Treatment of Acute Ischemic Stroke

Transcription

1 NEUROLOGY BOARD REVIEW MANUAL PUBLISHING STAFF PRESIDENT, GROUP PUBLISHER Bruce M. White EDITORIAL DIRECTOR Debra Dreger SENIOR EDITOR Miranda J. Hughes, PhD ASSISTANT EDITOR Rita E. Gould EDITORIAL ASSISTANT Kara V. Warner EXECUTIVE VICE PRESIDENT Barbara T. White, MBA EXECUTIVE DIRECTOR OF OPERATIONS Jean M. Gaul PRODUCTION DIRECTOR Suzanne S. Banish PRODUCTION ASSOCIATES Tish Berchtold Klus Mary Beth Cunney PRODUCTION ASSISTANT Stacey Caiazzo ADVERTISING/PROJECT MANAGER Patricia Payne Castle MARKETING MANAGER Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Psychiatry and Neurology. Endorsed by the Association for Hospital Medical Education The Association for Hospital Medical Education endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in medical education as they affect residency programs and clinical hospital practice. Treatment of Acute Ischemic Stroke Series Editor and Contributor: Steven K. Feske, MD Assistant Professor of Neurology Harvard Medical School Director, Stroke Division Department of Neurology Brigham and Women s Hospital Boston, MA Table of Contents Introduction Nonspecific Therapies Acute Antithrombotic Therapy Acute Thrombolytic Therapy Treatment of Severe Brain Edema Experimental Therapies Case Patients Summary Points References Cover Illustration by Craig Zuckerman Copyright 2002, Turner White Communications, Inc., 125 Strafford Avenue, Suite 220, Wayne, PA , All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications, Inc. The editors are solely responsible for selecting content. Although the editors take great care to ensure accuracy, Turner White Communications, Inc. or GlaxoSmithKline, will not be liable for any errors of omission or inaccuracies in this publication. Opinions expressed are those of the authors and do not necessarily reflect those of Turner White Communications, Inc. or GlaxoSmithKline. Neurology Volume 7, Part 2 1

2 NEUROLOGY BOARD REVIEW MANUAL Treatment of Acute Ischemic Stroke Steven K. Feske, MD I. INTRODUCTION Therapy for acute ischemic stroke has advanced rapidly in the last decade. Before the mid-1990s, acute therapy in clinical practice still revolved around the optimal application of antithrombotic therapies and the provision of supportive care for stroke complications. Carefully designed studies to investigate the use of thrombolytic therapies were carried out in the late 1980s and early 1990s. These studies led to the publication in December 1995 of the first successful trial of a thrombolytic agent (ie, recombinant tissue plasminogen activator [rt-pa]) for acute ischemic stroke. 1 The success of this work has been transferred to clinical practice. Much work has been done to refine the indications and use of this therapy. Another line of investigation has sought to apply various neuroprotective agents to the treatment of acute stroke; however, this work has not yet produced a clearly effective therapy. This article will review the current status of therapy for acute ischemic stroke emphasizing the application of intravenous and intra-arterial thrombolytic therapy. Two case patients are presented to highlight essential features of therapy for acute ischemic stroke. The diagnosis of acute ischemic stroke was discussed in the first article of this volume, Diagnosis of Ischemic Stroke (Hospital Physician Neurology Board Review Manual, Volume 7, Part 1). II. NONSPECIFIC THERAPIES Patients with acute ischemic stroke should receive nasal oxygen as well as treatment for fever, hyperglycemia, dehydration, and active cardiovascular problems, such as congestive heart failure and cardiac arrhythmia. Although such therapies have not been shown to be effective, these therapies are generally safe; their application is based on an understanding of physiologic principles, extrapolation from animal studies, and data from patients with various disorders. Management of blood pressure in the acute situation is more complex and is discussed in the next section. BLOOD PRESSURE MANAGEMENT There are 2 competing goals for the management of blood pressure in patients with acute ischemic stroke. Concern for focal cerebral perfusion suggests maintaining elevated blood pressures; however, concerns for hemorrhagic conversion, edema, and medical complications suggest lowering excessively elevated pressures. Brain tissue perfusion depends on cerebral blood flow (CBF), which varies according to the following relationship: CBF = (CPP)/(CVR), where CPP = cerebral perfusion pressure, and CVR = cerebrovascular resistance. CPP = (MAP) (CVP), where MAP = mean arterial pressure, and CVP = central venous pressure. In the setting of focal cerebrovascular stenosis or occlusion, vascular resistance is greatly increased at the site of the vascular lesion causing a critical drop in focal CBF. Under these conditions, regional autoregulation is lost and regional perfusion is dependent on arterial blood pressure. 2 Also, many patients with acute stroke have underlying hypertension causing a shift in the autoregulation curve such that loss of autoregulation and passive blood pressure dependence begin at a higher mean pressure. 3 This loss of perfusion can be offset in part by increasing the MAP and thus the CPP. Therefore, in the setting of acute cerebral ischemia, it is desirable to maintain a high MAP to enhance direct and collateral perfusion of the area at risk. 4 The American Heart Association has published guidelines for management of blood pressure in acute stroke. 5,6 Recommendations for a threshold above which to treat elevated blood pressure are based on physiologic understanding, but they have not been validated in controlled studies. The main principle is to avoid overtreatment of high blood pressure in order to allow maximal perfusion past a fixed stenosis or via collateral vessels around such a focal stenosis or occlusion. Situations in which blood pressure should be decreased include certain medical conditions (eg, aortic dissection, acute myocardial infarction [MI]) and evidence of a hypertensive urgency (eg, encephalopathy, papilledema, heart failure, renal failure). When none of these 2 Hospital Physician Board Review Manual

3 conditions is present, then it is probably desirable to treat (1) diastolic blood pressures above 140 mm Hg with intravenous sodium nitroprusside, and (2) systolic blood pressures above 220 mm Hg or diastolic blood pressures above 120 mm Hg with gently titrated medication, such as labetalol or esmolol. 5 When β-blockers are contraindicated, intravenous enalaprilat is a useful alternative agent. Without another clear indication for treatment, blood pressures below 220/120 mm Hg should probably not be treated acutely. In most patients, such elevated pressures will decrease within hours of the stroke onset. 7 A special situation arises with the use of intravenous t-pa. Pilot studies of t-pa for stroke as well as t-pa studies of patients with acute MI have suggested that excessive blood pressure elevation increases the risk of a complicating intracranial hemorrhage. 8 In the National Institutes of Neurological Disorders and Stroke (NINDS) study of intravenous t-pa for stroke, patients blood pressures were managed based on a protocol shown in Table 1. Although this represents a compromise solution, trading off possibly desirable higher blood pressures for a presumed lower risk of hemorrhage, the unique success of this trial suggests that these guidelines should be followed when intravenous t-pa is given. These guidelines will need validation in future controlled trials of thrombolytic therapy for stroke. Low blood pressures caused by dehydration, cardiac arrhythmia, or heart failure should be corrected by treatment of the underlying problem. Because some patients may respond to elevation of the blood pressure during the acute phase of a stroke, it is reasonable to induce hypertension pharmacologically in some patients with acute stroke. So far, data that support this practice are limited; however, efforts to acquire wellcontrolled data for validation are underway. 9 Table 1. Protocol for Treatment of Blood Pressure Elevation in Patients with Stroke after Intravenous Tissue Plasminogen Activator Monitor arterial BP during the first 24 hr after starting treatment with t-pa every 15 min for 2 hr after starting infusion, then Every 30 min for 6 hr Every 60 min for 24 hr If systolic BP is mm Hg or diastolic BP is mm Hg for 2 readings 5 to 10 min apart: Give labetalol 10 mg IV over 1 2 min. Repeat or double the dose every min up to a total dose of 150 mg Monitor BP every 15 min during labetalol treatment and observe for development of hypotension If systolic BP is > 230 mm Hg or diastolic BP is mm Hg for 2 readings 5 10 min apart: Give labetalol 10 mg IV over 1 2 min. Repeat or double the dose every min up to a total dose of 150 mg Monitor BP every 15 min during labetalol treatment and observe for development of hypotension If response is not satisfactory, infuse nitroprusside ( µg/kg per min) If diastolic BP > 140 mm Hg for 2 readings 5 10 min apart: Infuse nitroprusside ( µg/kg per min) Monitor BP every 15 min during infusion of nitroprusside and observe for development of hypotension BP = blood pressure; IV = intravenous; t-pa = tissue plasminogen activator. Adapted with permission from Adams HP Jr, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1996;27: FLUID AND GLUCOSE MANAGEMENT Choice of intravenous fluid therapy should take into account the need for adequate blood pressure, the possible detrimental effect of high glucose concentrations, the potential for severe cytotoxic edema in the case of large infarcts, and any complicating medical conditions. In general, patients should be maintained euvolemic with isotonic solutions to avoid excess available free water that will exacerbate cytotoxic edema. For acute therapy, normal saline without glucose is a good choice to avoid iatrogenic hyperglycemia. Serum glucose levels should be controlled with insulin. The optimal degree of glucose control is not clear; however, recent data demonstrate that patients in surgical intensive care benefit from normalization of their serum glucose with intensive insulin therapy. 10 TEMPERATURE REGULATION Elevated temperature increases infarct size in animals and patients studied after acute ischemic stroke. 11,12 When fever occurs, the cause should be sought and quickly treated. Aspiration pneumonia is the most common cause of early fever in patients with acute stroke. Elevated temperatures should be treated with acetaminophen. If temperatures increase despite this therapy, then a cooling blanket should be used, which is set to Neurology Volume 7, Part 2 3

4 Table 2. Possible Indications for Early Anticoagulation Cardioembolism Atrial fibrillation Dilated cardiomyopathy Intracardiac thrombus Acute MI with mural thrombus Atrial thrombus Prosthetic heart value Marantic endocarditis (NBTE) Paradoxical embolism PFO, ASD, pulmonary AV fistula Carotid artery stenosis Intracranial stenosis Arterial dissection Hypercoagulable states (eg, antiphospholipid antibody syndrome) ASD = atrial septal defect; AV = arteriovenous; MI = myocardial infarction; NBTE = nonbacterial thrombotic endocarditis; PFO = patent foramen ovale. avoid shivering. Animal studies have demonstrated a neuroprotective effect of mild induced hypothermia. 13,14 A trial is underway to investigate the possible benefit of therapeutically induced mild hypothermia. 15 PROPHYLAXIS FOR DEEP VEIN THROMBOSIS Deep vein thrombosis is a major complicating condition in patients after acute stroke. 16,17 Heparin and low-molecular-weight (LMW) heparins can lower this risk and are safe to use in this setting Therefore, all patients who are confined to bed because of stroke and for whom there are no contraindications should receive heparin or LMW heparin at prophylactic doses. Patients who cannot tolerate this therapy should be treated with pneumatic compression boots. 21 Therapy should continue until patients are mobilized. III. ACUTE ANTITHROMBOTIC THERAPY ACUTE USE OF HEPARIN, HEPARINOIDS, AND LOW-MOLECULAR-WEIGHT HEPARINS A decision about whether to use anticoagulant agents early in the course of a patient with acute stroke should be made based on the available clinical data. Possible benefits of early use are a reduction in the size of the presenting stroke and prevention of early reinfarction. Acute anticoagulation has been advocated for many types of acute ischemic stroke (Table 2). Although evidence supports the use of anticoagulants for many of the conditions listed in Table 2, none has been fully supported by adequate controlled studies that address the acute situation. In contrast, long-term use of antithrombotic therapy for stroke prevention has been more carefully studied for many situations. The traditional recommendation of early use of anticoagulants in patients with cardioembolic stroke finds its best validation in several studies in the 1980s. These studies suggested a relatively high rate (2% 22% within 2 weeks) of early reinfarction in patients with cardioembolic infarction as well as a reduction in this rate in patients treated with heparin Observation of individual cases suggested an increased risk of secondary intraparenchymal hemorrhage in patients with large infarcts (eg, full middle cerebral artery [MCA] territory), with infarcts involving basal ganglia, with excessive prolongation of the activated partial thromboplastin time (aptt) and international normalized ratio (INR), and in those who receive bolus doses of heparin. 23,24 These data have supported the common practice of beginning anticoagulation early in patients with presumed embolic strokes of a small-to-moderate size; however, recent data raise questions about the validity of this practice. Six large randomized studies address the question of early use of anticoagulants for acute ischemic stroke. 18,25 29 A meta-analysis of 10 trials (3 of these studies and 7 smaller studies) has also been published. 30 These studies have shown no reproducible benefit of acute anticoagulation in large unselected populations of patients with acute ischemic stroke. The Fraxiparine in Ischaemic Stroke Study (FISS) did suggest that early use of LMW heparin was beneficial. 25 In this study, patients received either the LMW heparin nadroparin subcutaneously or placebo at the onset of acute stroke. At 6 months, patients who received treatment had significantly better outcomes when compared with control; only a trend of benefit was seen at 3 months. This finding is poorly understood. This study was small, and the benefit was not supported by the subsequent FISS bis study. 26 The TOAST (Trial of ORG in Acute Stroke Treatment) trial investigated the use of the heparinoid agent danaparoid for acute ischemic stroke. 29 This study found no overall benefit of early anticoagulation and an increased hazard; however, patients classified as having strokes caused by large vessel disease appeared to benefit. The IST (International Stroke Trial) enrolled almost 20,000 patients. 18 Patients were treated with high-dose 4 Hospital Physician Board Review Manual

5 heparin (12,500 IU twice daily [bid] subcutaneously), low-dose heparin (5000 IU bid subcutaneously), or placebo. (All 3 groups were subdivided into aspirin or no aspirin subgroups.) Heparin slightly reduced the risk of recurrent ischemic strokes at 14 days; however, this risk reduction was offset by a comparable increase in the risk of hemorrhagic stroke. Those with atrial fibrillation appeared to benefit more than the population as a whole (rates of events with [2.8%] and without [4.9%] heparin), although this effect was also largely offset by an increased risk of symptomatic hemorrhage. Treated patients had fewer episodes of pulmonary embolism. The TAIST (Tinzaparin in Acute Ischaemic Stroke) study randomly assigned patients either to high-dose or mediumdose LMW heparin or to aspirin with no control group. 27 Neither dose of LMW heparin conferred benefit over aspirin. Patients treated with the higher dose had an increased risk of intracranial hemorrhage. No study has demonstrated either a clear net benefit or detriment from acute anticoagulation. The FISS study suggests a possible benefit realized in the period of rehabilitation; the TOAST study suggests a benefit in the subgroup of patients with stroke caused by large vessel disease; and the IST suggests a possible benefit of therapy in those with atrial fibrillation. However, a study designed to investigate the benefit in this subgroup randomly assigned patients with atrial fibrillation to receive either LMW heparin or aspirin and found no benefit of anticoagulation. 28 Other subgroups have not been well studied in isolation; however, anecdotal evidence suggests that those with large artery dissection, intracranial stenosis, intracardiac thrombus, severe dilated cardiomyopathy, and certain hypercoagulable states may benefit from anticoagulation. Table 2 lists situations for which anticoagulants may reasonably be given early after acute stroke. The major justifications for early use of anticoagulants are (1) early secondary prevention, and (2) the maintenance of vessel patency after intra-arterial thrombolysis or mechanical recanalization in view of the lack of evidence in favor of benefit for the stroke at hand as previously summarized. In settings where there is an argument for early use, the risk of hemorrhage must be balanced against the potential benefit. Because the degree of benefit and the urgency of therapy have not been worked out clearly for any of these clinical situations, clinicians must continue to make unsupported judgments to determine individual therapeutic decisions. USE OF ANTIPLATELET AGENTS No study has addressed the benefit of true acute therapy with antiplatelet agents. However, IST and CAST (Chinese Acute Stroke Trial) address the issue for use within 2 weeks. 18,31 These studies argue for a slight benefit of aspirin when given early at the cost of a slight increased risk of extracranial hemorrhage. CAST and IST show that acute aspirin therapy yields about 9 fewer deaths or non-fatal strokes per 1000 in the first few weeks (and months) of follow-up. Therefore, unless specific contraindications prevail, all patients who will not receive acute thrombolytic therapy should start receiving aspirin or another antiplatelet agent as soon as possible. IV. ACUTE THROMBOLYTIC THERAPY INTRAVENOUS THROMBOLYSIS Many studies from the 1970s and 1980s looked at the potential benefit of thrombolytic agents in patients with acute ischemic stroke. This therapy was suggested initially because most vascular occlusions causing stroke are known to be thrombotic or thromboembolic and was suggested later because of the successful application of this therapy to patients with acute MI. These early studies had many methodological problems. Various agents were used at untested doses, small numbers of patients were studied without adequate control populations, and very long therapeutic windows were allowed. Although these studies failed to answer the question about the potential usefulness of thrombolytic agents, they did suggest that the agents could promote thrombolysis/revascularization and that they were associated with a significant hazard of serious intracranial hemorrhage. Three more rigorously designed studies of thrombolysis with streptokinase for acute ischemic stroke were done in the late 1980s and early 1990s Although a slight beneficial effect was suggested, these studies clearly demonstrated an increased risk of intracranial bleeding. In fact, all of these studies were terminated before full enrollment because of an increased incidence of intracranial hemorrhage and death from intracranial hemorrhage in the treatment populations. In December 1995, the first positive study of a thrombolytic agent for acute ischemic stroke was published. 1 The NINDS study of intravenous t-pa demonstrated a benefit of approximately 11% to 13% absolute risk reduction or 33% to 55% relative risk reduction upon follow up 90 days after the stroke over its various scales of assessment (Figure 1). Although the risk of symptomatic intracranial hemorrhage was significantly increased in the t-pa group, mortality did not differ Neurology Volume 7, Part 2 5

6 Placebo Modified Rankin Scale Death Table 3. NINDS Study of Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke: Intracranial Hemorrhage* t-pa Patients, % Figure 1. Outcome at 3 months after recombinant tissue plasminogen activator (rt-pa) treatment for acute ischemic stroke (the NINDS study). The modified Rankin scale is a simplified overall assessment of function based on a scale of 0 to 5 (where 0 = absence of symptoms and 5 = severe disability). A score of 1 or less was considered to indicate a favorable outcome. Values do not total 100% because of rounding. NINDS = National Institutes of Neurological Disorders and Stroke. (Data from Tissue plasminogen activator for acute ischemic stroke. The National Institutes of Neurological Disorders and Stroke rt-pa Stroke Study Group. N Engl J Med 1995;333:1585.) between the treatment and placebo groups (Table 3). ECASS I and II (European Cooperative Acute Stroke Study) have shown some evidence of benefit of intravenous t-pa given within 6 hours, but both failed to show more than a statistical trend in favor of therapy for the prespecified endpoints. 35,36 In both of these studies, the rates of hemorrhage and death from hemorrhage were similar to those in the NINDS study. The initial response to the NINDS study was mixed. There has been controversy about the wisdom of immediately applying the NINDS findings to clinical practice based on both safety considerations and the implications of the adoption of t-pa use as the standard of care for future clinical research However, many centers did begin to use t-pa because of the NINDS study and the subsequent FDA (US Food and Drug Administration) approval of t-pa for acute ischemic stroke. Although many centers have reported favorable local experiences with t-pa, some centers have not In 1999, the STARS (Standard Treatment with Alteplase to Reverse Stroke) study demonstrated outcomes and safety similar to the NINDS study in 57 academic and community hospitals. 47 The major factor limiting the broad applications of intravenous thrombolysis has been the very narrow therapeutic time window defined by the NINDS trial. Although the ECASS studies used a more liberal 0 6 hour window, neither showed a clear benefit. The ATLANTIS (Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke) part B trial addressed the use of intravenous t-pa in the 3 5 hour window. 48 (The ATLANTIS trial began before the NINDS trial was completed and originally enrolled Type of ICH rt-pa, n (%) Placebo, n (%) Symptomatic 20 (6) 2 (0.6) Fatal 09 1 Nonfatal 11 1 Asymptomatic 14 (4) 9 (3) ICH = intracranial hemorrhage; NINDS = National Institute of Neurological Disorders and Stroke; rt-pa = recombinant tissue plasminogen activator. *Data are compiled from parts 1 and 2 of the original table. Each group contained 312 patients. Data from Tissue plasminogen activator for acute ischemic stroke. The National Institutes of Neurological Disorders and Stroke rt-pa Stroke Study Group. N Engl J Med 1995;333:1586. patients in the 0 6 hour window. This interval was later changed to a 0 5 hour window based on safety concerns and ultimately to a 3 5 hour window after publication of the positive NINDS results within 3 hours.) The ATLANTIS trial did not show a benefit of therapy within the 3 5 hour window based on its primary outcome measures. This lack of efficacy appeared to be true within both the 3 4 and the 4 5 hour intervals. On a secondary measure of major neurologic recovery, treated patients were more likely to have a dramatic early recovery (11-point improvement or complete recovery on National Institutes of Health Stroke Scale [NIHSS] score at 30 days), but this did not translate into a higher rate of excellent recovery overall between the treated and untreated groups. Risk of symptomatic intracranial hemorrhage was increased by therapy (7.0% for t-pa versus 1.1% for placebo). Although this difference is comparable to that seen in the NINDS trial, the lack of compensating benefit argues that routine intravenous therapy should be limited to the less than 3 hour time window. Ongoing research is looking at the potential of magnetic resonance imaging (MRI) with diffusion and perfusion scanning to define a subset of at-risk patients with hypoperfused but uninfarcted brain who might benefit from therapy even though they fall outside of the therapeutic window as defined by the NINDS study. 49 Guidelines for t-pa Use The parameters for current standard use of t-pa for acute stroke have been established by the NINDS study 6 Hospital Physician Board Review Manual

7 Table 4. AHA Criteria for Using Intravenous Tissue Plasminogen Activator Therapy for Acute Stroke Inclusion criteria 1. Acute ischemic stroke with onset, clearly defined, less than 3 hours before t-pa will be given 2. Significant neurologic deficit expected to result in major long-term disability 3. Non-contrast CT scan showing no hemorrhage or well-established acute infarct 4. Patient does not have any exclusion criteria Exclusion criteria 1. Current use of oral anticoagulants or PT > 15 (INR > 1.7) 2. Use of heparin within 48 hours with prolonged PTT 3. Platelet count < 100,000/mm 3 4. Other stroke or significant head injury in the previous 3 months 5. Major surgery within the preceding 14 days 6. Pretreatment systolic BP > 185 mm Hg or diastolic BP > 110 mm Hg, or patient requires aggressive treatment to reduce BP to within these limits 7. Rapidly improving neurologic signs 8. Isolated, mild neurologic deficits 9. Prior intracranial hemorrhage 10. Blood glucose < 50 mg/dl or > 400 mg/dl* 11. Seizure at stroke onset* 12. Gastrointestinal, urinary, or pulmonary hemorrhage within the preceding 21 days 13. Recent myocardial infarction 14. Clinical presentation suggestive of subarachnoid hemorrhage, even with normal CT 15. Recent lumbar puncture AHA = American Heart Association; BP = blood pressure; CT = computed tomography; INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; t-pa = tissue plasminogen activator. *When a clear diagnosis of acute stroke can be established quickly (eg, by demonstration of a vascular occlusion on CT angiography), one might choose to treat patients despite glucose values outside these thresholds or seizure at onset. Adapted with permission from Adams HP, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1996;27: group. 6,50 Inclusion and exclusion criteria are shown in Table 4. When a clear diagnosis of acute stroke can be established quickly (eg, by demonstration of a vascular occlusion on computed tomography [CT] angiography), one might choose to treat patients despite seizure at onset or glucose values outside these thresholds. Eligible patients received a weight-adjusted dose of t-pa (0.9 mg/kg to a maximum of 90 mg) with 10% of the dose given as a bolus over several minutes and the remainder given over 1 hour. The maximum time from clearly identified stroke onset and initiation of treatment must be 3 hours. The reported outcomes at 24 hours suggested that earlier therapy within 1.5 hours might yield better outcomes; in practice, therapy should begin as early as possible. Although very severe deficits (NIHSS score > 20) predicted poorer outcomes and greater risk of hemorrhage, they also predicted poorer outcomes in the placebo group; therefore, severe deficits are not clearly a contraindication to therapy. 51 Many authors have reported successful treatment of patients with severe deficits. Blood pressure was carefully managed in the NINDS study according to the protocol in Table 1, and this should be incorporated into protocols for treatment. The NINDS study was designed to require only plain Neurology Volume 7, Part 2 7

8 Table 5. Outcomes from the PROACT II Study* Outcome r-prouk, Control, P Value Number Needed to Treat Measure % % to Assess Benefit or Harm MRS 2 at 90 days ICH with neurological deterioration at 10 days Recanalization at 2 hours < ICH = intracranial hemorrhage; MRS 2 = modified Rankin score indicating patients with slight or no neurological disability; PROACT = Prolyse in Acute Cerebral Thromboembolism; r-prouk = recombinant pro-urokinase. *Note that patients received either pro-urokinase and heparin (n = 121) or heparin alone (n = 59). Data from Furlan AJ, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized controlled trial. JAMA 1999;282: head CT before treatment. This choice was intended to rule out intracranial hemorrhage and to screen for other diagnoses without interposing tests that might be unavailable in some centers or that might increase the time delay to therapy. In the NINDS study, patients with early hypodensities and mass effect were more likely than the population as a whole to have intracranial hemorrhage; however, this patient population was small. Limited data suggest that, although these CT findings (ie, early hypodensities and mass effect) predict a poorer outcome, patients may benefit on average from therapy. 52 This finding is comparable to the situation for those with large deficits. Subsequent reports have also suggested the hyperdense MCA sign, which is evidence of a thrombus lodged in the MCA stem, is a poor prognostic factor. 53 As mentioned, ongoing research is seeking to define subgroups of patients who might benefit from therapy beyond the 3-hour window defined by the NINDS study. 49 INTRA-ARTERIAL THROMBOLYSIS Preliminary studies done with angiography to establish the success of recanalization have demonstrated that smaller and more distal vessels are more readily recanalized by thrombolytics than are larger and more proximal vessels. Poorer outcomes after thrombolysis in patients with proximal lesions have also been supported by CT, CT angiography, and MR studies since the publication of the NINDS trial. 44,52,54 Hence, there is reason to consider the alternative approach of direct intraarterial delivery of thrombolytic agents. The advantage of this approach is that the site of occlusion can be established by angiography, direct access to the clot can be achieved, lower total doses of thrombolytic agents can be used, and mechanical means can be used to promote clot lysis. The major disadvantages are the delay in medication delivery necessitated by the more complex procedure, the risks of angiography, as well as the cost and logistical complexity. The PROACT (Prolyse in Acute Cerebral Thromboembolism) trials used intra-arterial thrombolytics in well-designed randomized studies using a stroke population with MCA occlusions. The PROACT I study randomly assigned patients with angiographically proven proximal MCA occlusion either to intra-arterial delivery of pro-urokinase (with either a high-dose or a lowdose heparin regimen) or to diagnostic angiography. 55 Recanalization rates were better with pro-urokinase therapy. High doses of heparin appeared to increase both the rates of recanalization and hemorrhage. The PROACT II study followed up with a similar treatment regimen (using a low-dose regimen of heparin for safety) and assessed clinical outcome; 56 this study demonstrated a benefit in patients treated within 6 hours (Table 5). The increased risk of hemorrhage was slightly higher than that for intravenous t-pas in the NINDS study of intravenous t-pa, but this risk did not translate into increased mortality or disability. This result may have been accounted for in part by the greater baseline stroke severity in the PROACT patients, all of whom had proximal MCA occlusions. Although this therapy has not been approved by the FDA, many centers now use off-label intra-arterial thrombolytics for selected patients. Table 6 summarizes the major large scale studies of thrombolytics for acute ischemic stroke. A small study looking at the outcome in patients treated with intravenous thrombolytics followed by angiography and intra-arterial therapy in those with persistent occlusions failed to show a benefit of this approach. 57 However, more work needs to be done to explore the possible benefit of combined intravenous and intra-arterial therapy. 8 Hospital Physician Board Review Manual

9 Table 6. Large Scale Studies of Thrombolysis for Acute Ischemic Stroke Study (Reference) Agent Major Findings MAST-E 32 IV SK High risk of ICH MAST-I 33 IV SK High risk of ICH ASK 34 IV SK High risk of ICH ECASS I 35 IV TPA No definite benefit with mixed results; increased risk of ICH ECASS II 36 IV TPA No definite benefit with mixed results; increased risk of ICH NINDS 1 IV TPA Benefit within 3 hr; increased risk of ICH ATLANTIS 48 IV TPA No benefit between 3 5 hr; increased risk of ICH PROACT I 55 IA pro-uk Benefit (recanalization) within 6 hr; significant risk of ICH Both risk and benefit may depend on heparin dose. PROACT II 56 IA pro-uk Benefit (functional) within 6 hr; significant risk of ICH EMS bridging 57 IV/IA TPA No benefit of IV/IA combined therapy over IA alone; significant risk of ICH STARS 47 IV TPA Community and academic hospitals may achieve results similar to NINDS ASK = Australian Streptokinase; ATLANTIS = Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke; ECASS = European Cooperative Acute Stroke Study; EMS = Emergency Management of Stroke; IA = intra-arterial; ICH = intracranial hemorrhage; IV = intravenous; MAST-E = Multicenter Acute Stroke Trial Europe; MAST-I = MAST Italy; NINDS = National Institutes of Neurological Disorders and Stroke trial; PROACT = Prolyse in Acute Cerebral Thromboembolism; pro-uk = pro-urokinase; SK = streptokinase; STARS = Standard Treatment with Alteplase to Reverse Stroke; TPA = tissue plasminogen activator. STROKE TEAMS AND STROKE CENTERS The severe time constraints upon safe and effective application of thrombolytic therapies for stroke have created a need within the medical community to organize themselves in ways that will promote the efficient use of these therapies. This organization will begin with education efforts directed at the community, emergency medical system, and hospital emergency departments as well as hospital staff and physicians. The full application of available therapies will best be accomplished by multidisciplinary acute stroke teams staffing stroke centers designated for their capacity to provide optimal up-todate care. V. TREATMENT OF SEVERE BRAIN EDEMA The cellular injury caused by ischemia leads to cytotoxic edema and, to a lesser extent, breakdown of the blood-brain barrier leads to vasogenic edema after acute stroke. This edema is a reversible pathologic change. Mild edema does not contribute to the ultimate morbidity and mortality of stroke. However, some patients with large infarctions or infarctions in the more confined posterior fossa will have major morbidity and increased risk of mortality because of severe edema. Edema causes mass effect; severe edema can increase intracranial pressure and then compromise cerebral blood flow. Compartmentalized edema, which occurs with focal strokes, can culminate in herniation of brain contents with morbidity due to compression of vital brainstem structures. Also, edema may cause secondary focal infarcts by compression and occlusion of arteries at vulnerable locations. Such arterial occlusions may occur in the anterior cerebral arteries from subfalcine herniation and in the posterior cerebral arteries from compression of these as they cross the tentorium. Severe cerebral edema caused by large middle cerebral infarcts or by posterior fossa infarcts is a major cause of mortality from acute ischemic strokes. MEDICAL THERAPY General medical approaches to control edema include elevation of the head to 30 degrees and midline positioning to avoid high jugular venous pressures. The optimal goals of blood pressure management have not been determined in this setting. However, it is clearly important to avoid low cerebral perfusion pressures; therefore, mean arterial pressure should be adequate to compensate for any intracranial pressure elevations to maintain CPP more than 70 mm Hg. Excessive blood pressure elevations can be expected to promote the vasogenic component of cerebral edema; however, this plays a relatively minor role after acute stroke. Patients should not be given excess free water, which will increase cytotoxic edema. Traditional medical therapy Neurology Volume 7, Part 2 9

10 applied using very small boluses of 23.4% saline to allow time for more definitive therapies. 58 It has also been done with continuous infusions of 2% to 3% saline to achieve moderate hypernatremia and hyperosmolality. 59 This work is based on children with brain trauma, and its validity in patients with ischemic stroke has not been clearly established. A B Figure 2. Computed tomograms (CT) showing a right cranial defect after hemicraniectomy. This 41-year-old right-handed man had a large, right, middle cerebral territory infarct after surgery. The initial CT showed a well-established infarct precluding thrombolytic therapy. He underwent right hemicraniectomy to minimize the effects of brain edema. (A, B) The swollen right hemisphere herniates through the surgical defect allowing minimal shift of midline structures. has been given with osmotic and loop diuretics, such as mannitol and furosemide; these are most effective when the blood-brain barrier is intact. Alternatively, hypertonic saline may be used to create a state of mild hypernatremia and hypertonicity. This has been SURGICAL THERAPY Patients with acute ischemic stroke may require acute surgical therapy when posterior fossa infarction results in mass effect; this is a long-established indication for decompressive suboccipital craniotomy. Patients may develop obstructive hydrocephalus that requires placement of a ventricular drain. Patients who have large middle cerebral infarctions may develop severe cerebral edema in the first week after infarction. Decompressive hemicraniectomy is probably the most effective way to minimize the morbidity and mortality associated with malignant cerebral edema. Patients with full clinical MCA syndromes including early depression of the level of consciousness, headache, and vomiting and with large territory strokes by imaging are at highest risk to develop such malignant cerebral edema. Clinical studies have demonstrated decreased mortality and shorter intensive care unit stays in patients undergoing hemicraniectomy when compared with historic controls (Figure 2). 60 When informing patients proxy decision makers about this procedure, it is important they understand that surgery will increase the chance of survival but that the patient will have severe deficits and disabilities from the stroke. That is, they must understand that decompressive hemicraniectomy will promote survival with severe disability. VI. EXPERIMENTAL THERAPIES The successful application of thrombolytic therapies to patients with acute ischemic stroke has opened up the potential to make a major effect on the outcome of this common and disabling disease. Research now underway will lead to innovations in therapies directed at early revascularization in such patients. Agents that decrease the vulnerability of neurons to ischemia have theoretical appeal, and many of these have shown promise in laboratory models of stroke. Such potential agents include calcium channel blockers, inhibitors of glutamate release, antagonists of glutamate receptors, membrane stabilizers, free radical scavengers, neurotrophic agents, and nitric oxide synthase inhibitors. Induced hypothermia is also a potential method of 10 Hospital Physician Board Review Manual

11 neuroprotection. Currently, none of these therapies has shown adequate promise in clinical trials to warrant their general use. VII. CASE PATIENTS PATIENT 1 Presentation Patient 1 is a 51-year-old man who is brought to the emergency department 1 hour after sudden onset of speech arrest and right-sided weakness. He has a history of atrial fibrillation for which he takes warfarin. His pulse is irregular with a ventricular rate of 60 to 70 bpm. Blood pressure is 195/100 mm Hg. He has global aphasia, right hemianopia to a visual threat, right gaze paresis as well as dense right hemiplegia, and sensory loss. His NIHSS score is 22. Head CT shows subtle loss of gray-white junction in the left basal ganglia capsular region with no hemorrhage. The most appropriate next step(s) in his management include(s) (CHOOSE ALL THAT APPLY): A) Administration of intravenous t-pa at 0.9 mg/kg B) Rapid measurement of INR C) Administration of intravenous heparin D) Discussion of risks and potential benefits of thrombolytic therapy with his wife Discussion The correct answers are B and D. Patient 1 has presented with an acute left MCA territory stroke within the therapeutic time window for administration of intravenous t-pa. However, he has several issues that might contraindicate therapy. First, he takes warfarin. In the NINDS trial, patients with an INR more than 1.7 were excluded for enrollment; therefore, the safety of therapy in such patients has not been established. He should clearly have an INR measurement done as rapidly as possible to help in decision making. His systolic blood pressure is above the threshold for contraindicating therapy in the NINDS study. If his blood pressure can be readily lowered within the time window, then therapy can be considered. The NINDS study did not exclude patients with CT scan changes of early infarction. The European studies have excluded those with changes in two thirds or more of the MCA territory, that is 2 of the 3 areas: anterior cortical, posterior cortical, and deep structures; however, this has not been validated as an exclusion criterion. NIHSS scores more than 20 predicted a higher risk of hemorrhage and a higher risk of poor outcome in the NINDS study. However, in the group with high NIHSS scores, treated patients fared better on average than those who received placebo. Therefore, NIHSS scores more than 20 are not an absolute exclusion criterion, although this issue and risk should be considered carefully before therapy is given. Although intravenous t-pa has been approved by the FDA for acute ischemic stroke and formal informed consent is not required, it is prudent to discuss risks and benefits with available proxies when making decisions. There is no evidence that acute anticoagulation is beneficial for embolic stroke. In view of patient 1 s atrial fibrillation, anticoagulation is indicated as early as safely possible in the setting of this large stroke. In this situation, the patient is on warfarin and the INR is not yet known. In addition, immediate anticoagulation will eliminate the option for intravenous t-pa. Depending on the vascular lesion, some physicians might choose to pursue urgent angiography and intraarterial revascularization for this type of patient. CASE PATIENT 2 Presentation Patient 2 is a 62-year-old woman who presents 1 hour after an episode of left face and arm weakness lasting 30 minutes. On examination, her blood pressure is 150/90 mm Hg. There is a right carotid bruit. There is a mild left central facial paresis and pronator drift of the left upper extremity. The examination is otherwise normal. Head CT is normal. MRI diffusion-weighted imaging shows a small acute infarction in the right frontal cortex. Carotid Doppler ultrasound demonstrates atheromatous plaque in the proximal right internal carotid artery with an estimated 90% stenosis. The most appropriate immediate therapeutic step is (CHOOSE THE SINGLE BEST ANSWER): A) Intravenous t-pa B) Anticoagulation with heparin C) Induced hypertension D) Nimodipine 60 mg orally every 4 hours Discussion The correct answer is B. Although controversial, this response is based on the subgroup data from the TOAST trial of heparinoid for acute ischemic stroke. Although the entire patient group did not benefit, patients with large vessel lesions did benefit from anticoagulation therapy. This patient s NIHSS score is too low to recommend acute thrombolysis. Although induced hypertension might be indicated should her Neurology Volume 7, Part 2 11

12 deficit recur, there is no clear indication for it at this time. Nimodipine has not been shown to benefit patients with acute ischemic stroke; in some cases, its antihypertensive effects could be harmful acutely. VIII. SUMMARY POINTS Recent advances in the application of thrombolytic agents have greatly changed the approach to patients with acute ischemic stroke. After the diagnosis of acute ischemic stroke, all patients should be considered for possible thrombolysis. Intravenous thrombolysis with tissue plasminogen activator (t-pa) has been successfully applied in a large clinical trial and is now approved by the FDA for use in acute ischemic stroke within strict guidelines. In special cases, intra-arterial therapies may be applied. This approach has now been validated in one clinical trial, although current use remains off label. The development of multidisciplinary stroke teams and designated stroke centers will facilitate the safe and efficient application of thrombolytic therapies. General therapies managing blood pressure; fluid, electrolyte, and glucose therapy; temperature regulation; and prophylaxis against deep venous thrombosis should be applied to all acute stroke patients. Despite much study, the early use of antithrombotic agents is controversial. Physicians must make individualized therapeutic decisions weighing the available evidence for benefit and risk. Medical and surgical therapies are available to minimize the secondary effects of cerebral edema after acute ischemic stroke. Theoretical considerations and laboratory experience suggest that neuroprotective strategies may provide an adjunctive therapeutic approach. Currently, clinical trials of many of these therapies have failed to demonstrate clear benefit. REFERENCES 1. Tissue plasminogen activator for acute ischemic stroke. The National Institutes of Neurological Disorders and Stroke rt-pa Stroke Study Group. N Engl J Med 1995; 333: Symon L, Branston NM, Strong AJ. Autoregulation in acute focal ischemia. An experimental study. Stroke 1976; 7: Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance of acute, drug-induced hypotension [editorial]. Circulation 1976;53: Powers WJ. Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology 1993;43(3 Pt 1): Adams HP Jr, Brott TG, Crowell RM, et al. Guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1994;25: Adams HP Jr, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1996;27: Broderick J, Brott T, Barsan W, et al. Blood pressure during the first minutes of focal cerebral ischemia. Ann Emerg Med 1993;22: Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992;23: Rordorf G, Cramer SC, Efird JT, et al. Pharmacological elevation of blood pressure in acute stroke. Clinical effects and safety. Stroke 1997;28: van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the surgical intensive care unit. N Engl J Med 2001;345: Reith J, Jorgenson HS, Pedersen PM, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 1996;347: Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: A significant clinical concern. Stroke 1998; 29: Yager JY, Asselin J. Effect of mild hypothermia on cerebral energy metabolism during the evolution of hypoxicischemic brain damage in the immature rat. Stroke 1996;27: Coimbra C, Drake M, Boris-Moller F, Wieloch T. Longlasting neuroprotective effects of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia. Stroke 1996;27: Krieger DW, De Georgia MA, Abou-Chebl A, et al. Cooling for acute ischemic brain damage (COOL AID): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 2001;32: Ginsberg JS. Management of venous thromboembolism. N Engl J Med 1996;335: Collaborative overview of randomised trials of antiplatelet 12 Hospital Physician Board Review Manual