Transcript Document 7193599

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
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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
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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 4060ml/100g of brain/min
• When rate is <10ml/100g of brain/min cell
membrane failure occurs:
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 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?
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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
• From carotid system
• Supplies 80% of brain
Posterior Circulation
• From vertebral system
• 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
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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
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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
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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
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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
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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: 12:288293
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
headache with
hemiparesis
• Post-ictal paresis
(Todd’s paresis)
• Hypoglycemia
• Cerebral tumor
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Cerebral infection
Subdural hematoma
Drug intoxication
Malignant
hypertension
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.
2.
3.
4.
5.
6.
Level of consciousness
Visual assessment
Motor function
Cerebellar function
Sensation and neglect
Cranial nerves
Imaging and Lab All patients should have:
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Brain CT
ECG
Serum Glucose
Electrolytes
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Creatinine
CBC
PT/INR
aPTT
Selected Patients
• LFTs
• Tox screen and EtOH
(if uncertain about hx)
• Preg test
• ABG (if hypoxic)
• CXR (if lung
pathology suspected)
• LP (if suspecting SAH
and CT is negative)
• 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:
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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 12min
• 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 90day 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/00201.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 placebocontrolled 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_archivedetail.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 nondominant 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
Consciousness-3
• LOC of questions-2
• LOC of Commands-2
• Best Gaze-2
• Visual Fields-3
• Facial Palsy-3
• Motor Arm: L and R-4
each
• Motor Leg: L and R-4
each
• Limb Ataxia-2
• Sensory-2
• Best Language-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 - (16880)/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.