is invari- For many years, it was thought that ODS was a ably surprise and a feeling of luck. A better disease of alcoholics. This is likely due to the understanding of the physiology that leads to chronic hyponatremia and hypo-osmolarity as- ODS would reveal that this patient is unlikely to sociated with chronic alcoholism. This led to become ill. hypotheses that there may be deficiencies in To understand ODS, it is important to under- specific nutritional cofactors that contribute to stand water and sodium balance in the brain. the predisposition to ODS. No cofactors have Because of the unique relationship between the been found to date, and the current theory of vascular endothelial cells, astrocytes and neurons organic osmole loss accounts for the syndrome that make up the BBB complex, solute manage- well enough that other factors need not be con- ment in the brain is dissimilar from that of many sidered. It is now recognized that patients with 202 . Neurological Complications and Consultations in General Intensive Care Units cancer, severely malnourished patients, solid or- pathophysiology. It is clear that certain parts of gan transplantation patients, and patients who the brain, particularly deep gray structures, are take medicines that cause the chronic syndrome more susceptible to demyelination. The reasons of inappropriate antidiuretic hormone (SIADH), forthisareunclear. as well as other causes of chronic hyponatremia, Imaging with MRI is more sensitive than CT. are at increased risk of ODS. The lesions are hypointense on T1-weighted There is still debate whether rapid correction images and hyperintense on T2 and FLAIR lesion. of sodium in nonchronically hyponatremic There may be the T2 shine-through phenomenon individuals can overwhelm the Na-K ATPase on diffusion-weighted images (DWIs). The diag- pump. There is no conclusive evidence that nosis is made by the acute development of this is the case but most practitioners practice lesions in classic areas in a patient with hypona- prudence in the acute situation because there tremia and acute neurological deterioration. are rarely times when rapid correction of The areas most often seen in this syndrome are sodium is necessary. The exceptions are cases of the central pons, thalamus, basal ganglia, and severe hyponatremia with seizures or cardiac deep cerebellar nuclei. Occasionally, the subcor- arrhythmias. tical white matter is also affected. In some cases, this syndrome can be confused with PRES.

Treatment CAUTION There are no effective treatments for ODS, so Remember hidden sodium sources in prevention is the most important strategy. With intravenous fluids, medications and food in reported mortality ranging from 6% to greater patients in whom sodium is being repleted. It than 90% and permanent morbidity common, is imperative that serum sodium levels be the careful and slow correction of sodium has monitored frequently with appropriate become the norm. Most guides suggest correct- changes in therapy based on these results. ing hyponatremia no faster than 10–12 mEq/L Reliable bedside sodium analysis is most per day. There are clearly patients who survive advantageous. rapid correction without demyelination and some patients who develop the syndrome at slower correction rates. There are reports that hypokalemia may potentiate the effects of rapid SCIENCE REVISITED correction. ODS is due to the inability of the brain to rapidly adjust to osmolarity changes in blood after compensatory changes in the brain to TIPS & TRICKS control brain edema in the setting of chronic hyponatremia. Once organic osmoles are ODS is better prevented than treated. Replete transported out of the brain, rapid correction sodium no faster than 10–12 mEq/L/day can cause cell contraction and particularly in patients susceptible to ODS: demyelination. chronic alcoholics, severely malnourished patients, transplant and cancer patients.

Imaging There are a number of theoretical treatments The initial description of ODS focused on de- that have been proposed. Acutely lowering serum myelination of the central pons region leading to sodium in a patient with symptoms of ODS could thenamecentralpontinemyelinolisis(CPM). theoretically reverse some of the cellular contrac- Later reports coined the term extrapontine tion and may decrease morbidity. Administration myelinolysis (EPM). The term ODS is an of myoinositol, a naturally occurring intracellular attempt to unify the diagnosis based on the osmole, could be taken up by the brain and 22 Etiologies of Posterior Reversible Encephalopathy Syndrome . 203 mitigate the oncotic stress. Steroids and plasma Bartynski WS, Boardman JF. Distinct imaging pheresis have also been tested with good results patterns and lesion distribution in posterior in very small studies. reversible encephalopathy syndrome. Am J Neuroradiol 2007; 28(7): 1320–1327. TIPS & TRICKS Hefzy HM, et al. Hemorrhage in posterior reversible encephalopathy syndrome: imaging It is prudent to cautiously replace sodium and clinical features. Am J Neuroradiol 2009; in all patients regardless of risk factors. 30(7): 1371–1379. Aggressive potassium replacement may also King JD, Rosner MH. Osmotic demyelination help prevent ODS. syndrome. Am J Med Sci 2010; 339(6): 561–567. Kleinschmidt-DeMasters BK, Norenberg MD. Rapid correction of hyponatremia causes de- Prognosis myelination: relation to central pontine mye- There is a prevailing sentiment among neurolo- linolysis. Science 1981; 211(4486): 1068–1070. gists that this syndrome has a very poor progno- Lee VH, Wijdicks EFM, Manno EM, Rabinstein sis. This is partly due to the fact that the majority AA. Clinical spectrum of reversible posterior of patients encountered are alcoholic, and a leukoencephalopathy syndrome. Arch Neurol neurological disability with limited home sup- 2008; 65: 205–210. port structure entails a poor prognosis. The Lien YH. Role of organic osmolytes in myelino- mortality in more recent studies may be as low lysis. A topographic study in rats after rapid as 6%, and there are cases that many neurologists correction of hyponatremia. J Clin Invest 1995; see that do quite well. Good early rehabilitation 95(4): 1579–1586. may be important for good recovery. Mount DB. The brain in hyponatremia: both Bibliography culprit and victim. Semin Nephrol 2009; 29(3): 196–215. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease Silver SM, et al. Myoinositol administration im- occurring in alcoholic and malnourished proves survival and reduces myelinolysis patients. AMA Arch Neurol Psychiat 1959; after rapid correction of chronic hyponatremia 81(2): 154–172. in rats. J Neuropathol Exp Neurol 2006; 65(1): 37–44. Adler S, Verbalis JG, Williams D. Effect of rapid correction of hyponatremia on the blood–brain Sterns RH, Silver SM. Brain volume regulation in barrier of rats. Brain Res 1995; 679(1): 135–143. response to hypo-osmolality and its correction. Am J Med 2006; 119(7 Suppl 1): S12–S16. Bartynski WS. Posterior reversible encephalopa- thy syndrome, part 1: fundamental imaging Verbalis JG, et al. Hyponatremia treatment guide- and clinical features. Am J Neuroradiol 2008; lines 2007: expert panel recommendations. 29(6): 1036–1042. Am J Med 2007; 120(11 Suppl 1): S1–S21. Bartynski WS. Posterior reversible encephalopa- Yang B, Zador Z, Verkman AS. Glial cell thy syndrome, part 2: controversies surround- aquaporin-4 overexpression in transgenic mice ing pathophysiology of vasogenic edema. Am J accelerates cytotoxic rain swelling. J Biol Chem Neuroradiol 2008; 29(6): 1043–1049. 2008; 283(22): 15280–15286. Part VI Acute Neuroimaging and Neuromonitoring in Neurocritical Care 23 Application of MR Diffusion, CT Angiography and Perfusion Imaging in Stroke Neurocritical Care Carlos Leiva-Salinas1, Wade Smith2 and Max Wintermark3

1Department of Radiology, Neuroradiology Division, University of Virginia, Charlottesville, VA, USA 2Department of Neurology, University of California, San Francisco, CA, USA 3Department of Radiology, Neuroradiology Division, University of Virginia, Charlottesville, VA, USA

Introduction lytic devices have provided a means to improve Stroke is one of the leading causes of mortality the clinical outcome of acute ischemic stroke world wide. In the United States more than patients and to reduce the proportion of patients 750,000 new strokes occur each year and, approx- with disability and death. imately every 3 minutes, someone dies from a The imaging evaluation of patients with stroke. Furthermore, stroke is the leading cause suspected acute ischemic stroke has markedly of adult disability in North America; indeed, a changed over the past few years. With the significant portion of stroke victims are left with a advent of functional imaging modalities such as devastating disability for the rest of their lives. perfusion-CT (PCT), perfusion-weighted mag- The direct and indirect costs of a stroke represent netic resonance (MR) imaging, and the develop- a major economic burden to society and health- ment of fast and robust noninvasive angiographic care systems, and this is likely to increase in the techniques, neuroimaging is no limited to just years to come. anatomy. Routine imaging now includes vascular An ischemic stroke results from a reduction of and perfusion imaging, which are used to guide the blood supply to the brain parenchyma, usu- therapy. ally caused by the occlusion of an intracranial Therefore, it is important for all physicians artery. Ischemic strokes account for more than caring for stroke patients to be familiar with 80% of strokes. Rapid determination of the cause current multimodal CT and MR stroke imaging. and degree of existing brain injury, and of the They should be familiar with the different com- vascular status, can be critical in making the ponents, strengths and limitations, and their role correct therapeutic decision and limiting the ex- in stroke diagnosis, ischemic tissue characteriza- tent of irreversible brain damage. In particular, tion, and selection of patients for reperfusion thrombolytic agents and mechanical thrombo- therapies.

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

207 208 . Acute Neuroimaging and Neuromonitoring in Neurocritical Care

Why Image an Acute Stroke can be diagnosed with imaging techniques. The Patient? most common include intracranial and subarach- noid hemorrhage, subdural hematoma, seizures, toxic/metabolic disturbances, and space-occupy- TIPS & TRICKS ing lesions Interestingly, most patients with stroke mimics have a disorder that is likely to benefit Modern neuroimaging targets six main from an urgent neurologic intervention. aspects of the initial assessment of patients Gradient-recalled echo (GRE) and other T2* suspected of an acute ischemic stroke: sequences are equally sensitive for the detection (1) exclusion of intracerebral hemorrhage, of acute intracranial hemorrhage. For the evalu- (2) exclusion of other stroke mimics, ation of frequent nonhemorrhagic stroke mimics, (3) confirmation and localization of MR imaging is clearly superior to NCT. In partic- ischemia, (4) localization of the clot, ular, conventional T2 and fluid attenuation (5) differentiation of infarct core and inversion recovery (FLAIR) images can depict penumbra, and (6) assessment of post-ictal changes, mass lesions, and some met- bleeding risk. abolic disorders, thus avoiding potentially harm- ful reperfusion stroke therapies.

SCIENCE REVISITED Location of Ischemia Perfusion imaging allows differentiation SCIENCE REVISITED between infarcted brain tissue and potentially salvageable penumbra in acute Diffusion-weighted MR imaging is the most cerebral ischemia. The presence and extent sensitive imaging method for the depiction of of an ischemic penumbra is time and patient hyperacute ischemia (see Plate 23.1). dependent. A growing number of clinical Although DWI lesions can be partially trials have used the concept of penumbra to reversible in the very early phase of ischemia, select patients for reperfusion therapy baseline diffusion-weighted imaging (DWI) is beyond 3–4.5 hours from symptom onset. useful in predicting the outcome and lesion volume in the majority of stroke patients. Direct visualization of the infarct core and Vascular imaging provides an additional di- assessment of the brain tissue viability is mension to the understanding of individual probably the main advantage of MR over CT in stroke pathophysiology. Current noninvasive an- stroke patients. giographic techniques allow for an acute assess- ment of the patient’s vascular status, detecting both intracranial arterial occlusions and cervical Signs of cerebral ischemia on T2-weighted and artery pathology. Finally, imaging may also help FLAIR images are not visible until 3 hours post- to identify patients at an increased risk of hem- stroke (see Plate 23.2). A “mismatch” between orrhagic transformation after thrombolysis. positive DWI and negative FLAIR allows for the identification of patients within the 3-hour time CT and MR Imaging of Acute window with high specificity and positive predic- Stroke tive value. Exclusion of Intracranial Hemorrhage TIPS & TRICKS and Other Stroke Mimics Up to 30% of patients initially diagnosed with The presence of early ischemic signs on NCT ischemic stroke are later diagnosed with a stroke should not be considered a contraindication mimic. Three-quarters of these mimicking condi- to thrombolytic treatment. tions are neurologic disorders, and many of them 23 Application of MR Diffusion, CT Angiography and Perfusion Imaging in Stroke Neurocritical Care . 209

Figure 23.1. Insular ribbon sign in a 62 year-old man with suspected left MCA stroke. Noncontrast CT of the head (NCT) obtained 3 hours after the onset of symptoms shows loss of the definition of the left insular white- grey matter differentiation (black arrow). DW MR image (DWI) obtained 6 hours later shows the acute ischemic injury as a region of relative hyperintensity.

CT is comparable to T2-weighted or FLAIR CAUTION magnetic resonance images in its ability to detect early signs of ischemic stroke. However infarct Unlike these subtle findings, areas of frank detection with NCT in the first 3 hours after onset hypoattenuation are highly specific for has low sensitivity (25%), when compared with infarct, and their extent is predictive of the DWI-MR. CT sensitivity increases in the 6-hour clinical outcome and the risk of hemorrhagic time window to 40% or 60%. Early CT signs of transformation. As such, a frank ischemia include: hypoattenuation represents a contraindication to thrombolysis. 1. Insular ribbon sign. The insular cortex is sup- plied by the insular segment of the MCA and its branches. When the proximal middle cere- bral artery is occluded, the insular ribbon is Location of Clot particularly vulnerable as it is the most distal CTA images demonstrate arterial abnormalities region from the anterior and posterior cerebral in up to 95% of patients with acute ischemic collateral circulations. When ischemic, this infarcts. MRA demonstrates abnormalities in region shows loss of definition of its gray– 75% of cases. white interface (Figure 23.1). 3D time-of-flight (TOF) noncontrast MR angi- 2. Obscuration of the lentiform nucleus. Due to ography (MRA) is the preferred technique for the its blood supply through end-arteries, the bas- MR evaluation of intracranial vessels. This non- al ganglia are particularly vulnerable to early contrast MR sequence provides image contrast infarction, with obscuration of its contour (see that is dependent on the flow of blood protons Plate 23.2). through a selected slab of brain (see Plate 23.2). 3. Hyperdense artery sign. Contrary to other CT For the evaluation of the extracranial arteries, signs of early brain ischemia, the dense artery additional contrast-enhanced sequences may sign hallmarks an acute thrombo-embolic be required. CT angiography (CTA) allows for event. This will be discussed later (Figure 23.2). the evaluation of both intra- and extracranial 210 . Acute Neuroimaging and Neuromonitoring in Neurocritical Care

Figure 23.2. Hyperdense middle cerebral artery sign in a 76-year-old woman admitted to the emergency department after sudden onset of right face-arm-leg hemisyndrome. Non-contrast CT of the brain (NCT) shows a hyperdense left MCA (black arrowhead). Concurrent CTA maximum intensity projection (MIP) image shows a filling defect of the left MCA, consistent with an intraluminal thrombus. vasculature, using one single contrast injection with proximal MCA branch occlusion, tandem (see Plates 23.1, 23.3, and Figure 23.2). lesions, or significant thrombus burden, might be poor candidates for intravenous thrombolytics, and may be better candidates for intra-arterial or TIPS & TRICKS mechanical thrombolysis. Moreover, the pattern of vascular obstruction has a prognostic value in Vascular imaging in stroke is used for the terms of the clinical outcome after recanaliza- detection of vascular stenosis, arterial tion. For example, early recanalization in a pa- clots and the characterization of collateral tient with an isolated middle cerebral artery oc- flow. clusion has a higher rate of clinical response than a patient with a tandem ICA-MCA occlusion. Conventional imaging can sometimes detect ar- Analysis of the source images is the most ac- terial clots. Due to the high concentration of deox- curate approach to characterize the site of occlu- yhemoglobin in the acute thrombus, T2*-weighted sion. An area on CTA that reveals a paucity of images are able to detect intraluminal clots as linear vessels has been shown to represent the infarct or dot-shaped low signal areas of magnetic suscep- core with a sensitivity of 72% and a specificity of tibility (Figure 23.3). Similarly, the presence of a 98%. Analysis of the maximal intensity projection hyperdense thrombus or embolus in the MCA (MIP) images is the most accurate approach to creates a linear hyperattenuation on NCT. This has characterize the degree of collateral circulation. been labeled the “hyperdense middle cerebral The collateral flow estimate on MIP CTA images artery sign.” This sign is seen in approximately has been shown to be inversely related with the one-third of acute stroke patients and it is associ- final infarct volume. ated with poor clinical and radiologic outcome. Patients that may benefit from recanalization should be differentiated on the basis of the Differentiation of Infarct Core and amount of ischemic penumbra and the location Penumbra of clots that can be treated with reperfusion In cerebral ischemia blood flow to a certain brain therapies. The location of the clot has been territory is compromised. The central core of shown to predict recanalization success. Patients tissue that dies initially is labeled the infarct core. 23 Application of MR Diffusion, CT Angiography and Perfusion Imaging in Stroke Neurocritical Care . 211

Figure 23.3. Thrombus detection of with gradient-recall echo (GRE) images in a patient with right MCA ischemic stroke. The linear black signal in the right MCA illustrates the susceptibility artifact crated by an acute thrombus (black arrowhead). The time-of-flight MR angiography (MRA) identify the site of occlusion in the M1 segment of the right MCA.

Surrounding this core is an area of brain that is the volumes of PWI and DWI, this is termed a hypoperfused but still viable. This area of brain, PWI/DWI “match.” This occurs in patients who which is ischemic but potentially salvageable, is do not have penumbral tissue. It is not yet clearly called the ischemic penumbra. demonstrated which parameter gives the best Brain imaging allows for the distinction of approximation to critical hypoperfusion and al- infarct core and penumbra by measuring capil- lows for differentiation of infarct from penum- lary perfusion. In MR imaging, the method bra. However, Tmax and MTT seem to give the most commonly used in clinical practice is the best results. dynamic susceptibility contrast-enhanced per- PCT imaging relies on the analysis of the signal fusion-weighted imaging (PWI) technique. In density curve produced by the entry and washout this technique a bolus of gadolinium-based of a bolus of standard iodinated contrast injected paramagnetic contrast agent is injected and the into a peripheral vein. The linear relationship signal change is tracked by susceptibility- between contrast concentration and CT tissue weighted, T2*-weighted MR sequences. Relative density allows for quantitative brain capillary semiquantitative measures reflecting cerebral information. Characterization of ischemic tissue blood volume (CBV), mean transit time (MTT), with PCT requires intact cerebral autoregulation. Tmax, and cerebral blood flow (CBF) can be In the penumbra, where autoregulation is intact derived from the signal intensity-over-time or mildly jeopardized, MTT is prolonged due to curve. arterial occlusion but CBV is maintained or in- MR delineation of the infarct core and ische- creased due to this compensatory vasodilatation. mic penumbra rely on the assumption that DWI On the other hand, in the infarct core where reflects irreversibly damaged tissue, whereas autoregulation is damaged, MTT is prolonged PWI represents an overall area of hypoperfusion. and CBV is reduced. Therefore, by combining The volumetric difference between these abnor- MTT and CBV results, PCT has the ability to mal areas, called the PWI/DWI “mismatch,” re- reliably identify reversible ischemic penumbra presents the MR correlate of the ischemic pen- and irreversible infarct core in acute stroke pa- umbra (see Plate 23.2). If there is no difference in tients (see Plates 23.1 and 23.3). Quantitatively, 212 . Acute Neuroimaging and Neuromonitoring in Neurocritical Care the parameter that most accurately describes Damage to the blood–brain barrier (BBB) is tissue at risk of infarction is the relative MTT. considered as one of the main contributing me- The optimal threshold for describing tissue at risk chanisms to hemorrhagic transformation after is 145%. The parameter that most accurately reperfusion. Early detection of a damaged BBB describes the infarct core on admission is the could potentially be used to identify patients who absolute CBV. The optimal threshold for this are more likely to develop hemorrhagic transfor- parameter is 2.0 mL/100 g. mation (HT) after reperfusion. Measurement of BBB permeability by using perfusion CT and MR is based on dynamic contrast-enhanced imaging SCIENCE REVISITED of microvascular permeability that allows for quantification of BBB disruption. BBB disruption Both CT and MR estimates of infarct core and can also be identified as delayed gadolinium ischemic penumbra have been validated by enhancement of the cerebrospinal fluid space on prospective studies and a comparison with fluid-attenuated inversion recovery (FLAIR) positron emission tomography (PET) or images. This sign has been termed the hyperin- Xenon CT. tense acute reperfusion marker (HARM). In re- cent investigations, it was found that defects in the blood–brain barrier predispose for both spon- taneous and thrombolytic-associated hemor- Prediction of the Risk of Bleeding rhagic transformation in ischemic stroke (see Plate 23.4). Further clinical trials are required to SCIENCE REVISITED elucidate if BBB imaging has a role in therapeutic decisions. Thrombolysis in acute stroke increases the risk of cerebral hemorrhage. Severe CT and MR Imaging for the hemorrhage with mass effect occurs in 4.8% of patients with stroke treated with rt-PA Selection of Patients for within 3 hours after symptom onset and in up Thrombolytic Therapy to 6.4% in patients treated between 3 and 6 Several clinical trials using MR perfusion imaging hours. A major goal for stroke imaging is to to extend the window for thrombolysis have identify patients at risk for post-thrombolytic demonstrated the safety and efficacy of this tech- intracranial hemorrhage. nique and strategy. The DIAS and DEDAS trials, randomized pa- tients within a 3–9 hour time window after stroke Hypoattenuation on NCT or restricted water using a DWI/PWI mismatch of at least 20% to diffusion on MRI are associated with increased either placebo or escalating doses of desmote- risk of thrombolytic-related hemorrhagic trans- plase, a new thrombolytic drug. Patients with formation. Clearly identifiable hypoattenuation early vessel recanalization and reperfusion involving more than one-third of the middle showed a significant clinical benefit: 60% of the cerebral artery territory is currently being used patients from the most effective dose tier had an as an exclusion criteria for tPA. excellent clinical outcome. Unfortunately, the Although chronic microbleeds are an indicator recently published DIAS 2 phase III trial did not of a hemorrhage-prone vasculopathy and are show any benefit in clinical outcome in either of associated with an increased risk of spontaneous the treatment groups. intracranial hemorrhage, their relationship with The DEFUSE trial showed that baseline MRI post-thrombolytic-related hemorrhage is still findings can be used to identify groups of patients debated. MRI with spin gradient echo or suscep- who are more likely to benefit from thrombolytic tibility-weighted sequences is more sensitive therapy. Patients with a baseline mismatch than NCT for the detection of these small hemo- between PWI and DWI of at least 20% and a siderin depositions. reduction in perfusion volume abnormality of at 23 Application of MR Diffusion, CT Angiography and Perfusion Imaging in Stroke Neurocritical Care . 213 least 10 mL had a better clinical outcome. Data Davis SM, Donnan GA, Parsons MW, et al. from this study suggested that a mismatch ratio Effects of alteplase beyond 3 h after stroke (PWI volume – DWI volume/DWI volume) of 2.6 in the Echoplanar Imaging Thrombolytic provided the highest sensitivity and specificity for Evaluation Trial (EPITHET): a placebo- identifying patients with whom reperfusion was controlled randomised trial. Lancet Neurol associated with a favorable response. This study 2008; 7: 299–309. emphasized the importance of combining the Fiebach JB, Schellinger PD, Gass A, et al. Stroke information obtained from perfusion and vascu- magnetic resonance imaging is accurate in lar imaging. No relationship between early recan- hyperacute intracerebral hemorrhage: a multi- alization and favorable clinical outcome was seen center study on the validity of stroke imaging. in patients without a mismatch. On the other Stroke 2004; 35: 502–506. hand, no benefit could be expected if early re- Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous canalization of the occluded vessel failed, even in desmoteplase in patients with acute ischaemic the presence of a large mismatch. stroke selected by MRI perfusion-diffusion Although MRI has been used to extend the time weighted imaging or perfusion CT (DIAS-2): window for reperfusion, there are as yet no pub- a prospective, randomised, double-blind, lished prospective multicenter perfusion-CT placebo-controlled study. Lancet Neurol 2009; trials that can help to define how to best use this 8: 141–150. technique in acute ischemic stroke patients. Mul- Kidwell CS, Chalela JA, Saver JL, et al. Compari- ticenter clinical trials using a validated perfusion- son of MRI and CT for detection of acute CT software package to select acute ischemic intracerebral hemorrhage. J Am Med Assoc stroke patients are needed. 2004; 292: 1823–1830. Conclusion Tan JC, Dillon WP, Liu S, et al. Systematic com- Anincreasing number of studies support the role of parison of perfusion-CT and CT-angiography advanced neuroimaging techniques in selecting in acute stroke patients. Ann Neurol 2007; 61: patients for acute stroke treatments, including 533–543. reperfusion therapies in an extended time window. Wintermark M, Flanders AE, Velthuis B, et al. Physicians taking care of stroke patients should Perfusion-CT assessment of infarct core and be familiar with the different components of penumbra: receiver operating characteristic advanced multimodal stroke imaging, the infor- curve analysis in 130 patients suspected of mation provided by each component, and how this acute hemispheric stroke. Stroke 2006; 37: information influence management decisions. 979–985. Wintermark M, Reichhart M, Thiran JP, et al. Bibliography Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomog- Albers GW, Thijs VN, Wechsler L, et al. Magnetic raphy, at the time of emergency room admis- resonance imaging profiles predict clinical re- sion, in acute stroke patients. Ann Neurol 2002; sponse to early reperfusion: the diffusion and 51: 417–432. perfusion imaging evaluation for understand- ing stroke evolution (DEFUSE) study. Ann Wintermark M, Thiran JP, Maeder P, Schnyder P, Neurol 2006; 60: 508–517. Meuli R. Simultaneous measurement of re- gional cerebral blood flow by perfusion CT and Astrup J, Siesjo BK, Symon L. Thresholds in cere- stable xenon CT: a validation study. AJNR Am J bral ischemia - the ischemic penumbra. Stroke Neuroradiol 2001; 22: 905–14. 1981; 12: 723–725. 24 Advanced Monitoring of Brain Oxygenation and Metabolism Bharath R. Naravetla1 and J. Claude Hemphill III2

1Department of Neurology, Neurovascular Service, University of California, San Francisco, CA, USA 2Department of Neurology, University of California, San Francisco, CA, USA

Introduction (cerebral microdialysis). Given the complexity of metabolic changes in acute brain injury, the Current neuromonitoring techniques involve a concept of multimodality monitoring is also em- range of tools that focus on the measurement of phasized, in which information from multiple cerebral physiologic and metabolic parameters different monitoring modalities is integrated by with the goal of improving the detection and the clinician in order to provide a more complete management of primary and secondary brain picture than could be obtained using just a single injury in patients who have suffered traumatic monitor. brain injury (TBI), stroke, or subarachnoid hemorrhage (SAH), or have had neurosurgical procedures. Established methods have included Brain Tissue Oxygen Monitoring measurement of intracranial pressure (ICP) and Direct measurement of brain tissue oxygen ten- maintenance of cerebral perfusion pressure sion (PbtO2) utilizes a microelectrode placed in (CPP) or (EEG) monitor- the parenchyma of the brain (Figure 24.1). It has ing for the detection of seizures. become the most commonly used advanced neu- Recognition of underlying disturbances of romonitoring technique and allows quantitative cerebral oxygen delivery and cellular metabolism measurement of tissue oxygen tension in a focal in acute brain injuries has led to a strong interest region of the brain. Previously incorrectly con- in the development of techniques that would sidered as primarily an ischemia monitor, PbtO2 enable continuous, quantitative, and real-time is probably more representative of the interplay measurement of brain metabolism in the neuro- between cerebral blood flow and oxygen critical care unit. New tools that are currently diffusion. available for advanced cerebral monitoring in brain-injured patients include devices that can Equipment and Technique measure the brain tissue oxygen tension (PbtO2), At present, the only commercially available tool the jugular bulb venous oxygen saturation for PbtO2 monitoring is the LICOX system (Integra (SjvO2), the cerebral blood flow (CBF), and Neurosciences, Plainsboro, NJ), which uses a the concentration of extracellular metabolites polarographic Clarke-type microelectrode for

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

214 24 Advanced Monitoring of Brain Oxygenation and Metabolism . 215

Figure 24.1. Drawing of a coronal section through the brain at the level of the third ventricle, demonstrating a ventriculostomy drain inserted into the lateral ventricle, an intraparenchymal brain tissue oxygen probe, and an intraparenchymal intracranial pressure monitor. (Reproduced from Fauci, AS, et al., Harrison’s Principles of Internal Medicine, 17th edn, p. 1722; 2008, McGraw-Hill with permission from The McGraw-Hill Companies.)

oxygen tension measurement and includes an . Region at risk for vasospasm after integrated temperature probe. The PbtO2 probe aneurysmal SAH: ipsilateral hemisphere is placed directly into the brain parenchyma . Diffuse cerebral injury as in TBI: least injured usually with a fixed cranial bolt, approximately hemisphere 2–3 cm below the dura. The frontal white matter is the area most commonly targeted for placement. The location of probe placement remains a Measurement point of debate and various investigators have The probe is connected to an external monitor for suggested that placement should be targeted to a continuous reading of PbtO2 (expressed quan- pericontusional or penumbral regions or to rela- titatively in mmHg) and brain temperature. Gen- tively normal regions of the brain. Our approach erally, the initial readings during the first 2 hours is to place the probe in the ipsilateral hemisphere after placement are considered unreliable. The in patients with nontraumatic intracerebral hem- oxygen microelectrode measures the tissue oxy- orrhage, the frontal lobe that is presumed to be at gen tension in a focal region approximately 3 highest risk for vasospasm after aneurysmal SAH, 17 mm in volume. PbtO2 values are obtained and in the least injured hemisphere in the context continuously and in real-time. Proper function- of diffuse injury such as with head trauma. ing of the catheter can be confirmed using an “oxygen challenge” in which the FiO2 is tempo- rarily increased to 1.0 in order to demonstrate a SCIENCE REVISITED significant rise in PbtO2.

Location of PbtO2 probe placement. It remains Relationship with Other Physiological a point of debate and our approach is Parameters P O may vary with a number of physiological . Non-traumatic ICH: ipsilateral hemisphere bt 2 parameters. PbtO2 measurements have been 216 . Acute Neuroimaging and Neuromonitoring in Neurocritical Care shown to positively correlate with arterial oxygen venous circulations: PaO2 –PvO2). AVTO2 is prob- tension, inspired oxygen concentration (FiO2), ably an indicator of oxygen diffusion and thus the mean arterial pressure, CPP, CBF, hemoglobin relationships between CBF and oxygen extraction concentration, and inversely with oxygen extrac- are important to consider when investigating the tion fraction on positron emission tomography causes of low PbtO2. Experience is varied regard-

(PET) imaging and mean transit time on dynamic ing the relationship between PbtO2 and ICP; in

CT perfusion (CTP) imaging. general, PbtO2 decreases with increased ICP only

There is a linear correlation between PbtO2 and when the CPP is concurrently decreased. changes in end-tidal carbon dioxide measure- ments or CBF, and a sinusoidal correlation with Practical Aspects of Patient Management mean arterial pressure, suggesting that PbtO2 is A low PbtO2 reading should prompt further in- strongly influenced by factors that regulate the vestigation into a potential underlying cause.

CBF and cerebral autoregulation. In general, Because PbtO2 is a marker of CBF and oxygen acute hyperventilation decreases PbtO2. This is diffusion, a reasonable first step is to obtain an presumably mediated through a primary reduc- arterial blood gas in order to determine if the tion in the CBF due to cerebral vasoconstriction. patient’s lung function has deteriorated or if the Of the various physiologic parameters studied in patient has a decreased CBF due to hyperventi- brain-injured patients, FiO2 and MAP (or CPP) lation. Steps should then be undertaken to have had the strongest and most consistent determine if cerebral perfusion is inadequate. effect. In this circumstance, a CBF monitor may be useful as part of multimodality monitoring. Clinical Utility and Prior Studies Otherwise, consideration should be as to whether Several studies in patients with TBI have shown the CPP is too low, the ICP is too high, or the that patients with PbtO2 levels less than 10– patient has disturbed cerebral autoregulation. 15 mmHg for extended periods of time, or on A brief trial of more aggressive cerebrospinal fluid multiple occasions, have a worsened outcome. drainage or increased mean arterial pressure There appears to be a dose–response relationship using fluids or pressors may undercover a cere- in which longer durations and lower levels of bral perfusion deficit.

PbtO2 are associated with an increasing mortality In general, we do not advocate simply increas- risk. Lower PbtO2 levels have also been associated ing the FiO2 as this may correct the PbtO2 without with poorer performance on neuropsychological actually fixing the underlying perfusion failure and cognitive testing after head trauma. Although that led to the low reading. Limited data exists, there have been no randomized clinical trials however, to suggest that hyperoxic therapy might assessing the efficacy of PbtO2-directed therapy, improve some aspects of pericontusional cere- an observational study found that patients with bral metabolic function. Thus, this remains an severe TBI who were managed with PbtO2-guided unproven option if all reasonable aspects of in- therapy (goal PbtO2 > 25 mmHg) had a lower risk adequate oxygen delivery have been ruled out of mortality than historical controls managed and the PbtO2 remains critically low. with conventional ICP and CPP monitoring. Available data suggests that red blood cell Based on clinical and experimental studies, a transfusion has only a very modest effect on

PbtO2 level below 15 mmHg is now considered the PbtO2. abnormal. Notably, one study using PET identi-

fied a PbtO2 of 14 mmHg as the threshold at which critical oxygen extraction occurs. CAUTION It is likely that the parameters influencing ab- PbtO2 reading is solute PbtO2 levels are more complex than iden- tifying a threshold parameter. PbtO2 is probably . Unreliable initially during stabilization/ more closely representative of the relationship calibration of the probe (2 hours) between CBF and AVTO2 (the difference between . < 15 mmHg is considered abnormally low the partial pressure of oxygen in the arterial and 24 Advanced Monitoring of Brain Oxygenation and Metabolism . 217

. Low reading should prompt assessment jugular foramen on CT or cross-sectional lumen on ultrasound) is cannulated, usually under di- of PaO2 and CBF . May be low due to hypometabolism rect ultrasound guidance in order to avoid carot- from primary brain injury id puncture. Using the Seldinger technique, a 6 French pediatric introducer (5.5 cm in length) is placed. The oxymetric catheter is then advanced through the introducer until the catheter tip is Drawbacks placed at or near the jugular bulb to decrease Brain tissue oxygen monitoring is an invasive blood contamination from the extracranial procedure, although reported rates of complica- circulation. tions are exceedingly low. PbtO2 provides a focal measure of tissue oxygen partial pressure and Measurement therefore may not be representative of processes The catheter is connected to the external moni- occurring in other focal regions of the brain. tor for a continuous reading of SjvO2 expressed as a percentage. Blood is sampled for venous blood gas testing to allow the catheter to be Jugular Bulb Venous Oxygen calibrated at the time of insertion and once or Saturation (SjvO2) Monitoring twice daily. By calculating the venous blood Assessment of the venous oxygen saturation in oxygen content (CvO2) and subtracting this from the jugular bulb as blood is exiting the brain the arterial oxygen content (CaO2), the cerebral provides a measure of global cerebral oxygen arteriovenous oxygen difference (AVDO2)canbe delivery and a way to estimate the global rela- calculated. AVDO2 is the amount of oxygen used tionship between the CBF and cerebral metabo- by the brain. lism. SjvO2 monitoring can provide information on global cerebral hypoxia and indirectly on Relationship with Other Physiological cerebral hypoperfusion or hyperperfusion. Parameters

SjvO2 is influenced by parameters that relate to Equipment and Technique the cerebral oxygen delivery and metabolism. One simple method is to cannulate the internal SjvO2 is inversely related to the AVDO2. If the jugular vein and advance a catheter cephalad cerebral AVDO2 increases because the brain is until the tip resides above the level at which extracting more oxygen, then the SjvO2 de- there is flow from the external jugular supply creases, and vice versa. If the arterial oxygen (usually above the C3 level). Blood can then be content being delivered to the brain drops signif- drawn and sent for venous blood gas measure- icantly because of very low hemoglobin levels or ment, including the partial pressure of oxygen FiO2 (thereby decreasing arterial oxygen satura- tion), then the SjvO2 may decrease if the brain (PvO2) and the venous oxygen saturation. Most described methods also use an oxymetric cathe- extracts the same amount of oxygen as before. If ter that has a lumen for blood draws as well as a the brain extracts less oxygen because of large sensor (usually fiberoptic) that can measure the areas of brain infarction or cerebral metabolic blood oxygen saturation continuously. There is depression due to either disease or the effects of currently no commercially available kit designed sedative or anesthetic agents, then the SjvO2 may increase. Low cerebral perfusion due to inade- specifically for SjvO2 monitoring. Thus, equip- ment that is used is borrowed from critical quate CPP, elevated ICP, or hyperventilation may care monitoring tools designed for other uses. be reflected in lower SjvO2 values. We use an Edwards 4 French size fiberoptic oxygen sensing catheter (with blood draw lumen) Clinical Utility and Prior Studies attached to a Baxter–Edwards Vigilance Contin- Normal SjvO2 is approximately 60%, although in uous Oximetry Monitor. For placement, the brain-injured patients it may be higher. While the dominant jugular vein (based on the size of the precise SjvO2 threshold for cerebral ischemia 218 . Acute Neuroimaging and Neuromonitoring in Neurocritical Care may vary depending on the brain’s ability to Practical Aspects of Patient Management extract oxygen, an SjvO2 of < 50% for greater than The principal value of SjvO2 monitoring lies in its 10 minutes has generally been considered to ability to help clinicians to determine the global represent an ischemic desaturation. Previous oxygen delivery to the brain principally by asses- studies in TBI patients have found that ischemic sing whether cerebral blood flow is resulting in a desaturations are associated with worsened out- normal, oligemic, or hyperemic state. come in a dose-dependent manner. High SjvO2 A drop in SjvO2 should prompt an evaluation levels (typically > 80%) may reflect hyperemia of AVDO2 by assessing the arterial oxygen con- or an inability of the brain to extract oxygen due tent in an arterial blood gas. If CaO2, is sufficient, to metabolic depression from sedative agents, then an assessment turns to the adequacy of the poor oxygen unloading (e.g. sickle cell disease), cerebral blood flow. Assuming that the arterial or severe brain injury. Importantly, both blood gas does not suggest hyperventilation, abnormally high and low SjvO2 levels have been then the adequacy of the cerebral perfusion associated with poor clinical outcome in TBI pressure should be of concern. Measures to low- patients. However, it remains unclear whether er the ICP or raise the CPP should be undertaken. this is causative (especially in those with high Additionally, the possibility of an enlarging in- SjvO2 levels) or whether this is principally a tracranial mass should be considered, especially marker of the severity of brain injury. if simple measures to treat the ICP or CPP do not SjvO2 monitoring was used in a pivotal quickly restore the SjvO2.Giventhatashort trial of CBF-directed therapy (to maintain a duration (10 minutes) of ischemic desaturation CPP 70 mmHg) versus ICP-directed therapy is associated with a worsened outcome, contin- (to maintain an ICP < 20 mmHg). This trial uous SjvO2 monitoring is preferred over demonstrated a dramatic reduction in ischemic just checking jugular venous blood gases desaturations in the patients undergoing CBF- intermittently. directed therapy. However, there was no differ- Conversely, an SjvO2 valueofmorethan80%is ence in 6 month outcome. This was thought likely generally considered as hyperemia or luxury due to a four-fold increase in ARDS in the CBF- perfusion. It may also indicate impairment of directed therapy patients. The results of this cerebral autoregulation. In this setting, especial- study have been used to suggest that advanced ly if the ICP is high, consideration could be neuromonitoring might be useful in targeting given to judiciously lowering the systemic blood optimal cerebral oxygen delivery while limiting pressure. systemic complications imposed by aggressive use of fluids and pressors. Drawbacks

SjvO2 monitoring (Figure 24.2) is an invasive SCIENCE REVISITED procedure and is associated with a small risk of infection, infiltration, hemorrhage, and carotid SjvO2 is inversely related to cerebral oxygen puncture. Because it functions as a global moni- ¼ extraction; AVDO2 Hgb 1.34 (SaO2-SjvO2) tor, focal or regional ischemic changes might not þ 0.0031 (PaO2 –PvO2) be detected, and a relatively large volume of brain

tissue must be affected before the SjvO2 level . Both low and high SjvO2 values are associated drops significantly. with poor outcome . Causes of low SjvO2 include low CBF, low CPP, fever, and seizures Cerebral Blood Flow Monitoring . High SjvO2 levels may reflect hyperemia or Cerebral blood flow is considered as an impor- inability of the brain to extract oxygen from tant physiologic parameter in the setting of sedatives, poor oxygen unloading (e.g. sickle brain injury, as the CBF reflects the delivery of cell disease), or severe brain injury substrate to tissue. It was one of the first para- meters to be measured, using various imaging 24 Advanced Monitoring of Brain Oxygenation and Metabolism . 219

Figure 24.2. Flow chart representing a general approach to the management of abnormal SjvO2 readings. Note that an abnormal value should be reconfirmed. The position and calibration of the catheter and light intensity are adjusted and if necessary a recalibration of the catheter should be performed before making any interventions for an abnormal value. 220 . Acute Neuroimaging and Neuromonitoring in Neurocritical Care and vascular dilution techniques. Only recently CAUTION has continuous monitoring in the neurocritical care unit become available. Monitors based on Quantitative continuous CBF monitoring two basic methodologies are available: thermal diffusion flowmetry (TDF) and laser Doppler . Values are highly dependent on location flowmetry (LDF). of the tip of the catheter . Brain-injured patients may still have intact

CO2 reactivity, but impaired pressure Equipment and Technique autoregulation TDF is based on the principle of thermal con- . CBF decreases by 3% for every 1 mmHg ductivity of cortical tissue, where the tempera- decrease in PaCO2 ture difference between two portions of a probe is detected and converted to quantitative CBF. Commercially available TDF microprobes in- clude the QFlow 500 Probe and Bowman Perfu- sion Monitor (Hemedex Inc., Cambridge, MA, Practical Aspects of Patient Management USA) and the Saber Cerebral Blood Flow Moni- Normal average CBF in the human is approxi- toring System (Flowtronics Inc., Phoenix, AZ, mately 55 mL/100 g of brain/min, but actual va- USA). The probe tip is placed 2–2.5 cm below the lues may vary widely across gray and white mat- cortical surface through a burr hole and is usually ter. TDF probe tips are usually placed in the white secured using a bolt. matter, with the generally accepted normal range LDF involves a probe which is directly inserted as 18–25 mL/100 g/min. The ischemic threshold into the brain parenchyma or over the surface of for CBF is usually considered approximately the brain. It is able to detect the density measure- 18 mL/100 g/min. The threshold for irreversible ments of moving blood, thereby providing mo- injury is 10 mL/100 g/min; however, this may be mentary percentage changes in local CBF. LDF lower in white matter. provides relative information but not absolute Although brain-injured patients may have quantitative values of CBF, thus limiting its impairment of pressure autoregulation, CO re- utility. 2 activity is usually retained and the CBF may respond to hyperventilation. The CBF is normally Measurement decreased by 3% for every 1 mmHg decrease in

The probe is connected to an external monitor PaCO2. Necessary steps taken to improve the CBF for a continuous reading of CBF expressed as include increasing the CPP by raising the MAP or mL/100 g (of brain)/min (for TDF probes). Values lowering the ICP. Current TBI guidelines suggest are dependent on the position of the tip of the that the autoregulation status should be consid- catheter as they vary widely across gray and white ered when targeting a specific goal CPP, and matter. continuous CBF monitoring may help with this assessment. Relationship with Other Physiological Parameters Drawbacks CBF is influenced by mean arterial pressure, ICP, Because these methods measure focal CBF, va- as well as the arterial partial pressure of carbon lues may not reflect processes in other parts of dioxide and oxygen depending on the patient’s the brain. Inaccurate values may occur if the tip injury and whether cerebral autoregulation is is near large vessels or, in the case of loss of intact. These relationships bring forth the im- tissue contact or displacement of the probe. portant principle of CBF and cerebral metabolic TDF probes may be non-operational during coupling, where CMRO2 is directly related to CBF fever (in order to avoid possible additional tis- and AVDO2. sue injury). 24 Advanced Monitoring of Brain Oxygenation and Metabolism . 221

Table 24.1. Advanced neuromonitoring modalities Modality Measured parameter Normal value Remarks Brain tissue oxygen Focal partial pressure Acceptable normal: Should be considered

monitoring (PbtO2) of tissue oxygen. 20–35 mmHg in the context of other Related to CBF and “Abnormal threshold”: variables and clinical oxygen diffusion. <15 mmHg condition Jugular bulb venous Global (measures Normal: 55–75% May not detect focal oxygen saturation saturation from Oligemia: < 50–55% ischemic changes

monitoring (SjvO2) single jugular vein) Hyperemia: > 75–80% Cerebral blood flow Focal rate of blood Normal (white matter): Indirect measure of monitoring (CBF) flow 18–25 mL/100 g/min adequacy of metabolic “Ischemic threshold”: oxygen delivery <18 mL/100 g/min Irreversible ischemia: <10 mL/100 g/min Cerebral Focal measure of Glucose <15, LPR Mitochondrial dys- microdialysis lactate-pyruvate ratio >30 are considered function may also (CMD) (LPR), glucose critical elevate LPR >40 concentration, LPR >40 glutamate, glycerol, indicates metabolic or other measured crisis metabolites

Cerebral Microdialysis Microdialysate is then collected in a microvial Cerebral microdialysis (CMD) differs from the which is placed in a microdialysis analyzer to other described advanced neuromonitoring tools obtain the concentration of specified metabolites because it does not measure physiological para- such as lactate, pyruvate, glutamate, or glucose. meters, but rather allows measurement of the The most commonly used commercially avail- concentration of chemicals found in the brain able system is made by CMA Microdialysis parenchyma. This may allow direct assessment of (Stockholm, Sweden). The CMD catheter is in- the metabolic consequences of primary and sec- serted through a burrhole in a manner similar to ondary brain injury (Figure 24.3). the placement of PbtO2 or TD-CBF probes, al- though it can be placed “freehand” without a bolt Equipment and Technique system if a specific area of the brain is targeted CMD utilizes the capillary technique to collect a during open craniotomy. sample of extracellular fluid from the brain (or other tissue being monitored). A CMD system Measurement comprises three basic components: the CMD Numerous parameters can be measured, includ- catheter, perfusate pump, and analyzer. The ing glucose, glutamate, lactate, pyruvate, glycerol catheter is a fine tube made with a semiperme- or even concentrations of drugs. There is an able dialysis membrane that allows diffusion of inherent delay between the collection of the molecules from the extracellular space; a com- fluid at the catheter and its eventual migration monly used version has a cutoff of 20 kD. A to the microvial. Current protocols often involve “mock” CSF or normal saline is instilled into sample analysis hourly; thus, analyzed values the microdialysis catheter via a small pump at represent events that occurred recently, but not a rate usually ranging from 0.3 to 1.0 mL/min. in real time. 222 . Acute Neuroimaging and Neuromonitoring in Neurocritical Care

35 50

PbtO2 25 40 (mm Hg) 2 O bt P 15 30

LPR LPR = lactate/pyruvate ratio 5 20

0 20 40 60 100 120 150 Time (min)

Figure 24.3. Advanced neuromonitoring in a 26-year-old woman with a GCS of 6 after severe TBI. Patient was inadvertently hyperventilated at the 60-minute mark, which caused secondary ischemia due to cerebral vasoconstriction and decreased cerebral blood flow. This was identified as a decrease in PbtO2 accompanied by an increase in the LPR. These abnormal cerebral metabolic parameters resolved when hyperventilation was discontinued.

Relationship with Other Physiological pressure, hypoxia, and CBF as measured by Parameters xenon CT or oxygen extraction fraction as mea- Microdialysis values of brain metabolites such as sured by PET. Metabolic crisis has also been lactate and pyruvate are generally considered to reported during nonconvulsive seizures and hy- be indicators of the state of brain injury and poglycemia. TBI and SAH patients with poor aerobic metabolism. The results of CMD para- clinical outcome have been shown to have ele- meters may be challenging to interpret because vated levels of excitatory neurotransmitters, ele- they may demonstrate intrinsic tissue injury from vated LPR, and abnormal lactate and glutamate the primary brain injury or secondary injury from levels. In a study of patients with severe TBI, additional insults such as hypoperfusion. Thus, increased lactate/glucose ratios and lactate levels direct correlation of lactate or lactate/pyruvate correlated with SjvO2 desaturations and an in- ratios with other common physiological para- creased risk of death. meters such as ICP or CPP may not be present unless there is a distinct and dramatic event SCIENCE REVISITED resulting in tissue metabolic crisis. Cerebral microdialysis Clinical Utility and Prior Studies . Intensive insulin therapy may be associated The most commonly measured values are lactate with cerebral hypoglycemia despite serum and pyruvate, with a lactate/pyruvate ratio (LPR) normoglycemia, and this may be associated >40 generally considered to represent a with poor outcome metabolic crisis of brain tissue. Increases in this . Consensus statement recommend lactate- ratio may represent ischemia or mitochondrial pyruvate ratio (LPR) as primary marker in TBI dysfunction. Pathologic alterations in cerebral . LPR > 40 considered as cerebral metabolic microdialysate concentrations have been corre- crisis lated to changes in other physiological para- meters, including PbtO2, SjvO2, ICP, blood 24 Advanced Monitoring of Brain Oxygenation and Metabolism . 223

Practical Aspects of Patient Management trauma and stroke, no one monitoring method A recent consensus statement recommended provides complete information. Thus, the above the use of LPR as the primary marker for ische- described invasive monitoring tools should be mia in TBI. Microdialysis glucose, glycerol, and considered in the context of a multimodality glutamate are additional markers of impending monitoring approach. Newer monitors can ischemia. Because of the variability in values complement the traditional measurements of related to tissue injury and the inherent delay ICP and CPP, findings on neuroimaging, as in values, the use of microdialysis targeted ther- well as clinical neurological assessment. Future apy has been challenging. However, CMD has approaches to integrating this complex bedside helped to provide insight into the impact of data into user-friendly clinical treatment other events on cerebral metabolic crisis and paradigms are challenging, but are likely to bear permanent tissue injury. For example, the use of fruit in the long term. insulin infusions to target normoglycemia has been found to lead to cerebral metabolic crisis Bibliography and low cerebral glucose in some cases. Non- Fauci, AS, et al., Harrison’s Principles of Internal convulsive seizures may lead to an elevated LPR Medicine, McGraw-Hill 2008. and cerebral metabolic crisis. Nonconvulsive Hemphill JC 3rd, Knudson MM, et al. Carbon seizures have also been found to correlate with dioxide reactivity and pressure autoregulation later brain atrophy. At present, CMD is reason- of brain tissue oxygen. Neurosurgery 2001; 48: ably considered as part of a multimodality mon- 377–383. itoring approach, but not exclusively as a single neuromonitor. Marcoux J, McArthur DA, et al. Persistent meta- bolic crisis as measured by elevated cerebral microdialysis lactate-pyruvate ratio predicts Drawbacks chronic frontal lobe brain atrophy after trau- Because of the inherent delay in microdialysate matic brain injury. Crit Care Med 2008; 36: transport through the catheter, values are not 2871–2877. real time. As a focal monitor, it may demonstrate Oddo M, Schmidt JM, et al. Impact of tight gly- only local changes in metabolism. Another im- cemic control on cerebral glucose metabolism portant limitation is the variability of results after severe brain injury: a microdialysis study. based on the location of the probe (in injured Crit Care Med 2008; 36: 3233–3238. tissue, normal tissue, or areas of penumbra), Robertson CS, Gopinath SP, et al. SjvO2 monitor- bringing into debate the ideal location for cathe- ing in head-injured patients. J Neurotraum ter placement. Table 24.1 provides a summary of 1995; 12: 891–896. several advanced neuromonitoring modalities. Robertson CS, Valadka AB, et al. Prevention of secondary ischemic insults after severe head Conclusion injury. Crit Care Med 1999; 27: 2086–2095. The ultimate goal of neuromonitoring in severe Rosenthal G, Hemphill JC 3rd, et al. Brain tissue brain injury is to assess neurological function and oxygen tension is more indicative of oxygen help to predict as well as improve outcome by diffusion than oxygen delivery and metabolism providing the ability to intervene while brain in patients with traumatic brain injury. Crit tissue is still viable and the patient is still salvage- Care Med 2009; 37: 379–380. able. New neuromonitoring tools that allow the Rosenthal G, Sanchez-Mejia RO, et al. Incorpo- assessment of brain oxygen delivery, blood flow, rating a parenchymal thermal diffusion cere- and metabolism provide a new window into bral blood flow probe in bedside assessment of the acute management of brain injury. Because cerebral autoregulation and vasoreactivity in of the complexity and heterogeneity of pro- patients with severe traumatic brain injury. cesses occurring in brain-injured patients after J Neurosurg 2011; 114(1): 62–70. 224 . Acute Neuroimaging and Neuromonitoring in Neurocritical Care

Stiefel MF, Spiotta A, et al. Reduced mortality rate after head injury. Anesth Analg 2004; 99: in patients with severe traumatic brain injury 230–234. treated with brain tissue oxygen monitoring. van den Brink WA, van Santbrink H, et al. Brain J Neurosurg 2005; 103: 805–811. oxygen tension in severe head injury. Neuro- Stocchetti N, Canavesi K, et al. Arterio-jugular surgery 2000; 46: 868–876. difference of oxygen content and outcome Index

abciximab 85 initial assessments, stabilization, airway management 12–20, ABCs 20, 25, 26, 41–4, 45–6, and transport 32–3, 36 25–31, 33–6, 41–2, 53, 56–62, 56–7, 65–9 management of ICUs 35–6, 65–9, 76–7, 89–91, 112–14, ABM see acute bacterial meningitis 195–6 144–51, 183–7 accessory muscles, neuromuscular nutritional requirements 35–6 ABCs 20, 25, 41–4, 45–6, 56–7 respiratory failure 144–50 respiration 33–4 algorithmic approaches 12, acetaminophen 51, 62, 82, 192–3 risk factors 32 18–20 acetazolamide 105 rotating beds 36 ASA task force 18–19 acetylcholine receptors 148–50, skin breakdown problems 35–6 ASCIs 33–6 162–73 steroids 34–5, 36 assessments 13, 76–7 acidosis 144–50, 163–4, 193 tips & tricks 33–4, 36 BiPAP 146–50 ACLS goals, strokes 45–54 treatments 35–6, 195–6 caution 13, 15, 20 acute bacterial meningitis acyclovir 130–1, 136 concepts 12–20, 25–31, 33–6, (ABM) 123–31 ADEM see acute disseminated 53, 56–7, 76–7, 112–14, see also bacterial meningitis encephalomyelitis 144–51 acute cerebral venous adrenal insufficiency 34, Cormack–Lehane scale 17–18 thrombosis 99–107 163–4 difficult airway algorithm 18–20 see also cerebral venous adrenal suppression, difficult airway intubation thrombosis etomidate 14, 34, 53 15–19, 114 acute disseminated encephalomy- adrenocortical necrosis 128 difficult mask ventilation 15–16 elitis (ADEM) 130, 132–3, 135, adult polycstic kidney disease 9 extubation considerations 15, 20 139, 163–4 Advanced Trauma Life Support fiberoptic intubation 18–20, see also encephalitis (ATLS), concepts 25 34–5, 53 concepts 132–3, 139 adynamic ileus 147 ICHs 56–62 acute endovascular stroke reperfu- AEDs see automated external induction drugs 13–14, 25 sion 87–91 defibrillators insertion caution 15, 18–20 acute ischemic strokes age risk factors 21, 32, 42–3, 80, intubation attempts 13–20, 25, see also ischemic strokes 95–6, 99–100, 102–3, 118, 33–4, 35–6, 41–2, 53, 56–7, concepts 6–8, 87–8, 180, 194–5, 155–61, 162–73, 175–81 65–9, 76–7, 89–91, 114, 144–50, 207–13 ASCIs 32 183–7 acute spinal cord injuries cardiac surgery 175–81 LEMON scores 16–17 (ASCIs) 32–6, 114–15, 195–6 CVT 99–100, 102–3 life-saving manoeuvers 18–20 see also primary...; secondary... delirium 155–61, Mallampati scores 16–17 acute management 32, 33–5 162–73 mechanical ventilation 144–50, ASIA grading scale 32–3 gastrointestinal infections 118 164–73, 182–7 complications 35–6, 114–15 hemicraniectomy 95 neuromuscular respiratory concepts 32–6, 114–15, 195–6 ICHs 95–6 failure 143–50 decompression 35 meningitis 123–4, 129 OBESE mnemonic 15–16 definition 32 SAHs 42–3, 80 pneumonia risks 114 epidemiology 32–6 TBIs 21 preparation 13–19 hypotension 34–5 agitation, delirium 167–73 support procedures 14–15, hypothermia 195–6 AHA guidelines 9 25–6, 33–5

Emergency Management in Neurocritical Care, First Edition. Edited by Edward M. Manno. Ó 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

225 226 . Index airway management (Continued ) concepts 9–10, 37–44, 73–83, antiplatelet agents 45, 49–50, suspected cervical spine 128–9, 215–23 57–62, 85 injuries 19–20, 25 epidemiology 37–8, 73–4 antipsychotics 171 TBIs 12–20, 25–31 post-procedural manage- antithrombin 102–3 tips & tricks 16, 17 ment 73–83, 214, 215–23 aortic arch atheroma 174–80 TMD 16 angiograms 39–40, 49, 75, 76–7, aortic dissection, hypertension ULBT 16 79, 89–91 3, 34 airways, definition 12–13 angioplasty 79, 86–91 APACHE II scores 169 albumin, ischemic strokes 52 animal bites 133 aphasia 63, 87–9, 100–7 alcohol 9, 64, 65, 168, 171–2, anoxia 64, 189–90, 193–4 APL see antiphospholipid syndrome 175–6, 201–3 anterior cingulate 162–73 apoptosis, hypothermia 189–91 ODS 201–3 anthrax 132 apparent diffusion coefficients SAH risk factors 9 antiarrhythmics 112, 163–4 (ADCs) 49 SE 64, 65 antibiotics 25, 104, 112–21, aquaporin-4 channels 80, 199 alfentanil 25, 27 125–31, 160, 163–4 ARAS see ascending reticular algorithmic approaches, airway bacterial meningitis 125–31 activating system management 12, 18–20 bloodstream infections 116–17 arboviruses 129–30, 133 ALIAS trial 52 CVT 104 areflexia 145–6, 183–7 allergies 6 incomplete meningitis arrhythmias 46–54, 57–62, 69, 78, alteplase 46 syndrome 124 112, 143–4, 145–8, 163–4, 171, alternative therapies for SE 67–8 infections 112–21 189–96, 202 Alzheimer dementia 55–6, 158 MDRO 112–14, 116–17, 121 arterial pulse contour analysis 79 Ambu self-inflating bags 15 MRSA 112–14, 116–17 see also LiDCO; PiCCO American College of pneumonia 112–14 arteriovenous malformations Neurosurgeons 22–3, 24, 33 seizure risks 120–1 (AVMs) 90–1 American Heart Association types 112–14, 115 ASA task force, airway manage- (AHA) 45, 61, 191, 195 urinary tract infections 115 ment 18–19 American Psychiatric anticholinergics 163–4 aSAHs see aneurysmal SAHs Association 155 anticoagulants 45, 52, 57–62, 84, ascending reticular activating American Spinal Injury Association 91, 95–8, 102–7, 176–7, 180, system (ARAS) 162–73 (ASIA) 32–3 190–6 ASCIs see acute spinal cord injuries American Stroke Association see also heparin aseptic meningitis 131, 145 40, 87 tips & tricks 85 ASIA see American Spinal Injury amino acids 158–61 antidepressants 163–4 Association aminocaproic acid 40–1 antiepileptics 41, 42, 61–2, 64–9, aspartate agonists 35, 160 ammonia, hepatic encephalopathy 83, 106, 112, 128–9, 163–4, aspiration risks 56–62, 114, 158–61, 163–4 171 143–50, 177 amnesia 63 see also levicetracam; phenytoin; ICHs 56–62, 114 amoxicillin 127–8 seizures; status epilepticus neuromuscular respiratory AMPA receptors, SE 68 antifibrinolytics, concepts 40–1 failure 143–50 ampicillin-sulbactam 113–14, antihistamines 163–4 aspirin 51, 87 117, 139 antihypertensive agents 3, 5–11 assaults on staff 27 analgesics 14–20, 25, 29–31, 171–2 see also beta blockers; calcium asterixis 159 anaphylaxis 58, 145–6 blockers; hypertension; nitric astrocytes 157–61, 201–3 anatomic changes in vessels fol- oxide vasodillators ATACH stroke trials 8, 57, lowing aSAH 74 concepts 5–11 96–7 Andrews, Peter J.D. 21–31 contraindications 7 ataxia 145–6, 159 anemia 5, 46, 81 doses 7 atelectasis 143–4 anesthesia 13–14, 51–2, 67, list 6–7 atlanto-occipital joint, airway 85–91 antimicrobial considerations in the management 14–20 see also sedation NCCU 120–1 ATLS see Advanced Trauma Life aneurysmal SAHs (aSAHs) antioxidants 6, 157, 186–7 Support see also subarachnoid antiphospholipid syndrome atrial fibrillation 89, 175–80 hemorrhages (APL) 102–3 atropine 5, 87, 150 Index . 227 attentiveness, delirium 155–6, beards, airway management body positions 162, 165–6, 172 15–17 ASCIs 33–4 Australia 8, 191–3 behavioural changes, encephalitis CVT 105 automated external defibrillators 132–40 ischemic strokes 53 (AEDs) 64–9 benzodiazepines 64–9, 156, 158, TBI 25, 26, 29 autonomic dysfunction 145 160, 163–4, 171–2 bones, primary ASCIs 32, 33 autonomic nervous system 23–4 see also lorazepam; midazolam Boston Scientific stents 87 avian H5N1 influenza virus 133 benzothaipine calcium bowel regimens, ischemic AVMs see arteriovenous blockers 5–6 strokes 52 malformations benzyl penicillin 127 Bowman Perfusion Monitor 220 Awakening and Breathing beta blockers brachial plexus injuries, cardiac Controlled trial 170 see also Esmolol; labetalol surgery 177 axons 145–50, 156–7, 182–7 concepts 5–6, 7, 40–1, 46–7, bradycardia 5, 7, 10, 30, 34–5, 57, azathioprine 150 49–50, 146–7, 163–4 79–80, 86–7, 146–7 azetazolamide 67 beta-lactams 112, 117, 120–1, brain abscesses 119 azithromycin 113–14 127–31 brain distortion, TBIs 27–8 aztreonam 117 biases, trials 8 Brain Injury Association of bilateral lesions, PRES 200 America 22 Baclofen 163–4 bilevel positive airway pressure brain tissue oxygen monitor- bacterial meningitis 123–31, 134 (BiPAP) 146–50 ing 214–23 see also meningitis bilirubin 159 see also oxygen... algorithm for emergency treat- BiPAP see bilevel positive airway caution 216–17 ment 125–6 pressure clinical uses and prior assessments 124–5, 134 Bivalirudin 84 studies 216 caution 127 bladder retention 145–6, concepts 214–23 clinical features 123–4 147 drawbacks 217 complications 128–9 blood pressure 3–11, 25–31, locational factors 215 concepts 123–31, 134 34–6, 39–40, 46–54, 65–9, measurement processes 215 definition 123–4 77–83, 87–91, 146–7, 177–8, other physiological differential diagnosis 124–5, 200–1 parameters 215–16 129, 130 see also hypertension overview 221 emergency management 125–7, aneurysmal SAH 9–10 patient-management 129 ASCIs 34–6 aspects 216–17 epidemiology 123–4, 128–9 concepts 3–11, 25–31, 34–6, science revisited 215 mortality rates 123, 124, 127 46–54, 77–83, 91, 146–7 Brain Trauma Foundation pathophysiology 123–4, 128–9 rebleeding complications (BTF) 22–3, 25, 28–31, risk factors 123–4 39–40, 44, 55–62, 73–4, 76, 83 114, 120 tips & tricks 129 TBIs 25–31 brain tumours 64, 100, 103, 163–4 treatments 124, 125–9 blood–brain barrier (BBB) 4–5, 6, brainstem 12–20, 23–4, 55–62, bags masks, airway management 10, 93–4, 134, 157, 189–96, 92–8, 139, 157, 159–60, 193–4 13–19 197–203, 212–13 bromocriptine 62 balloon angioplasty 79, 86–7, 175 hypertension 4–5, 6, 10, 93–4 bronchoscopy 13–14, 19–20 Balmuthia mandrillaris 124 hypothermia 189–96 bronchospasm 5 barbiturates 29–30, 53, 93–4, 161, ODS 201–3 BTF see Brain Trauma Foundation 163–4 bloodstream infections 53, 64, bulbar involvement 10, 143–50 barotrauma 19–20 111, 115–18 see also neuromuscular basal cisterns 125 see also sepsis respiratory failure basal ganglia 12–20, 55–62, 97–8, concepts 115–18 burns 13–15 133–40, 157, 202, 209–13 definition 115 buspirone 51, 192–3 basilar artery 37–44 diagnosis 115–16 Baxter–Edwards Vigilance microbiology 116–17 CAA see cerebral amyloid Continuous Oximetry prevention strategies 116–18 angiopathy Monitor 217 risk factors 115 CABG see coronary artery bypass BBB see blood–brain barrier treatments 116–17 graft surgery 228 . Index caffeine 195 cardioembolic ischemic strokes, see also oxygen... CAIs see community-acquired definition 45 caution 220 infections cardiopulmonary bypass concepts 3–11, 23–5, 30–1, calcium blockers 5–6, 7, 9, 40–1, (CPB) 176–9 42–4, 49–54, 74–83, 211–13, 46–7, 76–7, 157 cardiopulmonary complications of 214, 218–23 see also clevidipine; nicardipine; aSAH 80–1 drawbacks 220 nimodipine cardiopulmonary resuscitation equipment 220 California encephalitis 133 (CPR) 191 hypertension 3–11, 23–31, CAM-ICU see Confusion carotid artery stenosis 175, 179–80 49–54, 194 Assessment Method for the carotid artery stenting (CAS) 85–7, measurement processes 220 Intensive Care Unit 179–80 monitoring 214, 218–23 Campylobacter jejuni 145 carotid endarterectomy (CEA) other physiological cancers 21, 64, 100, 103–4, 163–4 85–7 parameters 220 Candida 115, 116–17 carotid revascularization patient-management candiduria 115 procedures 85–7, 174–81 aspects 220 Canhao, Patrı´cia 99–107 CAS see carotid artery stenting TBIs 23–5, 30–1, 194 carbamazepine 65–9 catecholamine levels 10, 44, 57–62 cerebral blood volume (CBV) carbapenems 113–14, 117, 120 catheter cephalads, jugular venous 23–6, 211–13 cardiac arrest oxygen saturation 217–23 cerebral edema 4–5, 6–8, 10, see also myocardial infarctions catheter-related bloodstream 22–31, 47–54, 56–62, 76–7, 80, hypothermia uses 189–96 infections (CRBSI) 114–20 87–9, 92–8, 100–1, 125, 129, mortality rates 191 catheters 17–18, 25–7, 28–9, 34–6, 157–61, 189–96 cardiac ischemia/arrhythmias 50, 77, 114–20, 145–6, 217–23 fulminant hepatic failure 160–1 46–54, 69, 78, 112, 143–4, guidelines 116–18, 119–20 hypertension 4–5, 6–8, 10, 145–8, 163–4, 171, 189–96, infections 114–20, 145 22–31, 47–54, 76–7, 80, 87–9, 202 tips & tricks 118 96–8 cardiac surgery 174–81 caudate 42–3, 55–62 ICHs 56–62 carotid artery stenosis 175, CBF see cerebral blood flow ischemic strokes 47–54, 80, 87, 179–80 CDC reports 127 92–8 caution 174–5 CEA see carotid endarterectomy cerebral embolisms 174–81 cognitive impairments 175–9 cefeprime 113–14, 117 cerebral endothelium 4–5, 73–4 174, 177 cefotaxime 127–8 cerebral ischemia see ischemic CPB 176–9 ceftriaxone 113–14, 117, 127–8 strokes encephalopathies 174–7 cell death 4–5, 21–2 cerebral microdialysis (CMD) 214, epidemiology 174–80 central venous catheters 221–3 evaluations of acute neurologic (CVCs) 25–7, 34–5, 77, 145 see also oxygen... deficits 180 central venous pressure clinical utility and prior intracranial hemorrhage 176–7 (CVPs) 25–7, 34–5, 77 studies 222 ischemic strokes 174–80 Centres for Disease Control and concepts 214, 221–3 mechanisms of neurologic Prevention 3, 119 drawbacks 223 injury 178–9 cephalosporins 114, 115, 127–31 equipment 221 neurological complications cerebellum 12–20, 55–62, 133–40, measurement processes 221–2 174–81 200, 202–3 other physiological optic neuropathy 174, cerebral amyloid angiopathy parameters 222 177–8 (CAA) 55–6, 57–62, 95–6 patient-management peripheral nerve injuries 174, cerebral aneurysms 84–5, 89–91 aspects 223 177 cerebral autoregulation, concepts science revisited 222 risk factors for neurologic 4–5, 9, 23–4, 90–1, 96–8, 157, cerebral perfusion pressure deficits 175–6 179–80, 185–6, 200–1, (CPP) 4–5, 9, 23, 24–6, seizures 177 211–13, 216–23 28, 29, 47–54, 62, 64, 75, tips & tricks 180 cerebral blood flow (CBF) 3–11, 91, 157, 160–1, 201, 214, cardiac system 46–54, 69, 78, 23–31, 42–4, 49–54, 74–83, 215–23 112, 143–4, 145–8, 163–4, 171, 174–80, 194, 207, 211–13, 214, cerebral salt wasting (CSW) 82 174–81 218–23 cerebral thermopooling 191 Index . 229 cerebral venous thrombosis clazosentan 80 concomitant injuries, SAHs 37–8 (CVT) 99–107 CLEAR-IVH trial 59, 97 Confusion Assessment Method see also dural sinus thrombosis clevidipine, concepts 6, 7 for the Intensive Care Unit assessments 99–103, 106 clonidine 163–4 (CAM-ICU) 156, 164–5, 168 clinical features 99–101, 103 clopidogrel 84–5, 87 conivaptan 82 CT scans 100–1, 105 Clostridium difficile 118–19 conjugate pneumococcal definition 99–100 see also gastrointestinal vaccines 123 epidemiology 99–100, 102–6 infections continuous EEG 63–9, 76–7, 93–4, evaluations 102–3, 106 CMA Microdialysis system 221 160, 165, 167, 214, 219 focal deficits 99–100, 106 CMD see cerebral microdialysis see also EEG... headaches 99–102, 103, 105–6 CMV 139 SE 63–9, 167 management 99–107 CNS angiitis 56 contraindications, antihypertensive mortality rates 103–5 CNS infections 64, 104, 118–21, agents 7 MRI 101–7 123–31, 132–40, 163–72 Controlling Hypertension and oral contraceptives 100, 102–3 see also encephalitis; meningitis; Hypotension Immediately prognosis 99, 103–6 ventriculitis Post-Stroke (CHHIPS) 50 risk factors 99–100, 102–3 CVT 104 convulsions 41, 42, 61–2, 63–9, specific treatments 104–5 prevention strategies 119–20 87–8, 106, 128–9, 163–4 symptomatic treatments 105–6 risk factors 119 see also epilepsy; seizures syndromes 99–100 SE 64 Cook exchange catheters 17–18 tips & tricks 100, 101, 104, 106 seasonal variations 129, 133–9 COOL AID trial 51–2 transient risk factors 100, 102–3 tips & tricks 119 COPD patients 5, 7 treatments 104–7 treatments 119–20 Cormack–Lehane scale, airway cerebrospinal fluid (CSF) 23–31, CO2 detectors 17–18, 24–5, 53 management 17–18 38–9, 43, 80, 124, 127, 131, coagulation indices 26, 46, Corona virus 139 133–5, 136–40, 157, 195, 212–13 65–6, 159 coronary artery bypass graft surgery encephalitis 133–5, 136–40 coagulopathies 46–54, 56–62, 116, (CABG) 174–81 meningitis 127, 131, 134, 157 145–6, 176–80 cotrimoxazole 127 SAHs 38–9, 43, 80 cocaine, seizure toxins 65 cough reflexes 12–14, 18–20, TBIs 23–31 Cochrane systematic review 30 114, 144 cerebrovascular diseases 3–11, cognitive impairments 132–40, coxsackieviruses 130 175–80 155–61, 168–73, 175–9 CPB see cardiopulmonary bypass cervical collars 17, 25, 26–7, 33 cardiac surgery 175–9 CPP see cerebral perfusion pressure cervical spine 14–20, 25, 32–6 delirium 168–73 CPR see cardiopulmonary see also acute spinal cord injuries encephalitis 132–40 resuscitation airway management 14–20, 25 metabolic encephalopa- cranial nerve examinations, deliri- suspected injuries 19–20 thies 155–61 um 165–6 TBIs 19–20, 25 coil embolization, cerebral cranial nerve nuclei 12–20, 183–7 Charcot–Bouchard micro- aneurysms 89–90 craniectomy, concepts 61, 89–90, aneurysms 55–6 colloid fluids 44 94–8, 105–6, 195 CHHIPS see Controlling Hyperten- comas 6, 8, 10, 13–14, 22, 28, 53, CRASH trial 31 sion and Hypotension 56–7, 59, 88, 100, 103–4, 106, CRBSI see catheter-related blood- Immediately Post-Stroke 124–31, 155, 157–61, 165, stream infections China 8, 87 167–73, 175–80, 191–6, 222 creatinine/BUN level 46, 119, 184 Chlamydia pneumoniae 112–14 communicating artery, SAHs cricoid pressure, airway manage- chloramphenicol 138 37–44 ment 13–14, 18–20 chlorhexidine 114, 116–18 community-acquired infections cricothyroidotomy, airway man- cholinesterase inhibitors 149–50 (CAIs) 111–14 agement 18–19 chronic meningitis, definition 123 complete blood counts 46 critical illness myopathy 182–7 ciprofloxacin 117 compliance critical illness neuromyopathy circulatory arrest 175, 178, 179, see also intracranial pressure 182–7 189–96 definition 23 see also neuromuscular... cistracurium 14 compression elimination, assessments 182–4 Claassen, Jan 63–70 concepts 23–4 clinical features 182–3 230 . Index critical illness neuromyopathy cytokines 124, 156–61, 162–73, examinations 165–7 (Continued ) 182–7, 190–6 ICU evaluations 164–7 concepts 182–7 see also interferons; interleukins ICU impacts 167–8 definition 182 cytomegalovirus 132 mortality rates 156, 167–9, diagnostic criteria 183–4 171, 172 electrophysiologic studies D-Dimers, CVT 102 non-pharmacological 183–5, 187 daltaparin 58 strategies 171–2 epidemiology 183–4, 186–7 Damian, Maxwell S. 123–31 pathophysiology 162–4 histiopathology 185 DCI see delayed cerebral ischemia RASS 167–8 mortality rates 186–7 DECIMAL trial 95 sedation-limiting arguments pathophysiology 185–6 decompression 35, 53, 80, 94–5, 169–70, 172 prognosis 186–7 105–6 sleep interventions 171–2 tips & tricks 187 see also hemicraniectomy tips & tricks 164, 165, 169, 172 treatments 186–7 ASCIs 35 treatments 170–3 critical illness neuropathy 182–7 CVT 105–6 dementias 55–6, 158, 162, 168–9 cross-clamping, cardiac ischemic strokes 53, 80, 94–5 demyelination 12–13, 21, 139, surgery 175–80 DEDAS trial 212–13 145–50, 185–7, 197–203 cryoprecipitate 89 deep brain stimulation, SE see also Guillain–Barre syndrome; crystaloid fluids 44 treatments 67 multiple sclerosis CSF see cerebrospinal fluid deep venous thrombosis denervated muscles 186–7 CSW see cerebral salt wasting (DVT) 27, 36, 51–2, 58–62, deoxyhemoglobin 210 CT scans 8, 26, 28, 33, 37–40, 41–2, 100–1, 103 depakote 42 46–9, 56–62, 65–9, 75, 89, 95, 97, ICHs 58–62 depression 21–2, 36, 43, 53, 103, 100–1, 105, 125–31, 134–40, ischemic strokes 51–2 147 159–60, 164, 167, 170, 174–6, Defense and Veterans Brain Injury depressive craniectomy, TBIs 29, 180, 200, 202–3, 207–13 Center 22 31 ASCIs 33 deferoxamine 97 desferoxamine 60 concepts 207–13 dehydration desmoteplase 212–13 CVT 100–1, 105 diuretics 6 DESTINY trial 95 encephalitis 134–40 ischemic strokes 51–2 dexamethasone 128, 163–4 ICHs 56–62, 95, 97 delayed cerebral ischemia dexemedetomidine 168, 172, ischemic strokes 46–9, 95, (DCI) 9, 73–83 192–3 174–6, 207–13 see also subarachnoid hemor- diabetes 45, 57, 114–15, 175–6 meningitis 125–31 rhages; vasospasm Diagnostic and Statistical Manual ODS 202 management of Mental Disorders (DSM), PRES 200 assessments 75–6 DSM-IV 155, 162, 164 SAHs 37–40, 41–2, 75 concepts 9, 73–83 diaphoresis 144 SE 65–9 emerging therapies 79–80 diaphragms strokes 8, 37–40, 41–2, 46–9, epidemiology 73–5 ASCIs 32–6 56–62, 75, 95, 97, 174–6, 207–13 etiology 73–5 neuromuscular respiratory TBIs 26, 28 interventions 76–83 failure 144–50, 183–7 CTAs (CT angiograms) 39–40, 49, monitoring procedures 75–6 diarrhea 118 75, 76–7, 174–6, 180, 207–13, delays in securing an aneurysm DIAS trials 212–13 216 41–2 diastolic blood pressure 3–11, cultures, encephalitis 134 delirium 64, 155–61, 162–73 49–54, 57–62 Cushing responses 30, 57, 93 see also sedation see also blood pressure; CVCs see central venous catheters assessments 155–6, 164–8 hypertension CVT see cerebral venous thrombosis CAD-ICU scale 156, 164–5 diazepam 64–9 cyanide toxicity, sodium clinical features 155–6, 162–3 difficult airway algorithm 18–20 nitroprusside 6, 7 concepts 155–61, 162–73 difficult airway intubation 15–19, cyclobenzepine 163–4 definition 155–6, 162–3, 165 114 cyclosporine 65, 199, 200–1 epidemiology 156, 162–5, difficult mask ventilation CYP2C19 85 167–72 (DMV) 15–16 cytochrome P450 system 120, 193 etiologies 162–4 digoxin 163–4 Index . 231 dihydropyrdine calcium blockers hypertension 5 meningitis 132, 134 5–6 ICHs 61–2 mortality rates 136–40 diphenhydramine 62 ischemia 5, 93–4 neuroimaging 134–40 Diringer, Michael N. 73–83 SAHs 42, 43, 76–7, 214 noninfectious causes 132–3, discs, primary ASCIs 32, 33 SE 63–70, 165, 167 135, 139 disturbance in consciousness 155, EFNS see European Federation of seasonal variations 133–9 159 Neurological Sciences serology testing 134–9 diuretics egg product allergies 6 specific organisms 135–9 see also mannitol EKG findings 43, 46, 65–9, 80 tips & tricks 133, 135 concepts 6, 59, 61, 105 electroconvulsive therapy, SE treatments 136–40 DMV see difficult mask ventilation treatments 67 vaccines 132 dobutamine 77–9 electrolyte disorder 46, 160 encephalopathies 6, 10, 64, dopamine 10, 34–5, 44, 62, 78, electrolytes, SE effects 69 99–107, 124–31, 155–61, 162–73 electrophysiologic studies, critical 162–73, 174–7 doptamycin 117 illness neuromyopathy see also comas; delirium; dorsolateral frontal cortex 12–20 183–5, 187 hepatic...; septic... doses, antihypertensive agents 7 electrophysiological signs of axonal cardiac surgery 174–7 doxycycline 113–14, 138 dysfunction, GBS 146–50 definition 155 drug abuse 45, 163–4 ELISA immune assay (EIA) 118, PRES 197–203 DSM see Diagnostic and Statistical 127, 138 endothelin 79–80, 130, 199–201 Manual of Mental Disorders Elsayed, Ali E. 132–40 endovascular interventions 77, 79, dural sinus thrombosis 99–103 embolectomy 89 84–91, 101, 104–5 see also cerebral venous embolisms 52, 58–9, 103–4, enoxaparin 52, 58 thrombosis 174–81 enrollment biases, trials 8 DVT see deep venous thrombosis embolization 84–91 Enteroccus 116–17 DWI (diffusion-weighted emergency management, bacterial enterolateral frontal cortex 12–20 imaging) 49, 75, 101–2, meningitis 125–7, 129 enteroviruses 129–31, 133–4 134–9, 157, 177, 180, 195, EMG (electronmicrography), epiglottis, airway management 200, 202, 207–13 critical illness 15–20 dysarthria 159 neuromyopathy 184–5 epilepsy 6, 10, 21, 27, 39, 41, dysautonomia 9–10, 146–50 enalaprilat, concepts 7 42, 61–2, 63–70, 76–7, 83, dysphagia 6, 56–7, 58–9, 61–2, 177 encephalitis 100, 118–19, 129, 106, 128–9, 165, 177, 189 dyspnea 144 130–1, 132–40 see also antiepileptics; seizures; see also Eastern Equine...; status epilepticus ear infections, CVT risk herpes...; Rocky Mountain...; concepts 39, 42, 61–2, 63–70, factors 100, 103 St Louis...; West Nile virus; 76–7, 83, 106, 165 Eastern Equine encephalitis Western Equine... epinephrine 25–6 (EEE) 133, 137 ADEM 130, 132–3, 135, 139, EPSP see excitatory post-synaptic ebtifibatide 85 163–4 potential ECGs 5 assessments 133–9 Epstein-Barr virus 130–1, 139 echinocandin 117 brain biopsies 134 erythropoietin 81 echocardiograms, SAHs 43 clinical features 132 Escherichia coli 123 eclpamsia, PRES 199–201 concepts 132–40 Eschmann ‘bougie’ catheters economic costs of strokes 207 CSF findings 133–5, 136–40 17–18 edema 4–5, 6–8, 10, 12–20, 22–31, cultures 134 Esmolol, concepts 5, 7 32–6, 47–54, 56–62, 76–7, 80, definition 132 esterases 5, 6 87–9, 92–8, 100–1, 125, 129, diagnostic studies 133–5 ethanol 195 157–61, 182–7, 189–96, 197–203 EEGs 135 etomidate 14, 34, 53 Edwards 4 French size fiberoptic epidemiology 132–3, 135–9 euglycemia 53 oxygen sensing catheters 217 general examinations 133 European Federation of EEGs 5, 42, 43, 61–2, 63–9, 76–7, historical background 133 Neurological Sciences 93–4, 135, 156, 157, 158, 159–60, human ehrlichiosis 138 (EFNS) 127–8 165, 167, 193–4, 214, 219 Listeria monocytogenes 138–9 Eurotherm3235 trial 29–30 encephalitis 135 management 132–40 euvolemia 51–2, 53, 76–83 232 . Index

EVDs see extraventricular drains flumazenil 160 Ginsberg, Myron 188 evidence-based guidelines focal deficits 37–9, 41–2, 56–7, 59, Glasgow Coma Scale (GCS) 8, management 60–1, 63–4, 99–100, 106, 13–14, 22, 28, 53, 100, 103–4, ASCIs 35–6 123–31, 132–40, 155–61 126, 189, 222 TBIs 22, 29–31 CVT 99–100, 106 glucagon 5 excitatory post-synaptic potential encephalitis 132–40 glucose controls in the NCCU (EPSP) 5 ICHs 56–7, 59, 60–1 critical illness neuromyopa- extracranial atherosclerosis 84–5 meningitis 123–31 thy 186–7 extracranial bleeding 52 metabolic encephalopathies ischemic strokes 50, 82 extraventricular drains (EVDs) 59, 155–61 glutamate 158–61, 162–3, 221–3 62, 76–7, 80, 93–8, 105–6, 216 SAHs 37–9, 41–2 glutamine 158–61 extubation considerations, airway SE 63–4 glycoprotein IIb/IIIa antagonists management 15, 20 focal neurological insults, 85, 89–91, 102, 135–6 midbrain 12–13 glycopyrrolate 150 facial twitching 63–4 focal probes 75–6 gram-negative bacteria 116, 119, facial weaknesses forced vital capacity (FVC) 144–50 123, 128, 160 critical illness neuromyopathy fosphenytoin 65, 66–9, 128–9 gram-positive bacteria 130 183–7 France, TBIs 21 gray matter 139, 159, 209–13 neuromuscular respiratory frank hypoattenuation 209 GRE (gradient-recalled echo) 37, failure 143–50 free radicals 6, 50–1, 60–2, 74, 101, 208, 212 family histories, SAH risk 190–1 Groysman, Leonid 45–54 factors 37 frontal cortex 12–20, 100, 135–6, guanosine monophosphate family members 200 (GMP) 6 ICHs 60–1 frontal lobe, brain tissue oxygen Guillain–Barre syndrome ischemic strokes 45–6, 175 monitoring 215–23 (GBS) 9–10, 143–51, 183 TBIs 26 Frontera, Jennifer A. 162–73 algorithm for initial FAST trial 58 fulminant liver failure 157, 159, evaluation 147 FDA 77 160–1 assessments 143–6, 147, 183 fentanyl 14, 25, 27, 167–8 FVC see forced vital capacity caution 146 Ferro, Jose M. 99–107 clinical features 143–4, 145–6 fetor hepaticus 159 GABA receptors 68, 120–1, 158, definition 143–4, 145 fevers 50–1, 53, 81–2, 93–4, 162–3 dysautonomia 9–10, 146–50 111–21, 123–31, 132–40, 218 gadolinium 101, 212 epidemiology 146–7, 148 see also meningitis gag reflexes 20 mortality rates 148 definition 111 gastric contents, airway manage- prognosis 148 epidemiology 111 ment 13–20 science revisited 145 meningitis 123–31 gastric stasis 68 treatments 143, 144–5, 146–50 tips & tricks 112 gastrointestinal infections gums, airway management 13, 15 fiberoptic intraparenchymal ICP 118–21, 133 Gupta, Rishi 84–91 monitors, brain tissue oxygen gastrointestinal prophylaxis, gyrus rectus 38 monitoring 215–23 ischemic strokes 52 fiberoptic intubation, airway gastroparesis 145, 147 Haemophilus influenza 113–14, management 18–20, GBS see Guillain–Barre syndrome 123, 128 34–5, 53 GCS see Glasgow Coma Scale HAIs see hospital-acquired fibrinogen 52–3, 89 Gebel, James M., Jr 55–62 infections Finland 129 gender risk factors 21, 43, 80, Haldol 156, 171 Fisher grades, SAHs 37–9, 74–5 99–100, 102–4 halo fixation 35–6 flail chest 13–14 CVT 99–100, 102–4 HAMLET trial 94–5 FLAIR (fluid attentuation inversion TBIs 21 HARM see hyperintense acute recovery), concepts 208–9, general anesthesia 85–91 reperfusion marker 212–13 general ICU TBI care 26–7 Harris Benedict Equation 26 fluconazole 115, 116–17 genotyping kits 85 Hazard Ratios 167 fluid management 51–3, 76–7, gentamicin 139 HCAP see health-care-associated 82–3 Germany, TBIs 21 pneumonia Index . 233 head positions hepatic encephalopathy 155, hyperdense artery signs, ischemia ASCIs 33–4 157–61 signs 209–13 CVT 105 assessments 159–60 hyperemia 4–5, 218 ischemic strokes 53 caution 161 hyperglycemia 61, 82, 119, 185–7, pneumonia risks 114 classifications 157–9, 160–1 193 TBI 25, 26, 29 clinical features 158–9 hyperintense acute reperfusion headaches 37–9, 41–2, 56–7, 59, definition 157–8 marker (HARM) 212 99–102, 103, 105–6, 123–31, epidemiology 157, 160–1 hyperkalemia 14, 34, 193 132–40, 145–6 mortality rates 157, 160–1 hyperosmolar therapy 30–1, 53, CVT 99–102, 103, 105–6 pathophysiology 157–8 80, 161 encephalitis 132–40 prognosis 159–60 see also hypertonic saline; ICHs 56–7, 59 tests 159–60 mannitol meningitis 123–31, 132 tips & tricks 159 hypertension 3–11, 13–20, 21–31, SAHs 37–9, 41–2, 100 treatments 160 37–44, 45, 46–54, 55–62, 78, HEADFIRST study 94 West Haven criteria 157–8 89–91, 93–8, 99–100, 105–7, health-care-associated pneumonia hepatic failure 155–61, 163–4, 124–31, 146–7, 158–61, 175–81, (HCAP) 112–14 168–9 198–203 Heidelberg group 95 hepatitis A 132 see also antihypertensive agents; hematomas 13–20, 47–54, 55–62, herniation 23–5, 28–9, 59–61, blood pressure; intracranial...; 83, 91, 96–8, 100–1, 105, 145–6 63–9, 89–91, 103–4, 105–7, strokes; vasopressors hemicraniectomy 61, 89–90, 94–8, 125–31 definition 3 105–6, 195 herpes simplex (types 1 and 2) epidemiology 3, 95–6 see also decompression (HSV) 124–6, 131, 132, 133–40 induced hypertension 78–9, 83 age risk factors 95 herpes viruses 124–6, 130–1, 132, management 3–11, 46–54, 55, CVT 105–6 133–40 57–62, 95–8, 105–7, 146–7, tips & tricks 94 herpes zoster 130, 133 200–1 hemodilution, hemodynamic high-intensity signals (HITS) 178 mortality rates 3, 8, 95–6 augmentation 78, 81 high-level paraparesis/plegia post-ICH secondary hemodynamic augmentation, 34–5, 128–9 damage 96–8 concepts 75–8 hippocampus 156–7, 162–3 PRES 198–200 hemodynamic stability histamine receptor 2-blocking scientific evidence 5 (hypotension) 25–31, 43–4, agents 114, 163–4 TBIs 21–31 75–8, 86–91, 145–6, 180 HIV/AIDS 21, 118, 125, 129–30, United States 3 hemorrhages 3–11, 12–13, 26–31, 131, 133 hypertensive crises 3–11 34–5, 37–44, 45, 48–9, 55–62, homeostasis 190–1 hypertensive emergencies 3–11 73–83, 92–8, 180, 193 horizontal tissue shifts, see also antihypertensive agents; hemorrhagic strokes 8–9, 34–5, concepts 92–8 life-threatening end-organ 37–44, 45, 48–9, 55–62, 73–83, hospital-acquired infections damage 89–90, 91, 92–8 (HAIs) 111–22 definition 3–4 see also intracerebral...; see also infections preferred agents 5–11 subarachnoid... human ehrlichiosis 138 statistics 4 concepts 8–9, 34–5, 37–8, human granulocytic anaplasmosis tips & tricks 5, 9 45, 48–9, 55–62, 73–83, (HGA) 138 hypertensive encephalopathy 6, 92–8 Hunt–Hess grades, SAHs 37–8, 10, 197–201 epidemiology 8, 37–8, 42–3, 45, 42–3, 74–5, 90 see also posterior reversible 55–8, 61–2, 73–5, 80–2, 89–90, hydralazine 147 encephalopathy 91, 92–3, 95–8 hydrocephalus 23–4, 39, 41, 42–3, hypertensive urgencies, mortality rates 8, 9, 37, 42–3, 45, 48–9, 59, 60, 76–7, 80, 97, 124–5, definition 3–4 55, 73, 89–90, 92–3 128–9 hypertonic saline 9, 29, 30, 59, 61, outcomes 8, 9 definition 80 80, 83, 93, 161 Hemphill, J. Claude, III 214–24 epidemiology 80, 97 hyperventilation considerations heparin 27, 36, 47, 52, 57–8, 84, SAHs 39, 42–3, 76–7, 80 CVT 105 85–8, 102–3, 104, 106, 178 hypercarbia 12–13, 143–50, 163–4, hepatic encephalopathy 161 see also anticoagulants 167 ICHs 59–60, 61 234 . Index hyperventilation considerations technical aspects of SE 64–9 (Continued ) applications 191–2 tips & tricks 112, 114, 118, ischemic strokes 53, 94 therapeutic targets 188–91 119, 121 meningitis 125 treatments 67, 68, 120, 161, inferior cerebellar artery 37–44 TBIs 25, 30–1, 222 188–96 inflammation 12–13, 56–62, 97, hypervolemia 48–9 hypotonic saline 83 123–31, 132–40, 155–61, hypnotics, airway management hypoventilation problems, airway 182–7, 189–96 14–20, 25 management 18–20, 25 inflatable bags, airway manage- hypo-osmolarity 201–2 hypovolemia, SAHs 76–83 ment 13–19 hypoalbuminemia 185–6 hypoxia 5, 6, 12–20, 25, 51–2, 69, influenza 112–14, 123, 128, hypocalcemia 79–80 143–51, 163–4, 167, 174, 132–4 hypoglycemia 5, 26, 45, 50–4, 217–23 inhaled anesthetics 67 64–9, 145–6, 163–4, 167, inhibitory post-synaptic potential 186–7, 222–3 ibuprofen 82, 192–3 (IPSP) 5 hypokalemia 202–3 ICA see internal carotid artery inotropic agents, DCI interven- hypomagnesemia 79–80 ICES trial 97 tions 78–81 hyponatremia 82, 177–8, ICHs see intracerebral hemorrhages INR see international normalized 201–3 ICP see intracranial pressure ratio hypoplasia 101–2 IHPOTOTAM study 128 insect bites 133, 136–7 hypotension 4–5, 10, 14–15, ileus 35, 119 see also mosquito bites; ticks 25–31, 34–5, 43–4, 48–54, 66, 68, immunocompromised indivi- insertion caution, airway manage- 75–8, 79–81, 86–91, 119, 145–6, duals 56, 123, 127–9, 136, ment 15, 18–20 157, 177–8 139, 199, 200–1 insular cortex 12–20 ASCIs 34–5 see also HIV... insular ribbon signs, ischemia pentobarbital 68 immunoglobulin (Ig) 134, 144–50, signs 209–13 SE 66, 68 186–7 Intensive Care Delirium Screening hypothalamus 162–3 immunomodulation, SE Checklist (ICDSC) 156 hypothermia 29–30, 51, 53, 67, 68, treatments 67 INTERACT stroke trial 8, 57, 96 82, 87, 93–4, 115–16, 120, 161, immunotherapy, neuromuscular intercerebral hemorrhage 188–96 respiratory failure 143–50 (ICH) 46–7 see also shivering; temperature impaired vascular reactivity fol- interferons 162–3, 186–7 controls... lowing aSAH 74 interleukins 124, 162–73, 182–7 ASCIs 195–6 incomplete meningitis intermediolateral horns of the bloodstream infections 115–16 syndrome 124 spinal cord 10 cardiac arrest uses 189–96 India, TBIs 21 intermittent pneumatic compres- complications 193 individualized therapies, sion (IPC) 52 concepts 67, 68, 120, 161, pharmacological internal carotid artery (ICA) 92–8, 188–96 therapies 120–1 210–13 historical background 188 induced hypertension 78–9, 83 internal caudate 55–62 induced uses in NCCU 120, 161, see also vasopressors International Liaison Committee 188–96 induction, airway manage- on Resuscitation (ILCOR) 189 ischemic strokes 51, 53, 82, 87, ment 13–20, 25 international normalized ratio 93–4, 188–96 infections 56, 61, 64–9, 81–2, 100– (INR) 52–3, 56, 58, 105 mechanisms of action 188–91 3, 111–22, 145–50, 163–4 intra-arterial opening of the neurological prognostication see also bloodstream...; CNS...; vessels 9, 79, 101–2 193–4 fevers; gastrointestinal...; intracerebral hemorrhages nonventricular fibrillation pneumonia; urinary tract... (ICHs) 8–9, 39, 55–62, 73, 91, arrest 189–90 caution 115 92, 95–8, 100–1, 159–60, 163–4, rewarming techniques 192–3 CVT risk factors 100–3 195–6, 200, 208, 212, 215–23 SAHs 195 delirium 163–4 assessments 56–9, 91, 100, 208, science revisited 194 epidemiology 111–21 212, 215 SE treatments 67, 68 ICHs 56, 61 caution 59, 61 sepsis 193 mortality rates 111–14 clinical features 56–7 TBIs 29–30, 194 risk factors 111–12 definition 55–6, 95–6 Index . 235

epidemiology 55–8, 61–2, 91, treatment of raised ICP 29–31, fluid management 51–3, 82–3 92–3, 95–8 40–1, 49–54, 93–8, 105, 194–6, glucose controls in the family members 60–1 219 NCCU 50, 82 headaches 56–7, 59 intracranial stenting 84–91 hypothermia 51, 53, 82, 87, hematoma-expansion treat- intravenous cannulas, airway 93–4, 188–96 ments 96–7 management 18–19 intracranial hemorrhage 51–4, historical background 95–6 intravenous immunoglobulin 208, 212 initial medical critical care 57–8 (IVIg), concepts 144–50, large hemispheric strokes 92–8 iron 96 186–7 locational factors 208–10 mortality rates 55, 57–8, 92–3, intraventricular hemorrhages management 45–54, 92–8, 95–8 (IVHs) 59–62, 74–5, 97–8 207–13, 217–18 neuroimaging 56–62, 159–60, see also intracerebral mortality rates 8, 45, 47, 50, 51, 208 hemorrhages 92–8, 207 new treatments 92, 95–8 intubation attempts 13–20, 25, NCCU admission indica- pathophysiology 55–6, 95–6 33–4, 35–6, 41–2, 53, 56–7, 65–9, tions 47–8 post-ICH surgery 97–8 76–7, 89–91, 114, 144–50, 183–7 neuroimaging 46–9, 56, 88, 95, rebleeding complications invasive cooling devices 192–3 194–5, 207–13 55–62, 96–8 iodine 118 new treatments 92–8 risk factors 55 ipsilateral hemisphere, brain tissue nutritional requirements 51–2 secondary injury processes oxygen monitoring 215–23 outcomes 8 96–8 IPSP see inhibitory post-synaptic PEs 52 seizures 61–2 potential reperfusion 46–54, 86–91, steroids 61 iron, post-ICH secondary 189–96, 207–13 subsequent medical critical damage 96–8 reversibility factors 208–9 care 62 ischemia 3–11, 12–13, 32–6, 41, subsequent management in the subsequent neurological critical 43–4, 45–54, 56, 60, 63–4, neuroscience ICU 49–52 care 60–2 73–83, 87–91, 92–8, 157, 163–5, temperature controls in the tips & tricks 58, 59, 61, 62 174–80, 188–96, 207–13, 217–23 NCCU 50–1, 53, 81–2, 93–4, tPA 57–62, 97–8 cell death 4–5 188–96 treatments 56–62, 92, 95–8, 195, EEGs 5, 93–4 tips & tricks 46 212 hypertension 3–11, 46–54 tPA 46–54, 87–90, 95, 195, intracranial atherosclerosis ischemic strokes 6–8, 41, 43–4, 212–13 84–91, 207 45–54, 56, 60, 63–4, 73–83, treatments 45–54, 92–8, 194–6, see also ischemic strokes 87–91, 92–8, 163–5, 174–80, 208–13, 217–18 intracranial hemorrhage 188–96, 207–13, 217–23 isotonic fluids 82 cardiac surgery 176–7 see also delayed...; intracranial ISTICH trial 60 ischemic strokes 51–4, 208, atherosclerosis Italy, TBIs 21 212 aggressive BP treatments 50 IVHs see intraventricular intracranial hypertension 4–6, assessments 45–7, 56, 92–3, 180, hemorrhages 13–20, 21–31, 42, 47, 56–62, 207–13 IVIg see intravenous 93–8, 99–100, 105–7, 124–31, bowel regimens 52 immunoglobulin 158–61, 195, 201 cardiac surgery 174–80 see also hypertension categories 45 Japan 21, 87 TBIs 21–31 clinical features 45–7, 56, 174, jugular vein pressure (JVP), intracranial pressure (ICP) 4–5, 207–9 concepts 4–5, 26–7 22–31, 40–1, 42, 44, 51–4, 93–4, complications 46–7, 49, 52, 53, jugular venous flow, TBIs 26–7 105, 158–61, 194–6, 201, 214–23 63–4, 73–4, 163–4, 180 jugular venous oxygen caution 161 definition 45–7, 56, 174, 207–9 saturation 214, 217–23 management 28–31, 40–1, 44, DVT 51–2 see also oxygen... 51–4, 93, 105, 160–1, 214–23 epidemiology 8, 41, 43, 45–6, clinical utility and prior monitoring procedures 27–9, 87–91, 92–8, 175–6, 179, 180, studies 217–18 40–1, 160–1, 214, 219 207, 212–13 concepts 214, 217–23 pressure waveform 27, 77 the first 24 hours 46–9 drawbacks 218–19 TBIs 22–31 the first hour 45–6 equipment 217 236 . Index jugular venous oxygen lentiform nucleus, ischemia McCoy type laryngoscope blades, saturation (Continued ) signs 209–13 airway management 18 measurement processes 217 Leptospira 127 McCullagh, Iain J. 21–31 other physiological lesions 90–1, 92–8, 100–7, 208 McGill forceps 17–18 parameters 217–18 leukocytosis 112, 127–8, 185–7 Macintosh type laryngoscope overview 221 leukoencephalopathies 198 blades, airway manage- patient-management leukopenia 112 ment 15–16, 17–18 aspects 218 levateracitam 61 macroembolisms 174 science revisited 218 level of consciousness (LOC), macrolides 120 JVP see jugular vein pressure ICHs 56–7, 59–62, 76–7 McWilliams, Laurie 3–11 levetiracetam 83, 128–9 magnesium support ketamine 14, 67 levicetracam 42, 83 SAH 79–80 kidney injuries 6, 7 see also antiepileptics shivering 192–3 Klebsiella-Enterobacter 116–17, levofloxacin 113–14 malaria 133 123 levophed 25–6 malignant cerebral edema 47–54, Kress trial 170 LICOX system 214–15 92–8 LiDCO 79 Mallampati scores 16–17 L-type calcium channels 5–6 lidocaine 25, 53, 67 see also LEMON scores labetalol, concepts 5, 7, 40–1, life-saving manoeuvers, airway mandible, airway manage- 46–7, 49–50 management 18–20 ment 14–20 lacitol 160 life-threatening end-organ damage mannitol 9, 29, 30, 53, 59, 93, 161 lactate-pyruvate ratios see also hypertensive Manno, Edward M. 32–6, 92–8, (LPRs) 221–3 emergencies 155–61, 182–7, 188–96 lactulose 160 definition 3–4 MAP see mean arterial pressure lacuunar ischemic strokes, ligaments, primary ASCIs 32, 33 maxillary fractures 12–13 definition 45 limited neck extensions, airway maximal expiratory pressure Laerdal self-inflating bags 15 management 16 (MEP) 144–50 large hemispheric strokes 92–8 linezolid 113–14, 117 maximal inspiratory pressure see also ischemic... lipid metabolism disorders 6, 7 (MIP) 144–50 definition 92 lipohyalinosis 55–62 Mayo Clinic 95, 193–4 historical background 92–3 lips, airway management 13, 15 MCA see middle cerebral artery medical management 93–4 Listeria monocytogenes 123, MDROs see multidrug-resistant new treatments 92–8 127–8, 138–9 organisms large-artery atherosclerotic LMA placement, airway manage- mean arterial pressure (MAP), ischemic strokes, ment 19–20 concepts 4–5, 10, 23–4, 25–6, definition 45 LOC see level of consciousness 29–31, 35–6, 49–54, 87, 89–91, laryngeal masks 17–18 locational factors 93, 201, 215–23 laryngoscope blades, airway brain tissue oxygen mean transit time (MTT) 211–13 management 15–16, monitoring 215 measles 129, 132, 133–4 17–20 ischemic strokes 208–10 mechanical ventilation 144–50, laryngoscopies 15–20, 25 SAHs 38–9 164–73, 182–7 laryngotracheal fractures 13–14 ‘log rolling’ techniques 25, 33 see also airway management larynx 12–20 lorazepam 64–9, 167–8, megacolon 119 lateral precentral gyri 12–20 171, 172 melatonin 162–3 lateral ventricle, brain tissue oxygen LPRs see lactate-pyruvate ratios MENDS trial 167–8, 169–71 monitoring 214–23 lumbar punctures meningitis 118–19, 123–31, 132, laxatives, ischemic strokes 52 meningitis 125–6, 129 134 LDF (laser Doppler flowme- SAHs 38–40, 43 see also bacterial...; chronic...; try) 220–1 Lyme disease 130, 133, 163–4 meningococcal...; viral... Legionella 112–14 lymphocytic choriomeningitis age risk factors 123–4, 129 Leiva-Salinas, Carlos 207–13 129, 133–4, 139 CSF findings 127, 131, 134, 157 LEMON scores definitions 123–4, 129–30, 132 see also Mallampati scores MA stents 87 encephalitis 132, 134 airway management 16–17 McAllen, Karen J. 111–22 strokes 128–9 Index . 237 meningococcal meningitis 123–8 mitochondrial dysfunction 156–7, myalgia 130, 137, 145–6 see also meningitis 185–7, 188–96, 221–3 myasthenia gravis (MG) 143–51, meningoencephalitis 132, 137, Modified Fisher scale, SAHs 74 183 139 Mollaret relapsing aseptic algorithm for early menthohyoid distance, airway meningitis 131, 145 management 149 management 16 Monroe–Kellie doctrine 23, 93 assessments 143–5, 148–9, 183 MEP see maximal expiratory morphine 167–8 caution 149 pressure mosquito bites 133, 136–7 clinical features 143–4, 146, meperidine 51, 62, 192–3 see also malaria; St Louis 148–9 Merci device 89 encephalitis; West Nile complications 150 meropenem 127–8 virus definition 143–4, 146, 148 metabolic acidosis 68 motor axons 182–7 mortality rates 150 metabolic encephalopathies 6, 10, motor examinations, prognosis 150 64, 99–107, 124–31, 155–61, delirium 165–6 REM sleep 149 162–73, 174–7 moxifloxacin 113–14 science revisited 148 see also comas; delirium; Moya Moya disease/syndrome 56 steroids 150 hepatic...; septic... MRAs (MR angiograms) 39, 48–9, tests 148 definition 155 75, 174–7, 180, 209–13 tips & tricks 148 tips & tricks 159 MRI (magnetic resonance imag- treatments 143, 144–5, 146, methicillin-resistant Staphylococ- ing) 33, 37–9, 42–3, 46, 47–9, 147–50 cus aureus (MRSA) 112–14, 56–7, 65–9, 75, 88, 95, 101–7, Mycoplasma 113–14, 127 116–17 126–31, 134–40, 157, 159–60, myelin 12–13, 21, 139, 145–50, methicillin-sensitive Staphylococ- 167, 170, 174–7, 180, 200, 202, 183–7, 197–203 cus aureus (MSSA) 113–14, 207–13 myelopathy 128–9 117 ASCIs 33 myocardial cooling techni- methylprednisolone 150 concepts 207–13 ques 177–9, 189–96 metoclopramide 147 CVT 101–7 myocardial infarctions 80, 85–6, metronidazole 119, 160 encephalitis 134–40 169, 176–80, 189–96 MG see myasthenia gravis ICHs 56–7 see also cardiac arrest microbiology of bloodstream ischemic strokes 46, 47–9, 88, myocardial revascularization, infections 116–17 95, 174–7, 207–13 CABG 174–81 microelectrodes, brain tissue meningitis 126–31 myocardial stunning 43–4, 80–1 oxygen monitoring 214–23 ODS 202 myocardial suppression 68 microembolisms 174 PRES 200 myoglobinuria 69 midazolam 14, 64–9, 168, SAHs 37–9, 42–3, 75 myoinositol 202–3 172, 189 SE 65–9 myopathy see critical illness midbrain 12–20 strokes 37–9, 42–3, 46, 47–9, myopathy middle cerebral artery (MCA) 56–7, 75, 88, 95, 174–7, myosin 184–7 37–44, 47–54, 87–91, 92–8, 207–13 209–13 MRSA see methicillin-resistant N20 responses 193 midpontine tegmentum 162–73 Staphylococcus aureus Naegleria fowleri 124 migraines with aura, CVT 99–100 MRVs (MR venography) 101–2 nafcillin 117 Miller Fisher GBS variant 145–6 MSSA see methicillin-sensitive naloxone 35 Miller type laryngoscope blades, Staphylococcus aureus Naravetla, Bharath R. 214–24 airway management 16, MTT see mean transit time nasal airways, airway 17–18 multidrug-resistant organisms management 15 milrinone 77–9 (MDROs) 112–14, 116–17, 121 nasopharyngeal cooling 192–3 minimally invasive surgical multiple sclerosis 21, 163–4 nasopharynx 12–20, 192–3 methods, ICHs 97–8 see also demyelination Nathan, Barnett R. 132–40 MIP see maximal inspiratory mumps 129, 132, 133–4 Natick stents 87 pressure muscle atrophy 183–7 The National Health and Nutrition MIP (maximum intensity muscle relaxation, airway manage- Survey (NHANES) 3 projection) 210–13 ment 13–14, 26–7, 114 National Institute of Disability and MISTIE trial 60, 97 MuSK antibodies 148–50 Rehabilitation Research 22 238 . Index

National Institute of Neurological see also cognitive impairments; nonconvulsive SE (NCSE) Disorders and Strok 22 comas; encephalopathies; see also epilepsy NCSE see nonconvulsive SE ischemic strokes concepts 63–9, 165 NCT (non-contrast CT of the neurological diseases, hyperten- epidemiology 64 head) 208–13 sion 3–11 noninfectious causes of neck, airway management neuromuscular blocking encephalitis 132–3, 135, 139 16–17 agents 30–1, 34–5, 186–7 nonventricular fibrillation arrest, necrotizing myopathy 182 neuromuscular complications hypothermia 189–90 Neisseria meningitides 123–31 see also critical illness... norepinephrine 25–6, 34–5, 77–8 neomycin 160 concepts 143–51, 182–7 see also vasopressors neoplasms, ICHs 56 sepsis 182–7 normothermia 51, 53, 189–96 neostigmine 147, 149 neuromuscular respiratory nutritional requirements neosynephrines 25–6 failure 143–51, 182–7 ASCIs 35–6 neurocardiogenic shock (Takotsabu see also critical illness...; critical illness neuromyopathy cardiomyopathy), SAHs 39, Guillain–Barre syndrome; 186–7 43–4, 77 myasthenia gravis; delirium 163–4 neurocognitive deficits 175–9 respiratory... ischemic strokes 51–2 see also cognitive impairments assessments 143–5 TBIs 26–7 neuroganglioside GM-1 35 clinical features 143–5 neuroimaging/neuromonitoring complications 143–4, 182–7 OBESE mnemonic, airway 8, 26, 28, 33, 37–42, 46–9, 56–62, concepts 143–50, 182–7 management 15–16 74–6, 81, 88, 95, 99–101, 125, science revisited 143, 145 obstruction of the airway 12–20 134–40, 157, 159–60, tests 144, 146 occipital lobes 198–200 167, 170, 175–7, 180, 194–5, tips & tricks 144, 146 ocular blobbing 159 199–202, 207–13, 214–24 neuromyopathy see critical illness ocular hemorrhages 37 see also CT...; DWI...; EEGs; neuromyopathy ODS see osmotic demyelination MRI...; oxygenation of the neurons 5, 60–2, 68, 201–3 syndrome brain; PET; PWI...; SPECT neuropathy 174, 177–8, 182–7 opiates 14, 25, 27, 156, 163–4, bleeding risk predictions see also critical illness... 167–8 212–13 neuropsychiatric abnormalities see also alfentanil; fentanyl; caution 209 155, 157 remifentanil concepts 207–13, neurotoxic vasogenic edema opthalmoplegia 145–6 214–24 syndrome see posterior optic neuropathy, cardiac differentiation of infarct core and reversible encephalopathy surgery 174, 177–8 penumbra 210–13 neurotransmitters 50–1, 156–61, oral contraceptives, CVT risk encephalitis 134–40 162–73 factors 100, 102–3 ICHs 56–62, 159–60, 208 see also acetylcholine; dopamine; organ systems, SE effects 69 ischemic strokes 46–9, 56, 88, GABA...; glutamate; organophosphates, seizure 95, 194–5, 207–13 melatonin; serotonin; toxins 65 SAHs 37–40, 41–2, 74–6, 208 tryptophan oropharynx 12–20, 135–40, 145–50 science revisited 208, 212 neutropenia 85 osmotic agents 53, 77, 161 selection of patients for niacin 163–4 osmotic demyelination syndrome therapy 212–13 nicardipine, concepts 6, 7, 40–1, (ODS) 197–8, 201–3 tips & tricks 208, 210 46–7, 49, 57–8, 147 caution 202 neurointensive care units NIH Stroke Scale (NIHSS) 8, 46, concepts 197–8, 201–3 complications 84–91 47, 48–9, 195 definition 197–8, 201–2 neurointerventional patient nimodipine, concepts 9, 76–7 etiology 201–2 care 84–91 nitric oxide (NO) 6, 7, 74, 81, mortality rates 202–3 neurointerventional patient care, 156–7, 186–7 neuroimaging 202 neurointensive care units nitric oxide vasodillators 6, 7, 74 prognosis 203 84–91 see also sodium nitroprusside pseudonyms 197, 202 neurologic injuries 111–12 nitroprusside drips 40–1, science revisited 202 neurological complications 49–50 tips & tricks 202, 203 of cardiac surgery 174–81 NMDA receptors 68, 188–9 treatments 197–8, 202–3 Index . 239 oxacillin 117 perihematomal edema, ICHs pneumothorax 34, 145–6 oxygen 9, 13–19, 24–31, 35–6, 75, 55–62, 96–8 poikilothermia 53 81, 178–9, 189–96, 214–24 peripheral nerve injuries polarographic Clarke-type micro- airway management 13–19, cardiac surgery 174, 177 electrodes 214–15 25–31, 35–6, 81 critical illness neuromyopathy polio 129, 133 ASCIs 35–6 182–7 polymerase chain reaction TBIs 24–31, 214–24 PEs see pulmonary embolisms (PCR) 118, 130, 134–5, 136–8 oxygen extraction fraction 216–22 PET (positive emission pons 12–20, 56–62, 201–3 oxygenation of the brain 9, 13–19, tomography) 81, 157, pontine nuclei 157–61 25–31, 35–6, 75, 81, 178–9, 212–13, 216 post-menopausal women 43 189–96, 214–24 pharmacodynamics 120–1 post-operative strokes, cardiac see also brain tissue oxygen pharmacokinetic alterations in surgery 174–81 monitoring; cerebral blood NCCU patients 120–1 post-procedural management of flow; cerebral microdialysis; pharmacological therapies 84–91, aSAHs 73–83, 214, 215–23 jugular venous oxygen 96–8, 111–14, 120–1, 162–73, post-traumatic seizures 27 saturation 186 post-traumatic stress disorder concepts 214–24 see also individual medications (PTSD) 171–2 monitors 28–30, 35–6, 75, 81, complications 84–91, 112, 114, postcentral gyri 12–20 214–24 162–73 posterior reversible neuromonitoring con- delirium 162–73 encephalopathy (PRES) cepts 214–24 fevers 111–12 197–203 vasospasm management 9 individualized therapies 120–1 see also hypertensive oxymetric catheters, jugular venous shivering 192–3 encephalopathy oxygen saturation 217–23 pharyngitis 130 caution 200 phenobarbital 42, 66–9 clinical features 198–9 P300 system 159 phenylalkylamine calcium concepts 197–201 P450 system 120, 193 blockers 5–6 definition 197–8, 199 pacemakers 87 phenylephrine 25–6, 34–5, 77–8 etiology 198–200 palmar erythema 159 see also vasopressors hypertension 198–200 papilloedema 59, 99–107, 124–31 phenytoin 41, 42, 65–9, 83, 112, neuroimaging 199–200 paraldehyde 67 128–9 pseudonyms 197 paralytics 14–20, 25, 29–31, 34, see also antiepileptics science revisited 199 51–2, 66, 189–90 photophobia, meningitis 123–31 tips & tricks 199, 200 paraparesis/plegia 34–5, 128–9, phrenic neuropathy 177, 183–7 treatments 197–8, 200–1 183, 187 PiCCO 79 potassium 193, 203 parasomnias 64 pineal 93 pre-eclpamsia, PRES 199–201 parietal lobes 198–200 piperacillin-tazobactam 113–14, prednisone 150 parietal paramedian lesions 100 117 pregnancy parietal-occipital lobes, plasma exchange (PE), concepts CVT risk factors 100, 103 concepts 10 144–5, 147–50, 157, 186–7, 203 encephalitis 138 Parker, Dennis 111–22 plasma glucose levels 26, 46, 50–4, hyperclampia 7 Parkinsonian rigidity 159, 162 82, 221–3 PRES 197–201 partial thromboplastin time ischemic strokes 50–4 PRES see posterior reversible (PTT) 52–3, 159–60 TBIs 26 encephalopathy PCC see prothrombin complex pneumococcal vaccines 123 PREVAIL trial 52 concentrate pneumonia 25, 35–6, 53, 56–7, 69, primary ASCIs, concepts 32–6 PCR see polymerase chain reaction 89–90, 111–21, 143–4, 177 PROACT II study 87–8 PE see plasma exchange concepts 111–21 probiotic diets 160 PEA see pulseless electrical activity diagnosis 112 procalcitonin 121, 130 penicillin 127–8, 139 epidemiology 111, 112–13 propanolol 27 pentobarbital 67–9 prevention strategies 114 prophylaxis 27, 36 perfluorochemical sprays, science revisited 112 propofol 14, 27, 34, 53, 67–9, 156, hypothermia 51 sputum samples 112–14 167–8 pericardial tamponade 34 treatments 112–14 prostaglandins 156 240 . Index protamine sulfate 58, 90 MG 150 rotating beds, deep venous prothrombin complex concentrate post-ICH surgery 97 thrombosis 36 (PCC) 58 stents 87 RSE see refractory status epilepticus prothrombin time (PT) 52–3, 56, TBIs 29–31, 104 rubella 132 58, 159–60 transfusions 81 proton pump inhibitors 85, 114 rebleeding complications Saber Cerebral Blood Flow Provencio, J. Javier 197–203 ICHs 55–62, 96–8 Monitor 220 providone-iodine 118 SAHs 39–44, 73–4, 76–7, 83 Safar, Peter 188 Pseudomonas aeruginosa 116–17 recanalization 210–13 SAHs see subarachnoid pseudophedrine 87 recombinant factor VII 96–8 hemorrhages pseudostatus 64 red blood cells (RBCs) 5, 6, 38–9, St Louis encephalitis (SEL) 133, psychiatric abnormalities 21–2, 60, 74, 81, 133, 216 134, 137 36, 43, 53, 103, 132, 139, 147, reflex swallowing 12–20, 35–6, 52, Sampson, Tomoko Rie 73–83 155, 157 58–9 scientific evidence, see also depression refractory status epilepticus (RSE), hypertension 5 psychosis 132, 139, 171 concepts 66–9, 195 scopolamine 150 PT see prothrombin time REM sleep, MG risks 149 SE see status epilepticus ptosis 145–6, 177–8 remifentanil 27 seasonal variations pulmonary capillary wedge renal insufficiency, encephalitis 133–9 pressure (CVP) 77 hypertension 3 viral meningitis 129 pulmonary embolisms (PEs) renal system 3, 69, 82–3, 100, 118, secondary ASCIs, concepts 32–6 CVT 103–4 145–6, 159, 199–201 secondary injury processes ICHs 58–9 reperfusion, ischemic strokes brain-oxygenation monitoring ischemic strokes 52 46–54, 86–91, 189–96, 214–24 pulseless electrical activity 207–13 post-ICH secondary damage (PEA) 189 respiration 12–20, 33–4, 56–62, 81, 96–8 putamen 55–62 130–1, 143–51, 182–7 TBIs 21–31, 214–24 PWI (perfusion-weighted see also airway... sedation 13–14, 51–2, 85, 88–91, imaging) 49, 207–13, 216 respiratory failure 10, 81, 143–51, 162–73, 174–80, 189–90, 219 pyridostigmine 149 182–7 see also anesthesia; delirium see also neuromuscular... airway management 13–14 QFlow 500 Probe 220 respiratory tract infections concepts 13–14, 162–73, 219 quadraparesis/plegia 34–5, see also pneumonia limitation arguments 169–70, 183, 187 concepts 112–14 172 quetiapine 171 resuscitation targets, TBIs 25–6 SEDCOM trial 168–71 quinolones 115, 120 retroviruses 130 seizures 6, 10, 27, 39, 42, 61–2, see also HIV... 63–70, 76–7, 83, 87–8, 90–1, rabies 133 reverse Trendelenburg uses 35 99–107, 120–1, 124–31, Rabinstein, Alejandro A. 143–51 rewarming techniques, hypother- 132–40, 159, 163–7, 177, radial nerves 177 mia 192–3 208, 218 ranitidine 27 rfVIIa 58 see also antiepileptics; epilepsy; Rankin scales 50, 87, 95, 96–7 rhabdomyolsis 69 status epilepticus rashes Rhoney, Denise H. 111–22 antibiotics 120–1 encephalitis 137–8 Richmond Agitation and Sedation cardiac surgery 177 meningitis 124–31 Scale (RASS) 167–8 CVT 99–107 RASS see Richmond Agitation and rickettsial disease 130, 137–8 delirium 163–4 Sedation Scale rifampin 120, 138 ICHs 61–2 RBCs see red blood cells rifamycin 160 SAHs 39, 42, 76–7, 83 RCTs Rifaximin 160 treatment and prevention 106 ASCIs 35–6 robinal 87 Seldinger technique 217 CAS 85–6 Rocky Mountain Spotted fever self-inflating bags, airway delirium 167–73 (RMSF) 137–8 management 15–20 hypothermia 189–96 rocuronium 14 sepsis 53, 64, 115–18, 155, 156–7, magnesium supplements 79–80 Ropper’s study 93 169, 182–7, 193 Index . 241

see also bloodstream infections; spectophotometry, SAHs 39 GBS 148 critical illness neuromyopathy spider nevi 159 ICHs 61 complications 182–7, 193 spinal cord 10, 21, 32–6, 114–15, MG 150 hypothermia 193 137–40, 162–3, 195–6 ODS 203 neuromuscular complications see also acute spinal cord injuries SE 67 182–7 intermediolateral horns 10 TBIs 31 septic encephalopathy 155, spirometers 144–50 STICH trials 60, 97 156–7, 182–3 sputum samples, pneumonia Streptococcus pneumoniae clinical features 157, 182–3 112–14 112–14, 123–31 concepts 156–7, 182–3 SSS see superior sagittal sinus stress 21–2, 36, 43 definition 156 Staphylococcus aureus 112–14, stress ulceration 27 pathophysiology 156–7 116–17, 119, 123 Stroke Guidelines 2010 8 treatments 157 Staphylococcus epidermidis stroke mimics 208–9 septic shock 116–17 116–17, 119, 123 see also intracranial hemorrhage serotonin 10, 162–73, 192–3 STAT repeat head CTs 58–9, 76 strokes 3–11, 12–13, 34–5, 37–44, Serratia 116–17 statins, DCI interventions 79–80 45–54, 55–62, 64–9, 87–91, 92–8, sertotype C meningococcal status asthmaticus 183 99–107, 128–9, 162–73, 174–80, vaccine 123 status epilepticus (SE) 63–70, 207–13 severe hypertension, definition 76–7, 83, 100, 103–4, 165, 167, see also hemorrhagic...; 3–4 169, 193, 195 ischemic... shivering 189–96 see also epilepsy; seizures cardiac surgery 174–80 see also hypothermia acute management 64–6 categories 45, 99–100 shunting, CVT 106 alternative therapies 67–8 definition 45–7, 56, 174 SIADH see Syndrome of Inappro- antiepileptic medications 65–8 economic costs 207 priate Secretion of AntiDiuretic assessments 63–4, 65, 165 epidemiology 8, 37–8, 41, 42–3, Hormone caution 66, 68 45–6, 55–8, 73–5, 80–2, 87–91, sickle cell disease 218 clinical features 63–4 92–8, 99–100, 175–6, 179, 180, side effects, antihypertensive definition 63 207 agents 5–11 epidemiology 63–4, 68, 69, 100, hypertension 3–11, 95–8 Sila, Cathy 174–81 103–4, 169 meningitis 128–9 sinus infections, CVT risk immediate management mortality rates 8, 9, 37, 42–3, 45, factors 100–3 steps 65–6 47, 50, 51, 55, 57–8, 73, 89–90, Sjogren syndrome 130 initial diagnostic work-up 65 92–8, 207 skin breakdown problems, mortality rates 69, 103 NIHSS 8, 46, 47, 48–9, 195 ASCIs 35–6 organ systems 69 post-operative strokes 174–81 sleep interventions, delirium prehospital treatments 64–5 treatments 6–11, 40–4, 45–54, 171–2 prognosis 69 55–62, 73–83, 92–8, 99–107, small-volume ventilation 18–19 RSE 66–9, 195 208–13 smallpox 132 tips & tricks 64, 66, 68–9, 165 subarachnoid hemorrhages Smith, Wade 207–13 treatment endpoints 68–9 (SAHs) 9–10, 37–44, 48–9, Society of Thoracic Surgeons 174 treatments 64–9, 195 55, 73–83, 89–91, 100, 128–9, socioeconomic risk factors, stent placements of stenosed 163–5, 195–6, 208, 212, TBIs 21 arteries 49 214–24 sodium stents 23–4, 28–9, 49, 59, 84–91 see also aneurysmal...; delayed nitroprusside 6, 7, 49 sternomental distance, airway cerebral ischemia; strokes; ODS 201–3 management 16 traumatic... soft palate, airway management steroids anemia 81 16–20 ASCIs 34–5, 36 assessments 37–40, 41, 43–4, Souter, Michael J. 12–20 critical illness neuromyopathy 73–6, 100, 208, 212, 214–23 South Africa, TBIs 21 182–7 cardiopulmonary complica- South Korea 8 CVT 105 tions 80–1 soy product allergies 6 delirium 163–4 caution 43, 77, 83 Spain, TBIs 21 encephalitis 139 clinical gradings 37–9, 42–3, SPECT 75–6 extubation considerations 20 74–5, 90 242 . Index subarachnoid hemorrhages (SAHs) substantial nigra 137, 157–61 temporal lobes, encephalitis (Continued ) succinyl choline 14–15, 34 134–6 complications’ management sufentanil 25 testosterone 186–7 39–44, 73–83, 128–9, 163–5 sulcal effacement 125, 129 tetracyclines 120 concomitant injuries 37–8 sundowning, delirium 163, 172 tetraplegia 10 CSF 38–9, 43, 80 Sung, Gene 45–54 thalamus 55–62, 100–1, 137, definition 37–8, 48–9 superior sagittal sinus (SSS) 100–7 157–61, 162–3, 202 delays in securing an support procedures, airway theopylline 65 aneurysm 41–2 management 14–15, 25–6, thermoregulation see temperature epidemiology 37–8, 42–3, 55, 33–5 controls... 73–5, 80–2, 89–90 supraglottal airways, airway thiamine 65–9 Fisher grades 37–9, 74–5 management 15 thiamine deficiency headaches 37–9, 41–2, 100 surgical management, SE 163–4 Hunt–Hess grades 37–8, 42–3, treatments 67 thiopental 14, 53 74–5, 90 swallow reflexes 12–13, 35–6, 52, thrombocytopenia 46, 61, 68, hydrocephalus complications 58–9 85, 138 39, 42–3, 76–7, 80 Swan Ganz intravascular thromboembolic complications, hyponatremia 82 monitoring 34–5, 43, 79 post-ICH secondary hypothermia uses 195 SWI (susceptibility-weighted damage 96–8 hypovolemia 77–83 imaging) 101 thrombolysis 87–91, 97–8, 104–6, locational factors 38–9 sympathomimetics, seizure 180, 207–13 management 39–44, 73–83, toxins 65 thrombolytics 6, 8, 41, 47–54, 89–90, 214–23 syncope 64 57–62, 95–8, 180, Modified Fisher scale 74 Syndrome of Inappropriate Secre- 207–13 mortality rates 37, 42–3, 73, tion of AntiDiuretic Hormone thrombotic thrombocytopenic 89–90 (SIADH) 82, 202 purpura 85 neurocardiogenic shock systemic vacular resistance thyroid 17–20, 163–4 (Takotsabu cardiomyopathy) (SVR) 78 thyromental distance (TMD), 39, 43–4, 77 systolic blood pressure (SBP) airway management 16 neuroimaging 37–40, 41–2, 3–11, 25–31, 40–1, 49–54, ticks 137–8 74–6, 208 57–62, 96–8 tinzaparin 58 post-procedural management of see also blood pressure; tirilizad 35 aSAHs 73–83, 214, 215–23 hypertension tissue plasminogen activator rebleeding complications (tPA) 46–54, 57–62, 95, 97–8, 39–44, 73–4, 76–7, 83 T-type calcium channels 5–6 104–5, 195, 212–13 risk factors 9, 37–8, 80 table positions, tips & tricks 90 TMD see thyromental distance science revisited 43–4, 73–4, tachycardia 10, 14, 30, 144, 147, TNF-alpha 124, 156 79–80 189–96 TO-ACT trial 104–5 seizures 39, 42, 76–7, 83 tachypnea 144 tobacco uses, SAH risk factors 9, symptoms and signs 37–9, 41, tacralimus 199, 200 37 43–4, 74 Taiwan, TBIs 21 Todd’s paralysis 63 tips & tricks 38, 39, 40, 41, 42, 44, Taqi, Muhammad A. 37–44 tongue, airway management 13, 74, 77, 78, 80, 81 TBIs see traumatic brain injuries 14–20 transfusions 81, 85 TCD (transcranial Doppler) 48–9, tonic–clonic seizures 63–4 treatments 40–4, 73–83, 89–90, 75, 77–8, 178 see also epilepsy 195, 212, 214–23 TDF (thermal flowmetry) 220–1 TOR (time-of-flight) 209–10 vascular imaging 39 team approaches, TBIs 25 Torbey, Michel T. 37–44 WFNS grades 74 TED stockings 27 torculae 102 subcortical white matter 55–62, teeth, airway management toscanavirus 129 135, 139, 160, 200, 202, 215–23 12–13 tPA see tissue plasminogen activator subdural or epidural empyema temperature controls in the NCCU trachea, airway management 119, 129 see also hypothermia 14–20, 25, 26–7, 34–6, 53, subdural hematomas 48–9, 100–1, ischemic strokes 50–1, 53, 81–2, 112–14, 148–50 163–4, 176–7, 208 93–4, 188–96 tracheobronchitis 112 Index . 243 tracheostomies mortality rates 21–2, 28, 216 strokes 45–54, 55, 207 ASCIs 35–6 neuromuscular blocking TBIs 21–31 ICHs 62 agents 30–1 uvula, airway management 16–20 traffic injuries nutritional requirements 26–7 ASCIs 32 physiological targets around vaccines TBIs 21 resuscitation 25–6 encephalitis 132 tramodol 62 risk factors 21 viral meningitis 129–30 tranexemic acid 40–1 SAHs 37–9 vagus nerves 10, 67 transaminases 159 secondary injury processes vallecula, airway management transcranial magnetic stimulation, 21–31, 214–24 16–20 SE treatments 67 steroids 31 valproate 61, 65–9 transcutaneous pacing 10 team approaches 25 valproic acid 61, 67–9 transfusions tips & tricks 26, 27, 28 vancomycin 113–14, 116–17, 119, aSAHs 81, 85 treatments 22–31, 194–5, 127–8 red blood cells 216 214–23 VAP see ventilator-associated transient apnea 13–14 tricyclics, seizure toxins 65 pneumonia transient ischemic attacks trimethroprim/sulfamethoxazole varicella zoster 130, 133 (TIAs) 48–54, 63–4, 87–9 115, 139 vascular imaging 39, 48–54, transluminal balloon angioplasty triple-H therapy see hemodynamic 207–13 79, 86–7 augmentation see also neuroimaging... transplants troponin 46 vascular malformations, ICHs 56 hepatic encephalopathy 160–1 tryptophan 162–3 vasculitis 124, 128–9, 163–4 PRES 197–201 tuberculous meningitis 124–5, vasodilation 4–11, 23–31, 34–6, transtentorial herniation, 130 49–54, 74, 79–83, 87, 91, 193, concepts 23–4, 28–9, 59, tubing, airway management 220 92–8, 103–4 13–19, 35–6, 50 ASCIs 34–6 traumatic brain injuries tyrosine kinase 148–50 hypertension 4–11, 23–31, (TBIs) 12–20, 21–31, 37–9, 49–54 114, 118–20, 163–4, 190–1, 194, UK, TBIs 21 TBIs 23–31 214–24 ULBT see upper lipe vasogenic edema 197–203 see also acute spinal cord injuries bite test see also posterior reversible airway difficulties 12–20, 25–31 ulcers 27, 58, 150 encephalopathy barbiturates 29–30 uncal herniation, concepts 23–5, vasopressin 25–6, 78–9, 156–7 caution 26, 29 28–9, 59 vasopressors 5, 25–31, 34–6, 44, classifications 22 United States, hypertension 3 53, 68–9, 77–80, 147–8, 219 CMD 221–3 upper lipe bite test (ULBT), airway see also endothelin; hypertension; concepts 21–31, 37–9, 114, management 16 norepinephrine; 118–20, 194, 214–23 uremia 163–4, 167 phenylephrine CPP 23, 24–6, 28, 29, 214 urinary catheters 35–6, 50 vasospasm management 9–10, depressive craniectomy 29, 31 urinary tract infections 111, 37–8, 41, 48–54, 73–83, 90–1, epidemiology 21–31, 37–8, 216 114–15 215–23 evidence-based guidelines concepts 111, 114–15 see also delayed cerebral ischemia management strategies 22, diagnosis 114–15 vecuronium 14, 189 29–31 epidemiology 111, 114 ventilator-associated pneumonia family members 26 prevention strategies 115 (VAP) 112–14 GCS 22, 28 risk factors 114 ventricular fibrillation 51, general ICU care 26–7 treatments 115 189–90 head positions 25, 26, 29 urokinase 97 ventricular fluid catheters 28–9 hyperosmolar therapy 30–1 urosepsis 114–15 ventriculitis 118–20 hyperventilation considera- US ventriculostomy, brain tissue tions 25, 30–1, 222 ASCIs 32 oxygen monitoring 214–23 hypothermia uses 29–30, 194 cardiac surgery 174–81 verapamil 67 initial management 24–5 encephalitis 134–40 vertical tissue shifts, concepts intracranial hypertension 21–31 meningitis 127–9 92–8 244 . Index viral meningitis 123, 124–5, vitamin B12 163–4 white blood cells 69, 127, 130, 129–31 vitamin K 58 133–4, 138 see also meningitis volume-pressure response (VPR), white matter 55–62, assessments 124 concepts 23–4 135, 139, 160, 200, 202, caution 131 vomitus, airway management 209–13, clinical features 123, 124, 130 15 215–23 123, 124, 129–30 Wingspan stents 87 differential diagnosis 124–5, warfarin 56, 57–8, 96–8 Wintermark, Max 207–13 129, 130 Waterhouse-Friderichsen World Federation of Neurological epidemiology 129 syndrome 125, 128 Surgeons (WFNS) 74 management 130–1 West Haven criteria, hepatic pathophysiology 129–30 encephalopathy 157–8 xanthochromia 39 prognosis 130–1 West Nile virus (WNV) 129, 133, Xenon CT 212, 222 seasonal variations 129 134, 136–7 treatments 130–1 Western Equine encephalitis Yellow fever 132 vaccines 129–30 (WEE) 133, 137 visual changes 10 WFNS see World Federation of zinc supplements 160 vitamin B complex 163–4 Neurological Surgeons ziprasidone 171