STROKE

Bruke B. (BPharm, MSc clinical pharmacy, PhD in cardio

therapy, clinical pharmacy) WCU, Ethiopia

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INTRODUCTION
·  Stroke is an abrupt-onset focal neurologic deficit that
lasts at least 24 hours and is of presumed vascular origin.
· A TIA is the same but lasts <24 hrs & usually <30
minutes.

· Stroke can be either ischemic or hemorrhagic (87% and

13%, respectively, of all strokes in the 2012 AHA report).

· Hemorrhagic stroke, although less common, is

significantly more lethal than ischemic stroke, with 30-
day case-fatality rates that are two to six times higher.
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 Types of Stroke

· Ischemic
· Hemorrhagic

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EPIDEMIOLOGY

· There are currently 6.5 million stroke survivors in the US.

· Stroke (ischemic + hemorrhagic) is the leading cause of
adult disability & the 4th leading cause of death in the US,
behind CVD, cancer & chronic lower respiratory
diseases.
· African Americans have stroke rates twice those of
whites.
· According to the latest WHO data published in April
2011 Stroke Deaths in Ethiopia reached 54,816 or 6.67%
of total deaths.
The 2nd leading cause of death in Ethiopia
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1. ISCHEMIC STROKE
· DEFINITION
Interruption of blood flow to area of brain, causing
death of brain cells in area.
· ETIOLOGY
Local thrombus formation (e.g., cerebral
atherosclerosis)
Emboli from intra- or extracranial arteries that occlude
cerebral artery
Unknown causes

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PATHOPHYSIOLOGY
· Carotid atherosclerosis: Ruptured plaques lead to
thrombus formation that may cause local occlusion or
dislodge and travel distally, eventually occluding cerebral
vessel.
· Cardiogenic embolism: Stasis of blood flow in atria or
ventricles leads to formation of clots that dislodge and
travel through aorta to cerebral circulation.
 Resulting arterial occlusion decreases cerebral blood
flow and causes ischemia and infarction distal to
occlusion.

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Pathophysiology 
of ischemic stroke
1. In situ thrombosis of
an intracranial vessel,
typically affecting the
small penetrating
arteries, and
2. Hypoperfusion
caused by flow-
limiting stenosis of a
major extracranial
artery. 
3. Occlusion of an
intracranial vessel by
an embolus that
arises from a distant
site (e.g., cardiogenic
embolus),

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RISK FACTORS
· Nonmodifiable risk · Major modifiable, well
factors: documented risk
Increased age factors:
Male sex Hypertension
Race (African Cardiac disease (esp.
Americans, Asian– atrial fibrillation)
Pacific Islanders, Diabetes mellitus
Hispanics) Dyslipidemia
Family history of stroke Cigarette smoking
Low birth weigh
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CLINICAL PRESENTATION
· May need to obtain medical history from family members
or others because cognitive or language deficits may
preclude patient from giving reliable history.
· Signs and Symptoms
· Symptoms:
Weakness on one side of body
Inability to speak
Loss of vision
Vertigo
Falling
Headache
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· Signs of neurologic dysfunction depend on brain
area involved.
Hemi- or monoparesis and hemisensory deficits
common.
Posterior circulation involvement may present with
vertigo and diplopia/double vision.
Anterior circulation strokes result in aphasia/loss of
language.
Other potential signs:
• Dysarthria-difficulty in speech articulation
• Visual field defects
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• Altered levels of consciousness may be present.
· Sudden, severe headache, often with transient loss of
consciousness at onset; vomiting is common in
hemorrhagic stroke.

· Headache and loss of consciousness are uncommon

in ischemic stroke.

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DIAGNOSIS
· Laboratory Tests
Obtain tests for hypercoagulable states (protein C,
protein S, antithrombin III) only when cause cannot be
determined based on review of risk factors.

Obtain antiphospholipid antibodies in patients

younger than age 50 and those who have had multiple
thrombotic events or livedo reticularis.

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· Imaging
CT head scan
MRI of head reveals ischemic areas with higher resolution and earlier
than CT scan.
Carotid Doppler (CD) studies can identify degree of stenosis in carotid
arteries.
Transthoracic echocardiogram (TTE) can detect valve or wall motion
abnormalities that are sources of emboli.
Transesophageal echocardiogram (TEE) more sensitive for left atrial
thrombus.
Transcranial Doppler (TCD) can determine presence of intracranial
sclerosis (e.g., middle cerebral artery stenosis).

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· Diagnostic Procedures
ECG to determine whether atrial fibrillation is
possible cause.
· Differential Diagnosis
Hypoglycemia
Transient ischemic attack
Intracerebral hemorrhage or other mass lesion (e.g.,
tumor)
Focal seizure
Migraine
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DESIRED OUTCOMES

· The goals of treatment of acute stroke are to:

Reduce ongoing neurologic injury.
Decrease mortality and long-term disability.
Prevent complications secondary to immobility and
neurologic dysfunction.
Prevent stroke recurrence.

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 TREATMENT

· GENERAL APPROACH
Ensure adequate respiratory and cardiac support.
Determine quickly whether lesion is ischemic or hemorrhagic
based on CT scan.
Evaluate ischemic stroke patients presenting within hours of
symptom onset for reperfusion therapy.
TIAs also require urgent intervention to reduce the risk of
stroke, which is known to be highest in the first few days
after TIA.

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 BP vs Stroke
· Do not normalize elevated BP in acute period (first 7 days)
because of risk of decreasing cerebral blood flow & worsening
symptoms.
Lower BP if it exceed 220/120 mmHg or if there is evidence
of:
• Aortic dissection
• Acute myocardial infarction (MI)
• Pulmonary edema
• Hypertensive encephalopathy
If treating BP in the acute phase is a must, use short-acting
parenteral agents, for example: Labetalol, Nicardipine or
Nitroprusside
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Blood Pressure Treatment Guidelines in Acute
Ischemic Stroke Patients
Treatment Received t-PA Did Not Receive t-PA
None <180/105 < 220/120
Labetalol IV or 180–230/105–120 >220/121–140
Nicardipine IV
Nitroprusside Diastolic >140 Diastolic >140

 Labetalol IV = 10–20 mg, doubled every 10–20 minutes, to a

maximum of 300 mg. Also can use an infusion of 2–8 mg/min.
 Nicardipine IV = infusion starting at 5 mg/h up to 15 mg/h.
 Nitroprusside IV = infusion starting at 0.5 mcg/kg/min, with
continuous arterial blood pressure monitoring.
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· After acute phase, focus attention on:
Preventing progressive deficits (worsening)
Minimizing complications
Instituting appropriate secondary prevention strategies

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 NONPHARMACOLOGIC THERAPY
· Interdisciplinary approach to stroke care that includes early
rehabilitation reduces long-term disability.
· Surgical interventions in the acute ischemic stroke patient are
limited.
· In cases of significant swelling associated with a cerebellar
infarction, surgical decompression can be lifesaving.
· Carotid endarterectomy or stenting may be effective in
reducing recurrent stroke risk in appropriate patients.

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PHARMACOLOGIC THERAPY

· In general, the only two pharmacologic agents with

class I recommendations are:
intravenous t-PA (Alteplase) within 4.5 hours of
onset &
aspirin within 48 hours of onset.
· t-PA (Alteplase); early reperfusion
Reduces ultimate disability if initiated within 4.5
hours of symptom onset.

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 t-PA
· In the National Institute of Neurologic Disorders and Stroke
(NINDS) rtPA Trial, 624 patients were treated in equal numbers
with either tPA 0.9 mg/kg IV or placebo within 3 hours of
symptoms onset,
Minimal or no disability: 39% at 3 months VS 26%
Risk of ICH: 6.4% vs. 0.6%; a 10-fold ↑in the tPA-treated pts
Overall mortality was not significantly d/t; 17% VS 21%
The tPA group had better outcomes at 90 days even in patients at
highest risk for bleeding.

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· 13 yrs after the NINDS trial, the European Cooperative Acute
Stroke Study (ECASS) III demonstrated that, even when
administered b/n 3 & 4.5 hrs after the onset of symptoms, tPA
is beneficial vs placebo (52.4% vs. 45.2% excellent
outcome; P = 0.04).

· The International Stroke Trial (IST)-3: 3,035 patients treated

within 6 hours of ischemic stroke onset, reported that even
patients outside the rigid criteria set forth by both the NINDS
and ECASS III trials may experience improved functional
outcome.
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· Caution must be exercised when using this therapy, and
adherence to a strict protocol is essential to achieving positive
outcomes.
1. Activate stroke team.
2. Treat as early as possible within 4.5 hours of onset.
3. Obtain CT scan to rule out hemorrhage.
4. Meet all alteplase inclusion and no exclusion criteria.
5. Administer alteplase 0.9 mg/kg (maximum 90 mg) infused IV over 1
hour, with 10% given as initial bolus over 1 minute.
6. Avoid anticoagulant and antiplatelet therapy for 24 hours.
7. Monitor patient closely for: Elevated BP, Response, Hemorrhage

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 Inclusion and Exclusion Criteria for Alteplase Use
in Acute Ischemic Stroke

· Inclusion Criteria (all YES boxes must be checked before

treatment)
· YES    
Age 18 years or older
Clinical diagnosis of ischemic stroke causing measurable
neurologic deficit
Time of symptom onset well established to be <4.5 hours
before treatment would begin

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26
Antiplatelet Agents

· Antiplatelet therapy is the cornerstone of antithrombotic

therapy for the secondary prevention of ischemic stroke
and should be used in noncardioembolic strokes.

· ASA (is best studied), clopidogrel, and Extended-

release dipyridamole plus aspirin (ERDP-ASA) are
considered first-line antiplatelet agents.

· Cilostazol is also a recommended first-line antiplatelet

agent, but its use has been limited by a lack of data in
other than Asian populations.
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Aspirin

· Aspirin 50–325 mg/day started between 24–48 hours

after completion of alteplase reduces long-term disability
and death.
But it should never be given within 24 hours of the
administration of tPA because it can increase the risk
of bleeding in such patients.

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Oral Anticoagulants

· In patients with atrial fibrillation and a presumed cardiac

source of embolism, oral anticoagulation is recommended for
secondary stroke prevention.
· In the European Atrial Fibrillation Trial (EAFT), 669 patients
were randomized to warfarin (INR = 2.5 to 4), ASA 300
mg/day, or placebo.
Patients in the placebo group experienced stroke, MI, or vascular
death at a rate of 17% per year compared with 8% per year in the
warfarin group and 15% per year in the ASA group.
This represents a 53% reduction in risk with anticoagulation.

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· Use of warfarin (INR = 1.4 to 2.8) in the secondary
prevention of noncardioembolic stroke was not superior to
ASA 325 mg/day.
· Other pharmacotherapy recommended for secondary
prevention of stroke includes blood pressure lowering
and statin therapy.
· The Stroke Prevention by Aggressive Reduction
in Cholesterol (SPARCL) study demonstrated that
atorvastatin 80 mg daily reduced the risk of recurrent stroke
by 16% and coronary events by 42% in patients with no
cardiac history.

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Heparin for Prophylaxis of DVT
· The use of LMWHs or low-dose subcutaneous UFH
(5,000 units three times daily) can be recommended
for the prevention of DVT in hospitalized patients
with decreased mobility owing to their stroke and
should be used in all but the most minor strokes.

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 Recommendations for Pharmacotherapy of Ischemic
RecommendationStroke Evidencea
Acute treatment Alteplase 0.9 mg/kg IV (max 90 mg) over 1 hr in select patients IA
  within 3 hr of onset
  Alteplase 0.9 mg/kg IV (max 90 mg) over 1 hr between 3 and 4.5 hr IB
of onset
Aspirin 160–325 mg daily started within 48 hr of onset IA
Secondary prevention
Noncardioembolic Antiplatelet therapy IA
 
  Aspirin 50–325 mg daily IIa A (all 3 as
  initial options)
Clopidogrel 75 mg daily IIb B
(over aspirin)
Aspirin 25 mg + extended-release dipyridamole 200 mg twice daily IIa A
(over aspirin)
Cardioembolic Warfarin (INR = 2.5) IA
(esp. atrial fibrillation)
All patients Antihypertensive treatment IA
Previously hypertensive ACE inhibitor + diuretic IA
Previously normotensive ACE inhibitor + diuretic IIa B
Dyslipidemic Statin IA
Normal lipids Statin IB 32
PROGNOSIS

· Prognosis for survival better after ischemic than

hemorrhagic stroke.
· Extent of infarct determines potential for
rehabilitation.

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2. HEMORRHAGIC STROKE
· Hemorrhagic strokes include
1. Subarachnoid H. when blood enters the subarachnoid space
(where CSF is housed) owing to either trauma, rupture of an
intracranial aneurysm, or rupture of an arteriovenous
malformation (AVM).
2. Intracerebral H. when a blood vessel ruptures within the
brain parenchyma itself, resulting in the formation of a
hematoma mainly associated with uncontrolled high blood
pressure and sometimes antithrombotic or thrombolytic
therapy.
3. Subdural hematomas refer to collections of blood below
the dura (covering of the brain), and they are caused most
often by trauma.
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35
PATHOPHYSIOLOGY
· The pathophysiology of hemorrhagic stroke is not as well
studied as that of ischemic stroke.
· However, blood in the brain parenchyma damages brain
tissue through the mechanical effect it produces (mass
effect) and the neurotoxicity of its components and their
degradation products.
· Clot volume is the most important predictor of outcome,
regardless of location; >60 mL are associated with 71% to
93% mortality at 30 days.
· ~50% mortality is caused by the abrupt ↑in ICP that can lead
to herniation and death.

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 MANAGEMENT

· Currently no standard pharmacologic strategies for treating ICH.

· Manage of BP, raised ICP, & other medical complications of
ICH.
· When ICH occurs in a patient on warfarin (INR >1.3), rapid
reversal of anticoagulation to prevent expansion and allow
surgical intervention is recommended.
intravenous vitamin K, fresh-frozen plasma (FFP) & hemostatic agents
(factor VIIa and prothrombin-complex concentrate (PCC).
· The optimal approach is yet to be determined.

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· In patients with SAH, if an aneurysm is found by angiography,
endovascular coiling or clipping via a craniotomy should be
performed to reduce the risk of rebleeding.

· In ICH, patients may require external ventricular drainage

(EVD) if there is intraventricular blood and evolving
hydrocephalus (enlargement of the ventricles).

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· SAH owing to aneurysm rupture is associated with a
high incidence of delayed cerebral ischemia (DCI).
· Vasospasm of the cerebral vasculature is thought to
be responsible for DCI and occurs between 4 and 21
days after the bleed, peaking at days 5 through 9.
· The CCB nimodipine (60 mg Q4 hrs x21 days), along
with maintenance of intravascular volume with
pressor therapy, is recommended to reduce the
incidence and severity of neurologic deficits owing to
DCI.
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 Intracranial pressure control

· Increased intracranial pressure (ICP) due to ICH can

result from the hematoma itself and from surrounding
edema, and may contribute to brain injury and
neurologic deterioration.
· approach to the management of elevated ICP, beginning
with simple measures
 Elevate the head of the bed to 30 degrees, once
hypovolemia is excluded.
 Analgesia & sedation, particularly in unstable, intubated
patients
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Intracranial pressure control

· Glucocorticoids should not generally be used to

lower the ICP in patients with ICH.
A randomized trial found that dexamethasone did not
improve outcome but did increase complication rates,
primarily infection.

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 Intracranial pressure control
· Intravenous mannitol is the treatment of choice to lower
increased ICP, effectively lowering ICP and benefiting brain
metabolism.
· Dose: an initial bolus of 1 g/kg, followed by infusions of 0.25 to
0.5 g/kg every six hours.
· The goal of therapy is to achieve plasma hyperosmolality (300 to 310
mosmol/kg) while maintaining an adequate plasma volume.
· major side effects include hypovolemia & a hyperosmotic state
· Normal saline initially should be used for maintenance and
replacement fluids;
hypotonic fluids are contraindicated. 
· Mild hypernatremia should be tolerated, but marked 42
hyperosmolality should be avoided to prevent precipitation
Blood pressure control

· MAP is often elevated in patients with ICH.

· Severe elevations in BP may worsen ICH by
representing a continued force for bleeding

· However, an increased MAP may be necessary to

maintain cerebral perfusion in some patients
lowering the arterial pressure (eg, SBP below 130
mmHg) may cause ischemia and worsen neurologic
injury.

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Blood pressure control

· If SBP is >200 mm Hg or MAP is >150 mm Hg,

then consider aggressive reduction of blood
pressure with continuous IV meds monitor BP q 5
minutes.

· If SBP is >180 mm Hg or MAP is >130 mm Hg and

there is suspicion of increased ICP,
reducing BP using intermittent or continuous IV
meds to keep Coronary perfusion pressure (CPP)
>60 to 80 mm Hg
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Blood pressure control

· If SBP is >180 mm Hg or MAP is >130 mm Hg and

no suspicion of elevated ICP,
then consider a modest reduction of blood
pressure (eg, MAP of 110 mm Hg or target blood
pressure of 160/90 mm Hg)
• using intermittent or continuous IV medications to
control BP, and clinically reexamine the patient
every 15 minutes.

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EVALUATION OF THERAPEUTIC
OUTCOMES

· Patients with acute stroke should be monitored intensely

for:
neurologic worsening (recurrence or extension),
complications (thromboembolism or infection), or
adverse effects from interventions

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 Quize

1. Which one of the following is a category of stork with high

mortality than others
A) Hemorogic stroke B) Ischemic stroke, C) Transient
Ischemic Attack
2. Which one is not a modifiable risk factor for stroke
A) HTN, B) AF C) DM D) Dyslipidemia E) Low birth
weigh
3. Pharmacologic agents with class I recommendation in the
emergency management of stroke are the following, except
A) Fibrinolytics within 3-.5 hours B) Aspirin within 48 47
hours
 Quize

4. Which one of the following is incorrect matches in the

secondary management of Stroke recurrence
A) Aspirin for Noncardioembolic source of stroke
B) Warfarin for Cardioembolic source of stroke
C) Clopidogrel for cardioembolic stroke
5) One of the following is the absolute contraindication to not
to use the fibrinolytic drugs
A) Age > 18 years,
B) Hemorrhagic stroke
C) Previous year Ischemic stroke history
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 Quize
6) Which antilipid drugs is preferably recommended in stroke
secondary preventions
A) Statins B) Bile acid resins C) Niacin

7) Which one of medications are recommended for secondary

prevention of stroke regardless of underling disorder
A) Antihypertensves B) Antilipid medications C) All of the
above

8) Which one will be the pathophysiologic insults for stroke

A) Hypoperfusion induced stenosis B) Emboli C) local
cranial thrombus 49
Say True or false

9) Ischemic stroke is define if neurologic complication

is less than 24 hours. T
10) One sided body weakness is the usual clinical
presentation in stroke. T

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