Stroke Core Rounds Mark Y. Wahba Preceptor: Dr. Ian Rigby Oct. 16th, 2003 WHO definition: Stroke • “a neurological deficit of sudden onset accompanied by focal dysfunction and symptoms lasting more than 24 hours that are presumed to be of a non-traumatic vascular origin” WHO definition: Transient Ischemic Attack • “neurological events that have a duration shorter than 24 hours, followed by complete return to baseline” Outline • Introduction • clinical features, pathophysiology, types of stroke, differential diagnosis • Vascular Anatomy • Stroke Patterns • TIA • Management in the ED • Thrombolysis: good or bad? Facts • Leading cause of adult disability • 3rd leading cause of death in US • 75% of all strokes occur in pts >65yrs of age • In the US annual medical costs of stroke care is $30 billion • 20% of expenditures occur in the first 90 days after an event • The National Stroke Association. The brain at risk – Understanding and preventing stroke. 1998 Emergency Care Facts • 2% of all 911 calls • 4% of all hospital admissions from the ED involve patients with potential strokes Prognosis • Many pts present to ED with a „devastating neurological picture‟ • Substantial improvement may occur over time, even in the absence of specific therapy • 20% of patients who survive the initial event eventually have full or partial resolution of hemiparesis • Risk of repeated stroke is highest within the first 30 days • 25-40% of patients will have a repeat stroke within 5 yrs • EMR Sept 29,1997. Stroke: Comprehensive Guidelines for Clinical Assessment and Emergency Management (Part 1) Risk Factors • Hypertension-primary risk factor • Atrial fibrillation • Increasing age (particularly > 65) • Cigarette smoking • Diabetes • Black population • Hx of TIA • Male : Female 3:2 Stroke in the young Pt • 3-4% of strokes occur in people aged 15-45 • Sickle Cell anemia • Hypercoaguable states • Pregnancy, OCP use, antiphospholipid antibodies, protein C and S deficiencies • Drugs • Cocaine, phenylpropanolamine, amphetamines Pathophysiology • Cerebral blood flow provides brain with oxygen and glucose for energy at rate of 40- 60ml/100g of brain/min • When rate is <10ml/100g of brain/min cell membrane failure occurs: • extracellular K, intracellular Ca • ATP, profound cellular acidosis • Cell death • Electrical „silence‟ Pathophysiology: Ischemic penumbra • the area surrounding the primary injury • CBF is 10-18ml/100g of brain/min • Electrical silence but irreversible damage has not yet occurred • Animal studies: • reversible neurologic deficit if cerebral vessel occlusion lasts less than 2h • after 6h of occlusion: irreversible neurologic deficit • Thus the 2-6 hour therapeutic window for thrombolysis What are the types of stroke? • Ischemic • Hemorrhagic Ischemic Stroke • 85% of strokes • Thrombotic or Embolic • One month mortality: 15% Ischemic: Thrombotic local origin of clot • Usually develops at night during sleep • Symptoms perceived in morning • Suspect in hx of atherosclerosis, hypercoaguable states, and collagen vascular disorders Ischemic: Embolic proximal origin of clot • Occurs at any time • Frequently during periods of vigorous activity • Hx of Atrial fibrillation, valvular vegetations, thromboembolism from MI, ulcerated plaques in carotid system • Seizures in 20% of cases Hemorrhagic Stroke Hemorrhagic Stroke • 15% of strokes • intracerebral hemorrhage > subarachnoid hemorrhage • Occur during stress or exertion • Focal deficits rapidly evolve • Confusion, coma or immediate death Hemorrhagic • One month mortality: • 50% for SAH • 80% for intracerebral hemorrhage Vascular Anatomy Cerebral Blood Supply Anterior Circulation Posterior Circulation • From carotid system • From vertebral system • Supplies 80% of brain • Supplies 20% of brain Internal carotid territory Internal Carotid Artery • Anterior portion of the brain involving the frontal, temporal, and parietal lobes, is supplied by the carotid arteries (CA) • CA arises from the innominate artery on the right and aortic arch on the left. At level of upper neck CA branches into internal and external • the internal carotid artery terminates into the middle (MCA) and anterior (ACA) cerebral arteries • MCA perfuses the cortex, parietal lobe, temporal lobe, internal capsule, and portions of the basal ganglia • ACA forms the anterior portion of the circle of Willis and supplies portions of the frontal lobe Carotid Artery • Approximately half of patients with moderate stenosis (greater than 50% occlusion) will have a carotid bruit • about 90% of patients with a carotid bruit have at least moderate stenosis • Wiebers D, Whisnant J, Sanok B, et al. Prospective comparison of a cohort with asymptomatic carotid bruit and a population-based cohort without carotid bruit. Stroke 1990;21:984-988. • Ingall T, Homer D, Whisnant J, et al. Predictive value of carotid bruit for carotid atherosclerosis. Arch Neurol. 1989;46:418-422 Vertebrobasilar System • Perfuses the posterior part of the brain including the occipital lobe, cerebellum, and brainstem • vertebral arteries arise from the subclavian arteries • give off branches supplying the medulla and portions of the cerebellum • basilar artery is formed by the junction of the two vertebral arteries and gives off a variety of penetrating arteries supplying the brainstem and portions of the basal ganglia before dividing into the posterior cerebral arteries Vertebrobasilar System Posterior cerebral arteries Basilar artery Vertebral arteries Stroke Patterns Dominant Hemisphere • Majority of right handed and most left handed patients have dominance for speech and language located in the left hemisphere • Left hemisphere infarction is characterized by aphasia (both motor [Broca‟s] and sensory [Wernicke‟s]) and apraxia Nondominant Hemisphere • Less predictable syndromes • Attention defects: extinction and neglect • Behavioral changes: acute confusion and delirium Aphasia: Important? • Yes: usually localizes a lesion to the dominant cerebral cortex in the middle cerebral artery distribution • Rosen‟s Emergency Medicine 5th edition • Aphasia and dysphasia are used interchangeably • Don‟t confuse with Dysphagia Case • 80 yr old male • Sudden onset right side hemiplegia, hemianesthesia • eyes deviated to left • “babbling” MCA territory (image is of vascular territory, not specifically of previous case) Middle Cerebral Artery Middle Cerebral Artery • Embolism from ICA or heart to MCA is most common cause of cerebral infarction • Supplies most of the convex surface of brain • Deep tissue: basal ganglia, putamen, and parts of globus pallidus, caudate nucleus, and internal capsule MCA stroke • Contralateral hemiplegia and hemianesthesia: arm and face > leg • Deviation of the head and eyes toward side of infarct “Gaze preference” • Global aphasia (in dominant hemisphere) • Hemianopia, Hemineglect Case • 80 yr old female • Awoke with weakness in right leg • Slight right side weakness leg>arm • Family states she has “impaired judgment and insight” • “seems like a baby: sucking and grasping” Anterior Cerebral Artery Anterior Cerebral Artery • Supplies basal and medial aspects of the cerebral hemispheres • Extends to anterior two thirds of parietal lobe • Perforating branches supply anterior caudate nucleus, parts of internal capsule, putamen and anterior hypothalamus Anterior Cerebral Artery Infarction • weakness of the leg • +/- proximal muscle weakness in the upper extremities • Affect frontal lobe: impaired judgment and insight, change in affect • Presence of primitive grasp and suck reflexes • Language impairment (common finding) Case • 77 yr old male • Sudden onset of dizziness, double vision • On exam has pain and temp deficit on half of face and on opposite side of body Posterior Circulation Posterior Circulation/ Vertebrobasilar System • 2 Vertebral arteries basilar artery posterior cerebral arteries • Supplies brainstem, cerebellum, thalamus, auditory and vestibular centers of the ear, visual occipital cortex Vertebrobasilar System • Heterogeneous syndromes and presentations • Cranial nerve deficits and involvement of cerebellum and neurosensory tracts • diplopia, dysphagia, dysarthria, dizziness, vertigo, ataxia • pain and temp deficits in face occur on opposite side of body Vertebrobasilar System • Thalamic lesions: sensory symptoms involving loss of tactile, temp, and pain sensation, „numbness‟ on side of body opposite face • Occipital lesions: homonymous visual field defect (hemianopia or quadrantanopia) Case • 85 yr old black male • Diabetic, hypertension • Sudden onset of being unable to move left side of body • Able to talk • Sensation intact Lacunar Infarction • Lesion of small penetrating branch arteries into BG, thalamus, pons, internal capsule • “Pure” strokes • Motor, sensory, ataxic hemiparesis • Usually result in hemiparesis of face, arm and leg • Lack of impairment of consciousness, aphasia, or visual disturbances • More common in blacks and hx of HTN, DM • 60% of patients with lacunar infarctions will be independent at one year following stroke Case • 85 yr old female • In ICU, post AAA rupture repair • GCS 15/15 • Complaining of difficulty moving her leg and that it feels numb Watershed Infarction • occurs in vulnerable areas supplied by distal distribution cerebral arteries during periods of hypotension • infarction between the anterior and middle cerebral arteries presents with hemiparesis and hemianesthesia, predominantly in the leg • dominant hemisphere infarctions: decrease in verbal ability with preserved comprehension • Infarction involving the posterior watershed area presents with homonymous hemianopia +/- hypoesthesia in the face and legs Case • 77 yr old male • Sudden onset headache, vomiting • went unresponsive • GCS 3/15, elevated BP • What has happened? Hemorrhagic Stroke • Classic: sudden onset HA, vomiting, elevated BP • Focal neurologic deficits that progress over minutes • May present with agitation and lethargy but progresses to stupor or coma Transient Ischemic Attack Transient Ischemic Attack • Neurological deficit of sudden onset accompanied by focal dysfunction that has a duration of shorter than 24 hours • Most resolve within 15-30 minutes • Straightforward definition but complex and controversial management Common causes of ischemic stroke and transient ischemic attack TIA • Harbinger of ischemic cerebral infarction • In the absence of treatment: • 5-10% of pts will have a stroke within a month and 12% within a year • After 2 years a stroke will have occurred in 20-40% of TIA patients • Tuhrim S, Reggia JA. Management of TIA. American Family Physician 1986;315:1041 • Morris PJ et al, Transient Ischemic Attacks New York: Marce, Dekker, 1982 TIA management • Is the pt high risk? • Multiple TIA in last 2/52, severe deficit, crescendo symptoms, TIA caused by cardioembolic events • If so: CT head, admit for workup • Same for first time TIA TIA Management • If low risk: D/C home after seeing stroke team • FASTER trial: Fast Assessment of Stroke and TIA to prevent Early Recurrence • <12 hours of onset of TIA or minor stroke: • randomized to Anti-platelet therapy with ASA or ASA + clopidogrel (Plavix) • + randomized to Statin therapy with simvastatin vs. placebo • Outcome: stroke at 90 days, combined outcome of MI, stroke, or vascular death at 90 days, stroke severity What if they are already on ASA? • In Calgary: start patient on Clopidogrel (Plavix) as well Do we thrombolyse or is this just a TIA? • 312 pts randomized to placebo group in the NINDS trial • Medial time to treatment was 90 minutes • Only 2% were symptom free at 24 hours • “unlikely that patients with a persistent neurologic deficit of longer than 90 minutes will resolve spontaneously” • Borg KT et al TIA: an emergency medicine approach. Emergency Medicine Clinics of North America. Vol 20, 3, Aug 2002 Management of Patients with Ischemic Stroke Guidelines for the Early Management of Patients With Ischemic Stroke. A Scientific Statement From the Stroke Council of the American Stroke Association. Adams HP et al Stroke. 2003;34: 1056-1083. Hx and Physical “in general, the diagnosis of stroke is straightforward” • Emergency physicians correctly identified 152 or 176 consecutive stroke patients (sens 86.4%) and 1818 of 1835 patients without stroke (spec 99.1%) • Von Arbin M et al. Accuracy of bedside diagnosis in stroke. Stroke. 1981: 12:288- 293 But… • Errors in clinical diagnosis can occur • One series of 821 patients diagnosed with stroke: 13% were later determined to have other conditions • Norris JW. Misdiagnosis of stroke. Lancet. 1982;1:328-331 • Unrecognized seizures, confused states, syncope, brain tumors subdural hematoma hypoglycemia and other toxic or metabolic disorders Differential Diagnosis • Complex migraine • Cerebral infection headache with • Subdural hematoma hemiparesis • Drug intoxication • Post-ictal paresis • Malignant (Todd‟s paresis) hypertension • Hypoglycemia • Cerebral tumor History • Time of onset is critical • For treatment: the onset is assumed to be last time pt was symptom free • Recent medical or neurological events: Trauma, hemorrhage, surgery, MI, previous stroke • Meds: oral anticoagulants, antiplatelets Neurologic Examination • The examination recommended by the National Institutes of Health is broken down into 6 areas 1. Level of consciousness 2. Visual assessment 3. Motor function 4. Cerebellar function 5. Sensation and neglect 6. Cranial nerves Imaging and Lab - All patients should have: • Brain CT • Creatinine • ECG • CBC • Serum Glucose • PT/INR • Electrolytes • aPTT Selected Patients • LFTs • CXR (if lung • Tox screen and EtOH pathology suspected) (if uncertain about hx) • LP (if suspecting SAH • Preg test and CT is negative) • ABG (if hypoxic) • EEG (suspecting seizures ) Imaging MRI vs CT MRI • Standard MRI (T1, T2 weighted) is relatively insensitive to changes of acute ischemia within first few hours of stroke • Show abnormalities in <50% of patients (class A) • But, diffusion weighted imaging (DWI) visualizes ischemic regions within minutes of symptoms • Warach S et al. Fast MRI diffusion-weighted imaging of acute human stroke. Neurology. 1992;42: 1717-1723 Limitations of MRI • Difficulty in identifying ICH • Cost, limited availability, patient CI (claustrophobia, pacemakers, metal implants) • “Additional research is needed to determine the utility of MRI in place of CT for identifying hemorrhage among patients with suspected stroke” • Guidelines for the Early Management of Patients With Ischemic Stroke. A Scientific Statement From the Stroke Council of the American Stroke Association. Adams HP et al Stroke. 2003;34: 1056-1083. CT • CT is the gold standard to which other brain imaging studies are compared • CT accurately identifies most cases of ICH and helps discriminate nonvascular causes of neurological symptoms (brain tumor)- grade B • Jacobs et al. Autopsy correlations of computerized tomography: experience with 6000 CT scans. Neurology. 1976; 26:1111-1118 With r-tPA, interest in CT in: • Subtle early signs of infarction might affect treatment decisions: • hyperdense middle cerebral artery sign and loss of gray-white differentiation in the cortical ribbon are associated with poor outcome (class A evidence) • Presence of widespread signs of early infarction as this correlates with a high risk of hemorrhagic transformation (level 1) • But… MD‟s ability to reliably and reproducibly recognize early CT changes is variable (class B) • Guidelines for the Early Management of Patients With Ischemic Stroke. A Scientific Statement From the Stroke Council of the American Stroke Association. Adams HP et al Stroke. 2003;34: 1056-1083 Other CT scan techniques • Xenon enhanced CT provides a quantitative measurement of cerebral blood flow • Perfusion CT measures CBF by mapping the appearance of an IV contrast bolus • further studies are needed to determine their clinical utility Currently: Imaging Goal for patients who are candidates for thrombolysis: • Complete CT within 25 minutes of arrival to ED • Study interpreted within 20 min • Thus: door to interpretation time of 45 min • Marler JR et al. Proceedings of a national symposium on rapid identification and treatment of acute stroke; 1997. (GENERIC) Pamphlet. Other management issues ECG? • Acute MI can lead to stroke and acute stroke can lead to MI • Arrhythmias can occur in pts with ischemic stroke • Atrial fibrillation detected in the acute setting • Oppenheimer sm et at. The cardiac consequences of stroke. Neurol Clin. 1992;10:167-176 • Dimant J et al. ECG changes and myocardial damage in patients with acute CVA. Stroke. 1977;8 448-455 Cardiac Rhythm • Pts with Right hemisphere infarcts have high risk of arrhythmias • Thought to be due to disturbances in sympathetic and parasymp nervous system function (level V) • ECG changes in stroke include: ST seg dep, QT prolongation, inverted T waves, prominent U waves Blood Tests? • “Use of rtPA should not be delayed while waiting for INR or aPTT unless there is a clinical suspicion of a bleeding abnormality or unless the patient has been taking warfarin and heparin or their use is uncertain.” • Determination of platelets and INR is required in pts taking warfarin prior to administration of thrombolytics • Adams et al. Guidelines for thrombolytic therapy for acute stroke. Circulation. 1996;94:1167-1174 Hypoglycemia • Can cause focal neurological signs that mimic stroke • Can itself lead to brain injury • Therefore prompt measurement and rapid correction are indicated Hyperglycemia • Uncertainty whether hyperglycemia worsens stroke outcomes • Weir CJ et al. Is hyperglycemia an independent predictor of poor outcome after acute stroke? BMJ.1997;314:1303-1306. • “No data evaluating the impact of maintaining euglycemia during the period of acute stroke” • Reasonable goal is to lower markedly elevated glucose levels to <16.63 mmol/L (grade C) • Overly aggressive fluid therapy should be avoided because it can result in fluid shifts that may be detrimental to the brain Does everyone need a CXR? • Was previously recommended for all pts with acute ischemic stroke • A study found that clinical management was altered in only 3.8% of patients having routine CXR at time of admission for stroke • Sagar G et al. Is admission chest radiography of any clinical value in acute stroke patients? Clin Radiology. 1996;51:499-502 • test is of little use in absence of an appropriate clinical indication (grade B) Oxygen? • Pts with acute stroke should be monitored with pulse ox with a target O2 sat of >95% (level V) • An endotracheal tube should be placed if the airway is threatened (level V) • 50% of patients requiring endotracheal intubation will die within 30 days of stroke • Grotta J et al. Elective intubation for neurologic deterioration after stroke. Neurology. 1995;45:640-644 Fever? • Increased temp in setting of acute stroke has been associated with poor neurological outcome • Azzimondi G et al. Fever in acute stroke worsens prognosis: a prospective study. Stroke. 1995;26 :2040-2043 • “Source of any fever following stroke should be ascertained and the fever should be treated with antipyretics” • Studies investigating hypothermia for treatment of patients with stroke but efficacy has yet to be established Hypertension • Optimal management has not been established • Brott T et al. Hypertension and its treatment in the NINDS rtPA stroke trial. Stroke. 1998;29:1504-1509 • In the absence of organ dysfunction or thrombolytic therapy there is little scientific basis and no clinically proven benefit for lowering BP among patients with acute ischemic stroke • Powers WJ et al Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology. 1993;43:461-467 Hypertension • Situations that may require treatment: • Hypertensive encephalopathy • Aortic dissection • Acute renal failure • Acute pulmonary edema • Acute MI Consensus on Hypertension • Antihypertensive agents should be withheld unless the diastolic BP is >120 mmHg or unless the systolic BP is >220mmHg • Aim for a 10 to 15% reduction of BP • Use parenteral agents that are easily titrated: labetalol, sodium nitroprusside • level V evidence Hypertension in candidate for thrombolytics • Systolic BP must be <185 mmHg • Diastolic BP must be <110 mmHg • Pretreatment: Labetalol 10-20mg IV over 1- 2min • During treatment: monitor BP q 15min for 2h • Use labetalol, Na nitroprusside infusions Anticoagulants? • Several studies with heparin, LMW heparins, heparinoid • Conclusion: • parenterally administered anticoagulants are associated with an increased risk of serious bleeding complications (level I) • early administration of the rapidly acting anticoagulants does not lower the risk of early recurrent stroke, including among patients with cardioembolic stroke (level I) Anticoagulants • Recommendations: • Urgent routine anticoagulation with the goal of improving neurological outcomes or preventing early recurrent stroke is not recommended for the treatment of patients with acute ischemic stroke (grade A) • Guidelines for the Early Management of Patients With Ischemic Stroke. A Scientific Statement From the Stroke Council of the American Stroke Association. Adams HP et al Stroke. 2003;34: 1056-1083 Antiplatelets • 2 large trials with aspirin: • Chinese Acute Stroke Trial • International Stroke Trial Chinese Acute Stroke Trial (CAST) • Prospective, randomized, placebo controlled trial of >21000 pts, where ASA 160mg/day or placebo was given within 48h of stroke onset • Aspirin reduced early mortality • 3.3 vs 3.9%; p=0.04 • No effect on the proportion of patients who were dead or dependent at hospital discharge • 30.5 vs 31.6%; p=0.08 • (CAST: randomized placebo-controlled trial of early aspirin use in 20000 patients with acute ischemic stroke. Lancet 1997; 349: 1641-1649 International Stroke Trial (IST) • Prospective, randomized, open-label trial of ASA and unfractionated heparin in >19000 pts • half received ASA and half were instructed to avoid ASA, then half of pts in each group received unfractionated heparin • Significant reduction in recurrent events but acute mortality was not reduced (level I) • Small significant (0.1% absolute) significant increase in the incidence of intracranial hemorrhage (level I) • IST: a randomized trial of aspirin, subcutaneous heparin, both or neither among 19435 patients with acute ischemic stroke. Lancet 1997;349:1569-1581 Antiplatelets • Combined analysis revealed: • ASA had a small but statistically significant reduction of 9 (+/-3) fever deaths or nonfatal strokes per 1000 treated patients • Absolute RR of 0.9% • NNT of 111 • Anticoagulants and Antiplatelet Agents in Acute Ischemic Stroke. Report of the joint stroke guideline development committee of the American academy of neurology and American stroke association. Stroke 2002;33:1934-1942. Antiplatelets • Conclusion: use of aspirin within 24-48h after stroke in attempts to reduce death and disability is reasonable (level I) • Recommendation: Aspirin should be given within 24 to 48 hours of stroke onset in most patients (grade A) • Not recommended within 24 hours of thrombolytic agents (grade A) • Guidelines for the Early Management of Patients With Ischemic Stroke. A Scientific Statement From the Stroke Council of the American Stroke Association. Adams HP et al Stroke. 2003;34: 1056-1083 Thrombolysis for Acute Ischemic Stroke Are we doing the right thing? EMR Oct 13, 1997. Stroke: Comprehensive Guidelines for Clinical Assessment and Emergency Management (Part II) Thrombolysis: History • U. S. Food and Drug Administration approval of rtPA (recombinant tissue plasminogen activator) for the treatment of acute stroke in June of 1996 • based on the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study • less than 10 percent of stroke patients are eligible for thrombolytic therapy • EMR Oct 13, 1997. Stroke: Comprehensive Guidelines for Clinical Assessment and Emergency Management (Part II) To date: • 6 grade-one multi-center RCTs of thrombolytics for acute stroke demonstrated lack of benefit or worse outcomes with treatment • 3 trials of streptokinase were halted prematurely because of an excess of poor outcomes or deaths (level I) • the NINDS trial is the only published RCT of intravenous thrombolytic therapy that has been positive in favor of thrombolysis • Position Statement on Thrombolytic Therapy for Acute Ischemic Stroke, The CAEP Committee on Thrombolytic Therapy for Acute Ischemic Stroke http://www.caep.ca/002.policies/002-01.guidelines/thrombolytic.htm ECASS • compared rtPA (1.1 mg/kg) to placebo in patients with <6 hours of symptoms • early intracranial hemorrhage, fatal cerebral edema and early mortality were more common in treated patients than in controls • surviving t-PA recipients were more likely to have minimal or no disability at 3 months • authors concluded: while some patients benefit, the rate of negative outcomes was prohibitively high • Intravenous rtPA was not more effective than placebo in improving neurological outcomes at 3 months after stroke (level I) • Hacke W, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke, the European cooperative acute stroke study (ECASS). JAMA 1995;274:1017-25 ECASS vs NINDS • ECASS: higher dose, longer window of treatment • Post hoc analysis concluded that pts treated within 3 hours appeared to benefit from rtPA ECASS-II • applied the same eligibility criteria and used the same 0.9 mg/kg rtPA dose, but enrolled patients within 6 hours of symptom onset • More than 1/3 of pts in each group made and excellent recovery and no significant benefit was noted from treatment • rtPA did not significantly increase the rate of favorable 90- day outcomes (40.3% vs. 36.6%, p=0.277), and was associated with a higher incidence of parenchymal hemorrhage (11.8% vs. 3.1%), symptomatic intracranial hemorrhage (8.8% vs. 3.4%), and early death due to intracranial hemorrhage (11 vs. 2 cases) ECASS-II • no significant differences in 30- or 90-day mortality • subgroup analysis showed a trend towards improved neurological outcomes in patients with <3 hours of symptoms, but the numbers were small and statistically insignificant • ECASS-II therefore failed to reproduce the positive results of NINDS • Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D et al. Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Lancet 1998;352:1245-51 ECASS-II • Recruitment bias? • Avoided recruitment of pts with Multilobar infarctions • Thus severity of strokes was less than in other trials • Generally more favorable prognosis may have reduced the likelihood of detecting a therapeutic effect PROACT II • administered intra-arterial pro-urokinase (vs. placebo) to patients with <6 hours of symptoms • At 90 day follow-up, thrombolytic patients had a higher rate of favorable outcomes (40% vs. 25%; p = 0.04), defined as a modified Rankin score of 2 or less • ICH with early neurological deterioration was more common in prourokinase patients (10% vs. 2%; p = 0.6), and 90-day mortalities were similar between groups (25% vs. 27%) • suggests that intra-arterial prourokinase may confer some benefit, but at substantially increased risk of symptomatic intracranial hemorrhage • Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. JAMA 1999;282:2003-11 ATLANTIS • placebo-controlled, randomized clinical trial addressing the efficacy and safety of rtPA administered 3 to 5 hours after stroke onset • found no beneficial treatment effect, but a significantly higher rate of asymptomatic (11.4 vs. 4.7%) and symptomatic (7.0% vs. 1.1%) intracerebral hemorrhage with rtPA • Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. (The alteplase thrombolysis for acute noninterventional therapy for ischemic stroke [ATLANTIS] study). JAMA 1999;282:2019-26 NINDS • multicentre, randomized, placebo-controlled trial • 624 patients with ischemic stroke were treated with intravenous t-PA (0.9 mg/kg) within 3 hours of the onset of stroke symptoms. • Part 1: primary endpoint was neurological improvement at 24h (complete neuro recovery or improvement of 4 points or more on NIHSS) • Part 2: primary end point was global odds ratio for favorable outcome (defined as complete or nearly complete neurological recovery at 3 months after stroke) NINDS • Part 1: t-PA recipients did not suddenly improve, and there were no significant outcome differences at 24 hours • Part 2: patients treated with t-PA were more likely to have a favorable neurological outcome at 90 days (odds ratio 1.7; 95% CI, 1.2-2.6; p=0.008) • Compared to controls, t-PA recipients had a 12% absolute (32% relative) increase in the proportion with minimal or no disability But… • The benefit was similar at 1 year after stroke (level 1) • t-PA was associated with a 10-fold increase in symptomatic intracerebral hemorrhage (6.4% vs. 0.6%) (level 1) • the overall intracerebral hemorrhage rate (symptomatic + asymptomatic) was 10.1% • Mortality rate in the two treatment groups was similar at 3 months (17% vs 20%) and 1 year (24% vs 28%) • The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581 Number Needed to Treat • NNT = 1/Absolute Risk Reduction • ARR=CER-EER ARR =(165-65)/165 - (168-80)/168 ARR =0.08225 • about 8% absolute risk reduction if treated with tPA • NNT=1/0.08225 = 12. • This means you need to treat 12 patients to see an improvement in outcome at 90 days Number Needed to Harm • NNH 1/ARR • Absolute RR = 8/165 - 21/168 ARR=-0.0765 • In other words you have 8% absolute increased risk for CNS bleed if given tPA • NNH = 1/ARR which is 13 • Thus for every 13 patients you treat you will get a CNS bleed • take the asymptomatic bleeds out of the calculation the NNH is now about 17 • or treat 17 patients to get a symptomatic CNS bleed So… • You have to treat 12 patients to get a good outcome overall as per NINDS definition • That's not bad, except that for every 17 you treat you get a symptomatic/fatal CNS bleed. • Thus the cautious approach in EM to CNS lytics and the strict eligibility criteria Cochrane Stroke Group Trials Register • Up to January 2003 • Objective: assess safety and efficacy of thrombolytic agents in patients with acute ischemic stroke • Selection criteria: randomized trials of any thrombolytic agent compared with control in patients with definite ischemic stroke • 18 trials, 5727 patients • Urokinase, streptokinase, recombinant tissue plasminogen activator, recombinant pro-urokinase • 2 trials: intra arterial administration • 16 trials: intra venous administration • 50% of data from tPA • Little data over age 80 Thrombolytic therapy: • administered up to six hours after ischemic stroke, significantly reduced the proportion of patients who were dead or dependent at the end of follow-up at three to six months (OR 0.84, 95% CI 0.75 to 0.95) • a significant increase in: the odds of death within the first ten days (OR 1.81, 95% CI 1.46 to 2.24), the main cause of which was fatal intracranial hemorrhage (OR 4.34, 95% CI 3.14 to 5.99) • Symptomatic intracranial hemorrhage was increased following thrombolysis (OR 3.37, 95% CI 2.68 to 4.22) Thrombolytic therapy: • also increased the odds of death at the end of follow-up at three to six months (OR 1.33, 95% CI 1.15 to 1.53) • For patients treated within three hours of stroke, thrombolytic therapy appeared more effective in reducing death or dependency (OR 0.66, 95% CI 0.53 to 0.83) with no statistically significant adverse effect on death (OR 1.13, 95% CI 0.86 to 1.48) Cochrane conclusions: • Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. • However, this appears to be net of an increase in deaths within the first seven to ten days, symptomatic intracranial hemorrhage, and deaths at follow-up at three to six months • The data from trials using rtPA suggest that it may be associated with less hazard and more benefit Cochrane conclusions: • The data are promising and may justify the use of thrombolytic therapy with intravenous recombinant tissue plasminogen activator in experienced centers in highly selected patients • However, the data do not support the widespread use of thrombolytic therapy in routine clinical practice at this time Canadian Association of Emergency Physicians Position Statement on Thrombolytic Therapy for Acute Ischemic Stroke: basically • Similar to Cochrane findings • “The data show that t-PA therapy must be limited to carefully selected patients within established protocols”. • “Until it is clear that the benefits of this therapy outweigh the risks, thrombolytic therapy for acute stroke should be restricted to use within formal research protocols or in monitored practice protocols that adhere to the NINDS eligibility criteria” • “Stroke thrombolysis should be limited to centers with appropriate neurological and neuro-imaging resources that are capable of administering treatment within 3 hours • In such centers, emergency physicians should identify eligible patients, initiate low risk interventions and facilitate prompt CT scanning • Only physicians with demonstrated expertise in neuroradiology should interpret head CT scans used to determine whether to administer thrombolytic agents to stroke patients. • Neurologists should be directly involved prior to the thrombolytic administration” So what can we do? • “The Canadian Association of Emergency Physicians enthusiastically endorses the promotion of stroke therapies where the benefits clearly outweigh the risks. These include the use of ASA, prevention of aspiration, early rehabilitation, and the establishment of stroke units and protocols” Intra-arterial Thrombolyis • Still in experimental stages • Prospective, randomized, placebo control trial used intra-arterial r-prourokinase: successful in recanalizing more frequently but had increased risk of intracranial bleeding • Del Zoppo et al. Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by dircet arterial devlivery in acute middle cerebral artery stroke: PROACT investigators: Prolyse in Acute Cerebral Thrombolembolism. Stroke. 1998; 29:4-11 • May be used in occlusion of large intracranial arteries: basilar or middle cerebral • Requires adequate equipment and skilled clinician Summary Summary • Be familiar with stroke patterns • Be familiar with general medical management of stroke patients • Controversy regarding Thrombolytic therapy • Thanks to Dr. Ian Rigby for his help References • EMR Sept 29,1997. Stroke: Comprehensive Guidelines for Clinical Assessment and Emergency Management (Part 1) • EMR Oct 13, 1997. Stroke: Comprehensive Guidelines for Clinical Assessment and Emergency Management (Part II) • Thrombolysis for acute ischaemic stroke. Wardlaw JM et al. Conhrane Database of Systematic Reviews. 3, 2003 • Position Statement on Thrombolytic Therapy for Acute Ischemic Stroke, The CAEP Committee on Thrombolytic Therapy for Acute Ischemic Stroke http://www.caep.ca/002.policies/002- 01.guidelines/thrombolytic.htm • Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke, the European cooperative acute stroke study (ECASS). JAMA 1995;274:1017-25 • The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581 • Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D et al. Randomised double-blind placebo- controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998;352:1245-51 • Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. JAMA 1999;282:2003-11 References • Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. (The alteplase thrombolysis for acute noninterventional therapy for ischemic stroke [ATLANTIS] study). JAMA 1999;282:2019-26 • Taking the Initiative! An ED Based Stroke Team in a Community Teaching Hospital Jonathan A. Maise http://emedhome.com/features_archive- detail.cfm?SFID=090400&SFTID=news • Schmidley JW, Messing RO. Agitated confusional states inpatients with right hemispheric infarctions. Stroke 1984; 15: 883 • Rosen‟s Emergency Medicine 5th edition Extras SAH High attenuation is seen diffusely within the sulci on a noncontrasted head CT. High attenuation collections are also present within the occipital horns of the lateral ventricles. Moderate hydrocephalus is present Embolic stroke Motor Homunculus Vascular Territory Among patients undergoing angiography for atherosclerotic stroke: • 62% Internal Carotid Artery • 15% Vertebrobasilar Arteries • 10% Middle Cerebral Artery • Schmidley JW, Messing RO. Agitated confusional states inpatients with right hemispheric infarctions. Stroke 1984; 15: 883 • Attacks in the ICA distribution that involve the dominant hemisphere may present with symptoms such as motor dysfunction, amaurosis fugax, numbness, and/or aphasia • in the distribution of the ICA of the non- dominant hemisphere have similar symptomatology but without aphasia Clinical Features • Sudden devlp‟t of focal neurological deficit • Transient loss of consciousness is rare • Seizure • Headache in a minority of patients Atrial Fibrillation • Patients with A. Fib are 5 to 17 times more likely to develop stroke than those who do not have A. Fib • Strokes resulting from A. Fib are more likely to involve large cerebral vessels, be more severe, and have a higher mortality than non-A. Fib strokes • Jorgensen HS et al: Acute stroke with atrial fibrillation: the Copenhagen Stroke study, Stroke 10: 1765, 1996 • LiuHJ et al: Stroke severity in atrial fibrillation: the Framingham study, Stroke 27, 1760, 1996 National Institutes of Health Stroke Scale • Quantifies neurologic deficit, found to be reproducible and valid • Correlates well with amount of infarcted tissue on CT scan • Baseline NIHSS can determine pts appropriate for fibrinolytic therapy and those at risk of increased hemorrhage • NINDS trial of r-tPA score of >20 had a 17% chance of ICH, risk of bleeding was only 3% if <10 • Prognostic tool to predict outcome • Brott T: Utility of the NIH Stroke Scale, Cerebrovasc Dis 2:241, 1992 • Adams HP et al. Baseline NIHSS score strongly predicts outcome after stroke. Neurology. 1999; 53:126-131 NIHSS score out of 42 • Level of • Motor Arm: L and R-4 Consciousness-3 each • LOC of questions-2 • Motor Leg: L and R-4 each • LOC of Commands-2 • Limb Ataxia-2 • Best Gaze-2 • Sensory-2 • Visual Fields-3 • Best Language-3 • Facial Palsy-3 • Dysarthria-2 • Extinction and Inattention-2 NINDS • To get the number needed to treat (to meet the improvement outcome) it is calculated by 1/Absolute Risk Reduction. For this data the ARR =(165-65)/165 - (168- 80)/168. This gives you a number of 0.08225 (or about 8% absolute risk reduction if treated with tPA). So the NNT=1/0.08225 = 12. This means you need to treat 12 patients to see an improvement in outcome at 90 days. • To look at the NNH (number needed to harm) you look at table#6. It is essentially the same type of calculation. Absolute RR = 10/165 - 33/168 which is -0.1358 or - 13.6%. In other words you have a 13.6% absolute increased risk for CNS bleed if given tPA. The NNH = 1/ARR which is 7.36 (or about 7). Thus for every 7 patients you treat you will get a CNS bleed. • If you take the asymptomatic bleeds out of the calculation (OK, I guess), the NNH is now about 8.4 (or treat 8 patients to get a symptomatic CNSbleed). • So what to make of this? You have to treat 12 patients to get a good outcome overall (as per their definition). That's not bad, except that for every 8 you treat you get a symptomatic/fatal CNS bleed. Now I'm a little worried. Hence our cautious approach in EM to CNS lytics.