Treatment of Stroke in the Emergency Department Jim Holliman, M.D., F.A.C.E.P. Professor of Emergency Medicine Director, Center for International Emergency Medicine M. S. Hershey Medical Center Pennsylvania State University Hershey, Pennsylvania, U.S.A.

Stroke Lecture Outline Classification and epidemiology Risk factors Signs and symptoms Assessment in the E.D. Treatment Comparison of results of trials of thrombolytic agents Proposed neuroprotective agents

Stroke Classification Defined as neurological impairment caused by disruption in blood supply to a region of the brain 2 major categories : –Ischemic ƒ Due to occlusion of brain blood vessel ƒ Rarely causes death in first hour –Hemorrhagic ƒ Due to rupture or leak of a brain blood vessel ƒ Can be fatal at onset or cause rapid death

Types of Ischemic Stroke In U.S., 75 % of strokes are ischemic Two etiologies : –Clots develop locally in brain vessel (thrombosis) –Clots migrate from elsewhere (embolism) Two classes : –Strokes involving carotid artery distribution ƒ Called anterior circulation or carotid territory strokes & affect cerebral hemispheres –Strokes involving vertebrobasilar arteries ƒ Called posterior circulation or vertebrobasilar territory strokes & affect brainstem or cerebellum

CT scan showing lacunar infarct in right centrum semiovale

Ischemic infarct from left middle cerebral artery ; its wedge shape suggests embolic stroke from atrial fibrillation

Posterolateral thalamic infarct which caused contralateral falling and tilting

Types of Hemorrhagic Stroke Two classes : –Subarachnoid hemorrhage (SAH) ƒ Bleeding onto surface of brain ƒ Most common cause is berry aneurism ƒ 5 % due to arteriovenous malformation –Intracerebral hemorrhage (ICH) ƒ Bleeding into parenchyma of brain ƒ Most common cause is hypertension ƒ Amyloid angiopathy is common cause in elderly

Right putamen hemorrhage presenting as sudden left hemiparesis

Large subarachnoid hemorrhage

Another large subarachnoid hemorrhage

Right temperoparietal bleed (note also left temporal encephalomalacia)

Subarachnoid hemorrhage from a ruptured aneurism

Left sided ICH causing left sided weakness

Basal ganglia hemorrhage

Large right intracerebral hemorrhage causing hemiparesis and obtundation

Hemorrhagic infarct from left middle cerebral artery

Stroke Epidemiology Third leading cause of death in U.S.A. > 500,000 cases per year > 100,000 deaths per year Leading cause of brain injury in adults Leading cause of long term disability May be much higher percent of cases due to hemorrhage in some countries (such as Korea)

Concept of Stroke as "Brain Attack" Goal of this is to emphasize need to evaluate and treat stroke similar to the current standard rapid scheme for acute myocardial infarction ("heart attack") Involves 4 components : –Education of at-risk patients –Early recognitionof stroke symptoms & signs –Prompt prehospital evaluation & transport –Rapid emergency department evaluation ƒ May involve stroke team or stroke center

Transient ischemic attacks (TIA's) Prior stroke –4 to 14 % recurrence per year Carotid bruit Age > 55 –However, 25 % are younger than 65 Male gender Family history High blood pressure Smoking Heart disease Diabetes mellitus Hypercoagulable states (see next slide) Polycythemias Sickle Cell Anemia African race Risk Factors for Stroke

Hypercoagulable States Increasing Risk for Stroke Pregnancy Use of birth control pills (oral contraceptives with estrogens) Cancer Protein S deficiency Protein C deficiency

TIA's and Stroke TIA is a reversible episode of focal dysfunction of the brain or eye secondary to transient occlusion of an artery Typically Sx last < 30 minutes, but can last up to several hours 5 % of TIA cases have stroke in < 1 month 12 % of TIA cases have stroke by one year If > 70 % carotid narrowing with TIA, carotid endarterectomy is effective to prevent stroke Daily aspirin or ticlopidine effective prophylactically in some patients

Arch angiogram ; closed arrow denotes right internal carotid artery stenosis ; arrowhead denotes left internal carotid stenosis ; the open arrows denote patent vertebral arteries

Stroke Symptoms Findings much more common in hemorrhagic stroke : –Headache (could be only symptom) –Depressed level of consciousness –Nausea / emesis –Photophobia –Neck pain or stiff neck Most ischemic strokes do not have headache

Common Symptoms & Signs of Ischemic Stroke If carotid (anterior) circulation : –Motor weakness or paralysis ƒ Usually unilateral ƒ May have facial palsy –Numbness or paresthesias ƒ Usually same side as weakness –Language or speech disturbance ƒ Aphasia or dysarthria –Visual disturbance (usually monocular) ƒ Painless blurring or visual field loss

Right frontal thrombotic infarct, probably older than one day

Common Symptoms & Signs of Ischemic Stroke If vertebrobasilar (posterior) circulation : –Vertigo, often with nystagmus –Visual disturbances ƒ Diplopia, may have bilateral blurring ƒ Ocular palsy ƒ Dysconjugate gaze –Paralysis, may be focal or all 4 limbs –Numbness, may be focal or all 4 limbs –Dysarthria –Ataxia, may be only one limb

Prehospital Management of Suspected Stroke Rapid evaluation, & determine time of onset –Can use Cincinatti Prehospital Stroke Scale –Rule out hypoxia (check pulse oximetry) –Rule out hypoglycemia (check fingerstick blood sugar) ƒ Remember that hypoglycemia can present as any focal neuro sign which may mimic stroke –Rule out possible spine trauma ƒ Neck & back immobilization if history unclear or possible fall after onset of symptoms –Minimize total field time if stroke suspected

The Cincinatti Prehospital Stroke Scale Facial Droop (have patient show teeth or smile) –Normal –Abnormal (one side with less movement or droop) Arm Drift (have patient close eyes & hold arms out) –Normal –Abnormal (one arm does not move or drifts down) Speech (have patient say a simple sentence) –Normal –Abnormal (word slurring, inappropriate words, mute)

Initial Emergency Department Management of the Stroke Victim Airway management –Oropharyngeal or tongue muscle paralysis can cause airway obstruction –May need suction frequently if difficulty swallowing –May need nasopharyngeal airway –Check pulse oximetry & start supplemental oxygen on all patients (even if oximetry okay) –Immobilize cervical spine if possible fall or history unclear, & obtain radiographs

Initial Emergency Department Management of the Stroke Victim (cont.) Breathing management –Watch for apnea –If unconscious, usually endotracheal intubation (after use of meds such as lidocaine, benzodiazepine, etomidate, etc. ) and mechanical ventilation indicated –Abnormal patterns (such as Cheyne-Stokes) are indication also for intubation & controlled ventilation

Initial Emergency Department Management of the Stroke Victim (cont.) Circulation management –Check fingerstick blood sugar if not done yet (and treat with IV 50 % dextrose bolus if low) –Place intravenous line with normal saline TKO ƒ Hypotonic fluids contraindicated –Treat hypotension with fluid bolus +/- pressors –Hypertension usually does NOT need emergent Rx (exception is some acute bleeds) ƒ Labetolol, nitroprusside are safest agents (but require close continuous BP monitoring)

Initial Emergency Department Management of the Stroke Victim (cont.) Further care routinely indicated : –Obtain lab studies (see next slide) & EKG –Rapid but complete physical exam –If seizure, treat with IV benzodiazepine followed by IV diphenylhydantoin loading (18 mg/kg) –Obtain STAT head computed tomography scan ƒ Goal is to have scan done & read in < 45 minutes from time of E.D. arrival –Monitor vital signs frequently –May need foley or nasogastric tube –Alert appropriate consultants

Lab Studies to Routinely Consider For Stroke Patients Complete Blood Count (CBC) Clotting Studies (platelet count, PT, PTT) Electrolytes, Calcium, Magnesium Blood Urea Nitrogen (BUN), creatinine Blood sugar Medication levels (such as digoxin) Toxin, alcohol, or carboxyhemoglobin levels if exposure suspected Note Arterial Blood Gas NOT always indicated (may cause problem if thrombolytic used)

Considerations on Calling Consultants on Stroke Cases If Stroke Response Team already designated, call them early May otherwise need to wait till after CT scan is read to call correct consultant for admission –Neurosurgeon if : ƒ Intracranial hemorrhage or trauma ƒ Mass lesion such as tumor ƒ Hydrocephalus or shunt complication –Neurologist if ischemic stroke –Neuroradiologist if angiographic procedure needed –Nephrologist if dialysis or hemoperfusion needed –Intensivist if mechanical ventilation needed

Differential Diagnosis of Stroke Craniocerebral and / or cervical trauma Meningitis / encephalitis Hypertensive encephalopathy Intracranial cyst or tumor Seizure with postictal Todd's Paralysis Complicated migraine Hyperglycemia (nonketotic hyperosmolar coma) Hypoglycemia Medication overdose or toxin exposure

Flipped T waves from subarachnoid hemorrhage

Aspects of Computed Tomography for Stroke Scan can be normal in ischemic stroke 5 to 10 % of SAH cases have normal scan –Lumbar punture then indicated if SAH suspected & scan is normal –Lumbar puncture will exclude later use of thrombolytics Magnetic Resonance Imaging (MRI) can show some ischemic lesions missed by CT scan, but is not as good as CT in detecting hemorrhage

73 year old male presenting with aphasia, neglect, & visual field deficits ; CT (on left) was normal but MRI (on right) showed bilateral occipital infarcts

Subtle changes in right temporal area in scan done 4 hours after infarct

CT scan of same patient on prior slide 24 hours later showing obvious temporal infarct

General Treatment Considerations for Stroke Reverse anticoagulants if hemorrhage Treat fever with aggressive cooling Generally only treat hypertension if : –Systolic BP > 220 mg Hg –Diastolic BP > 120 mm Hg –Mean BP > 130 mm Hg –Usually do NOT drop < 140 systolic or 100 diastolic –Labetolol, enalapril, or nitroprusside are best May need direct Rx of increased intracranial pressure (ICP) Consider nimodipine (60 mg PO q 4h) if SAH & conscious Note heparin never shown by itself to be of benefit

CT scan on left shows left hemispheric infarct on day one ; CT scan on right shows bleed occurring on day 2 after treatment with heparin

Treatment of Increased Intracranial Pressure in Stroke Avoid hypotonic or overload of fluids Keep head of bed elevated 30 degrees Hyperventilation to pCO2 of 26 to 30 mm Hg Mannitol 0.5 to 2 gm/kg IV boluses Furosemide (0.2 to 1.0 mg/kg) or acetazolamide (250 to 500 mg) IV Barbiturates (thiopental or phenobarbital 1 to 5 mg/kg IV) –Cause cardiorespiratory depression so should only be used in ventilated monitored patients

General Considerations for Use of Thrombolytics for Stroke Most studies have shown increased mortality and / or morbidity in patients treated with thrombolytics compared to placebo Only the 1995 NINDS study alledgedly showed benefit –Treated patients 12 % more likely to have minimal or no disability at 3 months –NO improvement in mortality however –Follow-on studies from community hospitals show low enrollment and poorer outcomes than reported in this study at academic centers only

Features of the NINDS Study Reported in 1995 Conducted by the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group Randomized controlled trial Univ. of Cincinatti was lead center for study (8 academic centers enrolled patients) 624 patients enrolled from January 1991 to October 1994 in 2 part sequential study Alteplase (Activase, recombinant tPA) used in treatment arm at dose of 0.9 mg/kg (90 mg max.)

Inclusion Patient Selection Criteria for the NINDS Study Ischemic stroke with : –Clearly defined time of onset –Measureable deficit on the National Institutes of Health Stroke Scale (NIHSS) –No evidence of hemorrhage on CT scan Had to start to receive thrombolytic within 3 hours (180 minutes) since onset of Sx No anticoagulants or antiplatelet agents given for 24 hours after Rx

Exclusion Criteria for the NINDS r-tPA Study Prior stroke or head trauma within 3 months Major surgery within 14 days History of intracranial hemorrhage Rapidly improving or minor symptoms Symptoms suggestive of SAH GI or urinary tract hemorrhage within 21 days Arterial puncture at noncompressible site within 7 days Seizure at onset of stroke Anticaogulants or heparin within 48 hours High PTT, PT > 15 sec., Platelets< 100,000 Serum glucose 400 mg/dl BP > 185 systolic or > 110 diastolic, or "if aggressive Rx required to reduce BP to these limits"

Results of the NINDS r-tPA Study No significant differences in functional outcome in Part 1 of study (333 patients) Overall 3 month mortality 21 % in placebo and 17 % in tPA group (p=NS) In Part 2 patients treated in 91 to 180 minutes, improvement was 40 % in placebo group and 35 % in tPA group NIHSS score was significantly different (favoring tPA) only in Part 2 patients treated within 90 minutes, and in the combined Parts 1 and 2 patients treated within 90 minutes, but not in other subgroups

Adverse Bleeding Results in the r-tPA Treated Patients in the NINDS Study Symptomatic intracranial hemorrhage occurred in 7 % of tPA and < 1 % of placebo patients in first 36 hours – 4 more tPA and 2 more placebo patients had symptomatic bleeds in next 3 months –61 % of patients with symptomatic bleeds died in 3 months "Serious" systemic bleeds occurred in 5 tPA patients and zero placebo patients Minor bleeding occurred in 23 % of tPA patients and 3 % of placebo patients

Precautions About Overextrapolation of the NINDS Study Results No improvement in overall mortality Only 12 % absolute (30 % relative) improvement in function Results are from academic centers with strong interests in the study & dedicated stroke response teams Only applies to small % of total stroke patients Requires strict adherence to protocols

The NIH Stroke Scale (NIHSS) EXAM ITEM SCORE RANGE Level of consciousness (LOC) 0 to 3 LOC Questions 0 to 2 LOC Commands 0 to 2 Best Gaze 0 to 2 Visual Fields 0 to 3 Facial Palsy 0 to 3 Motor Arm and Leg 0 to 9 Limb Ataxia 0 to 9 Sensory 0 to 2 Best Language 0 to 3 Dysarthria 0 to 9 Extinction & Inattention 0 to 2 Distal Motor Function 0 to 2

Interpretation of NIH Stroke Scale Numbers Scale range is from zero (normal) to max. of 42 Those with minor deficits (scale <4) are not candidates for thrombolysis –Exceptions may be severe aphasia (scale = 3), or hemianopsia (scale = 2 or 3) Those with severe deficits (scale > 22) are at increased risk for hemorrhage, & so are also not thrombolytic candidates

3 Cautionary Studies Related to Use of Thrombolytics for Stroke Schriger et al. 1998: showed CT scans to physicians : –67 % correct by emergency physicians, 83 % correct by neurologists, 83 % correct by radiologists –"Physicians in this study did not identify cerebral hemorrhage sufficiently to permit safe selection of candidates for thrombolytic therapy" Engelstein et al –Set up NINDS criteria stroke protocol but had no eligible candidates for 3 years in a busy E.D. Katzan et al –Only 1.8 % of stroke patients received tPA –tPA group mortality was 15.7 % versus 5.1 % nontreated

Other Stroke Thrombolytic Trials With Worse Outcomes in the Thrombolytic Group ECASS-1 (1995, used tPA) ECASS-2 (1998, used tPA) MAST-I (1995, used streptokinase) MAST-E (1996, used streptokinase) ASK (1996, used streptokinase) ATLANTIS (1999, used tPA at 3 to 5 hours)

Study of Danaparoid Treatment of Acute Stroke Reported in JAMA 1998 TOAST Trial ("Trial of ORG in Acute Stroke Treatment") Used danaparoid (ORG 10172), a low molecular weight heparinoid, bolus then infusion for 7 days Randomized, double blind, placebo controlled trial Eligible if stroke Sx between 1 and 24 hours Enrollment of 1281 patients 1990 to 1996 No significant outcome improvement at 3 months 15 intracranial bleeds in ORG group versus 5 in placebo group

The PROACT 2 Study of Prourokinase for Stroke JAMA Dec Prolyse in Acute Cerebral Thromboembolism trial (PROACT) for strokes < 6 hours symptom duration Used intraarterial prourokinase (Prolyse) for MCA clots 12,323 stroke patients screened & 474 (4 %) had angiography, and 180 of these were randomized (121 to Rx group & 59 to control group) No difference in overall mortality Improved functional scores in treated patients Intracranial hemorrhage "with neurological deterioration" in 10 % of treated & 2 % of control patients

Angiogram of a 54 year old male with a left hemispheric stroke, showing embolic occlusion of the left MCA

The STARS Study of tPA for Stroke JAMA March 2000 Standard Treatment with Alteplase to Reverse Stroke (STARS) 57 centers, 389 patients from 1997 to 1998 No control group Patients refusing tPA not reported Protocol violations in 32 % 3.3 % had symptomatic ICH, 8.2 % had asymptomatic ICH 35 % had good outcome (Rankin score 0 to1) at 30 days

The STAT Study for Treatment of Stroke JAMA May 2000 Stroke Treatment with Ancrod (STAT) trial Used defibrinogenating agent Ancrod from Malaysian pit viper 72 hour infusion, begun within 3 hours of stroke onset Followup doses at 96 and 120 hours Mortality 25 % in both treated & placebo groups Improved favorable functional status in Ancrod group (42 % versus 34 %) Symptomatic ICH 5 % vs. 2 %, asymptomatic ICH 19 % vs. 11 % (both higher in Ancrod group)

Other Agents Being Investigated for Stroke Treatment Hopefully will be useful in patients with contraindications to thrombolytics or those presenting late, & also be safer Some act to limit reperfusion injury, & others act to improve or accelerate the neuronal repair process Some trial agents recently reported out as ineffective : –Selfotel –Cerostat –Tirilizad –Lubeluzole –Citocholine –Antiinflammatory agents

Treatment of Stroke in the E.D. : Summary Rule out hypoxia & hypoglycemia quickly & provide other supportive care Activate stroke team early if available Decide secondary Rx and consultants based on stat CT scan Consider use of reperfusion agents in carefully selected patients Obtain rehabilitative services for patient as soon as acute episode treated