Neurol Clin 26 (2008) 345371

Management of Acute Ischemic Stroke

Anna Finley Cauleld, MD*,
Christine A.C. Wijman, MD, PhD
Department of Neurology and Neurological Sciences, Neurocritical Care Program,
Stanford Stroke Center, Stanford University School of Medicine, 701 Welch Road,
B-325, Palo Alto, CA 94304, USA

Stroke is the third leading cause of death and the leading cause of disability in the United States and is associated with a tremendous cost burden to society [1]. Most strokes are ischemic, but about 15% of strokes
are caused by intracerebral or subarachnoid hemorrhage. Currently, there
is only one drug approved by the US Food and Drug Administration
(FDA), intravenous tissue plasminogen activator (tPA), for the treatment
of acute ischemic stroke within 3 hours of symptom onset [2]. Many stroke
patients do not receive intravenous tPA, however, most commonly because
they present beyond the 3-hour therapeutic window. More recently developed therapeutic strategies oer the hope of safe and eective treatment
beyond the 3-hour time window in selected patients. This article is an update of a recent publication that reviewed established and novel treatments
for acute ischemic stroke and the management issues that may arise in the
rst hours to days after symptom onset [3]. Blood pressure management,
management of intracranial hypertension, and temperature management
are discussed in greater detail elsewhere in this issue.

Initial management
The initial management of acute ischemic stroke involves medical stabilization, including airway protection and ventilatory and hemodynamic
Material for this article is reprinted in part from the American Academy of Neurology
2006 meeting syllabus titled Critical Care for Cerebrovascular Patients: What General
Neurologists Need to Know; with permission.
This is an updated version of an article that originally appeared in Critical Care Clinics,
volume 22, issue 4.
* Corresponding author.
E-mail address: afinley@stanford.edu (A. Finley Caulfield).
0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ncl.2008.03.016
neurologic.theclinics.com

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support, followed by neurologic assessment, brain imaging, and evaluation

of the appropriateness of thrombolytic therapy [4,5].
Airway and ventilatory support
Patients with acute stroke are at risk for respiratory failure from aspiration and pneumonia [6,7] often in the setting of diculty protecting the airway and clearing secretions because of facial or bulbar weakness or an
altered level of consciousness [8]. Hypoxemia may worsen the injurious effects of cerebral ischemia, and patients must be monitored closely with
a goal to keep oxygen saturation greater than 95% [4]. If a patient requires
endotracheal intubation, short-acting sedatives should be used, and the hemodynamic changes associated with intubation should be minimized
[5,9,10]. No prospective trials have been undertaken to establish the ideal
mode of ventilation in intubated stroke patients. A commonly used mode
for patients who are awake but in need of airway protection is pressure support ventilation, whereas synchronized intermittent mandatory ventilation
or assist control ventilation is recommended for patients who have intracranial hypertension or are comatose [5]. Excessive positive end-expiratory
pressures (ie, O10 cm H2O) may be deleterious in patients with elevated
intracranial pressure (ICP) [11,12].
Mechanically ventilated patients frequently require sedation; however,
sedatives may cause hypotension and additional brain injury by lowering cerebral perfusion pressure [1315]. Propofol, popular because of its short duration of action, has been associated with a propofol infusion syndrome
when used at high doses for prolonged periods. This syndrome originally
was described in pediatric patients, but it also can occur in adults. It presents
with metabolic acidosis, rhabdomyolysis, hypotension, bradyarrhythmias,
and death [16]. Frequent discontinuation of sedatives is indicated to monitor
carefully for changes in the patients neurologic status.
Blood pressure and uid management
Patients with acute ischemic stroke often have elevated blood pressures in
the rst few days after symptom onset. Elevated blood pressure may occur
for a variety of reasons, including physiologic compensation for cerebral ischemia, increased ICP, pain, or long-standing underlying hypertension [4].
Theoretic advantages of treating hypertension in acute ischemic stroke include concerns for hemorrhagic transformation of the ischemic infarct
and worsening cerebral edema. Lowering blood pressure may compromise
cerebral blood ow in the area surrounding the infarct, however, resulting
in stroke extension.
In normotensive individuals, cerebral blood ow is maintained over
a wide range of mean arterial pressures (50150 mm Hg) [17,18]. Chronically
hypertensive patients require a higher range of mean arterial pressures to

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347

maintain normal cerebral blood ow [1921]. Because many stroke patients

have long-standing hypertension, blood pressure lowering may result in cerebral hypoperfusion and worsening ischemia. It is generally accepted that
elevated blood pressures should not be lowered, unless the patient has received thrombolytic treatment; has a hypertensive emergency (aortic dissection, hypertensive encephalopathy, acute renal failure, acute pulmonary
edema, or acute myocardial infarction); or has another contraindication
to elevated blood pressure, such as recent surgery. In the absence of controlled clinical trials, the American Stroke Association guidelines recommend that antihypertensive agents should be withheld unless the systolic
blood pressure is greater than 220 mm Hg or the diastolic blood pressure
is greater than 120 mm Hg [20,2225]. If patients have received thrombolytic
therapy, the guidelines advocate maintaining systolic blood pressure less
than or equal to 180 mm Hg and diastolic blood pressure less than or equal
to 105 mm Hg [2,2225]. If blood pressure lowering is indicated, it should be
instituted cautiously to avoid hypotension. A variety of intravenous agents
may be used to lower blood pressures. a- and b-adrenergic blockers (labetalol), calcium channel blockers (nicardipine), and angiotensin-converting enzyme inhibitors (enalaprilat) are preferred in patients with acute stroke
because these agents are less likely to cause cerebral vasodilation and ICP
elevation, eects that might be anticipated with sodium nitroprusside or
hydralazine [4,5,2630].
Some patients with acute cerebral ischemia resulting from severe extracranial or intracranial vessel stenosis may benet from induced hypertension
[31]. Typically, mean arterial pressure is increased 20% to 25% from baseline using intravenous isotonic uids, phenylephrine, dopamine, or norepinephrine, while the patients neurologic status and hemodynamic stability
are monitored closely. The impact of this therapy on stroke outcome is
being evaluated in ongoing clinical trials.
In patients with ischemic brain injury, a key therapeutic goal is to maximize brain perfusion and collateral blood ow to the injured area. It is
important to assess the patients volume status and correct any dehydration. Because stroke patients may be dehydrated on admission, and
many of them cannot tolerate intake of oral uids, normal saline infusions
typically are started immediately. Hypotonic uids should be avoided because these may contribute to worsening cerebral edema and increased
ICP [32].
Neurologic examination
Assessing the patient for neurologic decits may be accomplished in an
ecient and reproducible manner by using the National Institutes of Health
Stroke Scale (NIHSS) [25,33,34]. This is a series of neurologic tests designed
to assess the patients level of alertness; comprehension; and motor, sensory,
visual, and language function (Table 1) [2].

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Table 1
The National Institutes of Health Stroke Scale
Tested item

Title

Responses and scores

1a

Level of consciousness

1b

Orientation questions (two)

1c

Response to commands (two)

Gaze

Visual elds

Facial movement

Motor function arm

a. left
b. right

Motor function leg

a. left
b. right

Ataxia

Sensory

Language

0
1
2
3
0
1
2
0
1
2
0
1
2
0
1
2
3
0
1
2
3
0
1
2
3
4
0
1
2
3
4
0
1
2
0
1
2
0
1
2
3
0
1
2
0
1
2

10

Articulation

11

Extinction or inattention

Alert
Drowsy
Obtunded
Coma/unresponsive
Answers both correctly
Answers one correctly
Answers neither correctly
Performs both tasks correctly
Performs one task correctly
Performs neither task
Normal horizontal movements
Partial gaze palsy
Complete gaze palsy
No visual eld defect
Partial hemianopsia
Complete hemianopsia
Bilateral hemianopsia
Normal
Minor facial weakness
Partial facial weakness
Complete unilateral paralysis
No drift
Drift before 10 seconds
Falls before 10 seconds
No eort against gravity
No movement
No drift
Drift before 5 seconds
Falls before 5 seconds
No eort against gravity
No movement
Absent
Ataxia in one limb
Ataxia in two limbs
Normal
Mild sensory loss
Severe sensory loss
Normal
Mild aphasia
Severe aphasia
Mute or global aphasia
Normal
Mild dysarthria
Severe dysarthria
Normal
Mild (loss 1 sensory modality)
Severe (loss 2 modalities)

Adapted from the National Institutes of Neurological Disorders and Stroke (NINDS).
National Institute of Health Stroke Scale. Available at http://www.ninds.nih.gov/doctors/
index.htm.

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Diagnostic work-up
Brain imaging
CT and MRI can assess rapidly the type of stroke (hemorrhagic versus
ischemic) and the condition of the cerebral vasculature. Advances in CT
and MRI techniques of cerebral perfusion hold the promise of identifying
patients with salvageable brain tissue who could benet from recanalization
therapies beyond the 3-hour time window.
The most widely used and available brain imaging technology is CT. A
noncontrast head CT scan quickly excludes an intracranial hemorrhage
and sometimes reveals an occluded artery that appears hyperdense because
of fresh clot in the vessel lumen (Fig. 1A). The admission CT scan also may
show early signs of infarction, including swelling of the brain parenchyma
(sulcal eacement); hypoattenuation (hypodensity) of the brain parenchyma; or loss of gray-white matter dierentiation (Fig. 1B) [3537]. Early
signs of cerebral infarction in the 3-hour time window slightly increase the
risk of hemorrhagic transformation after intravenous tPA, but are not considered a contraindication for tPA treatment [38]. A large area of hypodensity on the admission CT scan obtained within the 3-hour time window is
uncommon, however, and warrants verication of the accuracy of the reported time of symptom onset. Because a noncontrast head CT scan may
fail to detect subarachnoid hemorrhage in approximately 10% of cases,
a lumbar puncture to assess for the presence of subarachnoid blood is mandatory in patients who present with a clinical history of a sudden severe
headache and a normal brain CT scan [39].
CT angiography of the head and neck may be used to assess the intracranial and cervical circulation for stenoses and occlusions [40]. CT angiography uses a helical scanner to map out a contrast bolus as it passes through
the vessels. It requires adequate peripheral intravenous access for injection
of an iodine-based contrast bolus (150170 mL). Although CT angiography
increases the incidence of renal dysfunction, this risk is relatively small; in
one series of patients undergoing cerebral CT angiography and CT perfusion, only 4 (0.37%) of 1075 subjects had an increase in creatinine equal
to or greater than 0.5 mg/dL [41]. CT angiography may be particularly useful in patients who present just outside of the treatment window for intravenous thrombolysis, and who may be candidates for intra-arterial clot lysis
because it can provide valuable information as to the location and extent
of the clot. CT angiography also may be useful to assess the head and
neck vessels in patients who cannot undergo MRI because of the presence
of pacemakers or other metal objects in the body, claustrophobia, or critical
illness precluding extended periods in a MRI scanner. Perfusion CT assesses
cerebral perfusion of the brain by tracking the rst pass of an intravenously
administered bolus of contrast material using helical CT scanning [42]. This
technique is promising because of its ability to measure absolute cerebral

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Fig. 1. Nonenhanced brain CT scan obtained approximately 3 hours after sudden onset of leftsided weakness. (A) Hyperdense signal (hyperdense middle cerebral artery sign) is present in the
right middle cerebral artery consistent with a large clot. (B) Subtle early infarct signs with loss of
gray-white matter dierentiation are seen in the corresponding right middle cerebral artery territory (arrows).

blood ow to help identify the degree of reversibility of brain injury, but it is

limited in that not all vascular territories can be imaged completely. Several
studies have found that perfusion CT may be capable of dierentiating between regions of brain infarction and ischemic penumbra [43]. A complete
CT examination including noncontrast CT, CT angiography, and perfusion
CT can be performed in approximately 10 minutes [42].
MRI has better resolution of the brain parenchyma and, in particular,
evaluates the brainstem and cerebellum with higher resolution than
CT [44]. MRI diusion-weighted imaging (DWI) detects early cytotoxic
edema by measuring the random diusion of water molecules, which is restricted almost immediately in ischemic brain injury because of failure of
the energy-requiring active sodium and water transport mechanism. DWI
shows an abnormal signal within minutes of ischemia onset, whereas noncontrast brain CT may take several hours for an infarction to become apparent [4547]. Not all brain lesions with restricted diusion are caused
by cerebral infarcts. Brain tumors, seizures, brain infections, CreutzfeldtJakob disease, and toxic-metabolic disorders sometimes also cause areas
of brain injury with restricted diusion on DWI. Magnetic resonance angiography evaluates the blood vessels of the brain and neck. When it is used
without a contrast agent, magnetic resonance angiography creates vessel images by taking advantage of the ow voids caused by moving blood in the
magnetic eld. One of the drawbacks of magnetic resonance angiography
is that it may overestimate the degree of arterial stenosis or give the impression of an arterial occlusion when a complete occlusion may not exist.

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Contrast-enhanced magnetic resonance angiography is thought to decrease

the likelihood of overestimation of the severity of luminal stenosis [48,49].
MRI perfusion-weighted imaging (PWI) was developed to measure relative blood ow in the brain. A bolus injection of paramagnetic contrast
agent is given and tracked on the rst pass through the brain parenchyma.
A variety of parameters may be measured from this injection and displayed
on perfusion maps, including bolus arrival time, mean transit time, and relative cerebral blood volume [42,46,50,51]. Perfusion maps may take 5 to
40 minutes of postprocessing time. The use of PWI and DWI may identify
patients who would benet from recanalization therapy outside the established 3-hour time window for intravenous tPA. An example of a patient
in the 3- to 6-hour window with a mismatch between a large perfusion decit
and a small diusion abnormality and a persistent corresponding vessel occlusion is presented in Fig. 2 [52]. The patient received intravenous tPA 3 to

Fig. 2. MRI of the brain with diusion-weighted imaging (DWI) on the left, perfusionweighted imaging (PWI) in the middle, and magnetic resonance angiography on the right.
(Top row) MRI obtained approximately 5 hours after acute onset of aphasia and right-sided
weakness showing a small area of infarction (white) on DWI, a large area of decreased perfusion
of the left middle cerebral artery brain territory (white) at risk for infarction on PWI, and absent
ow in the left middle cerebral artery ow on magnetic resonance angiography. (Bottom row)
MRI obtained 4.5 hours later (after intravenous tissue plasminogen activator [tPA] administration) shows marked improvement in the PWI and reconstitution of ow in the left middle
cerebral artery. There is a marked improvement in neurologic function (National Institutes
of Health Stroke Scale [NIHSS] changed from 16 to 5) and no growth of the DWI lesion.
(Courtesy of Gregory W. Albers, MD, Palo Alto, CA.)

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6 hours after symptom onset, which resulted in vessel recanalization and resolution of the PWI decit. The patients neurologic status improved substantially (NIHSS improved from 16 to 5). If the vessel had remained
occluded, the DWI lesion likely would have grown to the size of the corresponding PWI lesion, reducing the chances of clinical improvement.
Emergent laboratory evaluation and other tests
In addition to brain imaging, several laboratory tests must be performed
expeditiously to evaluate whether the patient is a candidate for tPA, including a complete blood count, coagulation parameters, and serum glucose
(Box 1) [2,4,22,53]. An electrocardiogram is indicated in all patients with
acute stroke to detect myocardial ischemia and cardiac arrhythmias, such
as atrial brillation. Blood urea nitrogen and creatinine levels should be
checked, in particular in patients who will be exposed to iodine-based contrast agents. In selected patients, one should consider obtaining (1) arterial
blood gas measurements; (2) cardiac biomarkers, including troponin and
brain natriuretic peptide; (3) liver function tests and ammonia level (for
patients with an unexplained altered level of consciousness); (4) chest
radiograph (for patients with respiratory distress or hypoxia); (5) blood cultures (for patients with fever raising a concern for septic emboli); (6) urine
toxicology screen (for patients with possible substance abuse); (7) electroencephalogram (for suspected seizures); (8) lumbar puncture (for suspected
meningitis or subarachnoid hemorrhage); and (9) CT of the cervical spine
if neck trauma has occurred or is suspected [4].
Treatment of acute ischemic stroke
Antiplatelet therapy in acute ischemic stroke
For patients who are not eligible for tPA, aspirin is the only antiplatelet
drug that has been evaluated in the acute treatment of stroke. The Chinese
Acute Stroke Trial enrolled 21,106 patients to receive aspirin, 160 mg/d, or
placebo within 48 hours of stroke onset with continued therapy for 4 weeks
[54]. The aspirin-treated group had a small but signicant decrease in mortality (3.3% versus 3.9%; P .04) and recurrent ischemic stroke (1.6% versus 2.1%; P .01). The International Stroke Trial enrolled 19,435 patients
for randomized treatment with aspirin alone (300 mg/d), subcutaneous heparin alone, aspirin and heparin combined, or neither agent within 48 hours
of stroke onset [55]. In the aspirin-only group, there were signicantly fewer
recurrent strokes within the rst 2 weeks (2.8% versus 3.9%) and a trend
toward a reduction of death or dependence at 6 months (61.2% versus
63.5%). Based on the results of these trials, most experts agree that patients
should be treated within 48 hours of ischemic stroke with aspirin [25,53]. In
patients who receive tPA, antiplatelet therapy should start 24 hours after
thrombolytic therapy [2,4,22,25,53].

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Box 1. Characteristics of patients with ischemic stroke who

could be treated with recombinant tissue plasminogen activator
Diagnosis of ischemic stroke causing measurable neurologic
deficit
Neurologic signs should not be clearing spontaneously
Neurologic signs should not be minor and isolated
Caution should be exercised in treating a patient with major
deficits
Symptoms of stroke should not suggest subarachnoid
hemorrhage
Onset of symptoms less than 3 hours before beginning treatment
No head trauma or prior stroke in previous 3 months
No myocardial infarction in the previous 3 months
No gastrointestinal or urinary tract hemorrhage in previous
21 days
No major surgery in the previous 14 days
No arterial puncture at a noncompressible site in the previous
7 days
No history of previous intracranial hemorrhage
Blood pressure not elevated (systolic <185 mm Hg and diastolic
<110 mm Hg)
No evidence of active bleeding or acute trauma (fracture) on
examination
Not taking an oral anticoagulant, or if anticoagulant being taken,
international normalized ratio is 1.7 or less
If receiving heparin in previous 48 hours, activated partial
thromboplastin time must be in normal range
Platelet count equal to or greater than 100,000 mm3
Blood glucose concentration equal to or greater than 50 mg/dL
(2.7 mmol/L)
No seizure with postictal residual neurologic impairments
CT does not show a multilobar infarction (hypodensity greater
than one third cerebral hemisphere)
Patient or family members understand the potential risks and
benefits from treatment
From Adams H, Adams R, Del Zoppo G, et al. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines updateda scientific statement from the Stroke Council of the American Heart Association/American Stroke
Association. Stroke 2005;36:91623; with permission.

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Intravenous thrombolytic therapy within the 3-hour time window

tPA is a brin-specic thrombolytic agent that activates plasminogen to
form plasmin, a protease that cleaves brin. The National Institute of Neurologic Disorders and Stroke (NINDS) acute stroke study group enrolled
624 patients presenting within 3 hours of symptom onset in a randomized,
double-blind, placebo-controlled, two-part study evaluating the eect of intravenous tPA (at 75% of the recommended dose for myocardial infarction)
for all types of ischemic stroke [2]. The rst part of the study measured early
response to tPA and showed improvement in the NIHSS score by 4 or more
points at 24 hours after treatment [2,53]. The 3-month functional outcome
evaluation also showed improved neurologic outcomes in the tPA group,
which paved the way for verication of these results in the second part of
the study. The primary end point for part two was a combined 3-month outcome assessment using several rating scales: the NIHSS, Barthel index, modied Rankin scale, and Glasgow outcome scale. All outcome measures
showed benet in the tPA group with 11% to 13% absolute dierence in
neurologic scores in the tPA-treated patients [53]. The symptomatic intracranial hemorrhage rate was higher in the tPA group (6.4%) than in the placebo group (0.6%) (P!.001) [2]. Mortality rates at 3 months were similar in
both groups, however, at 17% for the tPA group and 21% for the placebo
group (P .30) [2]. Based on these results, the FDA approved the use of
intravenous tPA within 3 hours from stroke onset at a dose of 0.9 mg/kg,
with a maximum dose of 90 mg [2,53,56,57]. Box 1 lists the characteristics
of patients with ischemic stroke who are eligible for treatment with tPA [22].
Since the approval of intravenous tPA, two prospective, monitored,
phase 4 studies have shown similar results [58,59]. These studies were designed to assess the safety prole and clinical ecacy of intravenous tPA
therapy for acute ischemic stroke in clinical practice. The Standard Treatment with Alteplase to Reverse Stroke study enrolled 389 patients and
showed that 43% of patients treated with intravenous tPA had independent
functional outcomes (dened as a modied Rankin score of 02) at 1 month
post treatment [58]. The percentage of symptomatic intracranial hemorrhage
was 3.3%, and mortality was 13% at 1 month. The Canadian Activase for
Stroke Eectiveness Study enrolled 1132 patients and found that 36% of
tPA-treated patients had favorable outcomes at 3 months [59]. The rate of
symptomatic intracranial hemorrhage was 4.6% and mortality was 21%
at 3 months.
Intravenous thrombolytic therapy beyond the 3-hour time window
The European Cooperative Acute Stroke Study (ECASS) consisted of
two trials evaluating the use of intravenous tPA within 6 hours of symptom
onset in patients with a moderate-to-severe hemispheric stroke [60,61].
ECASS I [60] used 85% of the dose for myocardial infarction (1.1 mg/kg,

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355

maximum dose 100 mg), and ECASS II [61] used 75% of the dose for
myocardial infarction (0.9 mg/kg, maximum dose 90 mg). In ECASS I,
620 patients were enrolled, but 17% had protocol violations mainly because
of misinterpretations of the admission brain CT scans. After excluding the
patients with protocol violations, modied Rankin scores (asymptomatic
or minimal disability) were signicantly better in the tPA group compared
with the placebo group. Among all patients enrolled in ECASS I, there
was a 20% symptomatic intracranial hemorrhage rate in the treatment
group compared with 7% in the placebo group (P!.001). This increased
rate of hemorrhage in ECASS I likely is related to the tPA dose (1.1 mg/kg,
100 mg maximum), which was substantially higher than in the NINDS
tPA study. In ECASS II, 800 patients were enrolled with a primary end point
of 3-month favorable outcome dened as a modied Rankin score of 0 to
1 (asymptomatic or no signicant disability despite symptoms). The tPAtreated group faired slightly better at 3 months than the placebo group
with a 3.7% higher percentage of patients with favorable outcomes
[4,53,60,61].
The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke trial was a randomized, placebo-controlled trial evaluating
the use of 0.9 mg/kg of intravenous tPA in the 3- to 5-hour treatment window [62]. The study was stopped early when interim analysis revealed a low
likelihood of benet in the treatment group. Several clinical trials evaluated
intravenous streptokinase for acute stroke in Europe and Australia. The
Multi-center Acute Stroke TrialdItaly and Multi-center Acute Stroke
TrialdEurope used a 6-hour time window for intravenous treatment with
1.5 million U of streptokinase (100% of myocardial infarction dosage)
[63,64]. The Australia Streptokinase Trial used the same dose, but shortened
the time window to 4 hours [65]. All three trials were stopped early because
of an unacceptable high number of deaths and symptomatic intracranial
hemorrhages in the treatment groups.
Newer thrombolytic and antiplatelet agents
Recent studies have evaluated alternative thrombolytic agents, such as
ancrod (Viprinex), a viper-derived enzyme that cleaves brinogen and promotes endogenous release of plasminogen activator from the vessel wall
[4,6668]. The phase III Ancrod Study compared intravenous Ancrod
with placebo within 6 hours of stroke symptom onset and found no dierence in 3-month functional success dened as survival with a Barthel index
of greater than or equal to 95 (or return to prestroke value) between the
treated group (42%) and the placebo group (42%) [69]. Desmoteplase, a protease found in vampire bat saliva, is similar to human plasminogen activator, but in laboratory models works faster and causes a more sustained
vessel recanalization compared with tPA. Based on promising phase II trial
results (DEDAS and DIAS trials), it was evaluated in the DIAS 2 trial in the

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3- to 9-hour time window for acute stroke patients with a presumed penumbra based on MRI or CT imaging results [70,71]. The preliminary results of
this trial were presented at the 2007 European Stroke Conference and show
no signicant dierence in 3-month clinical outcome between the desmoteplase-treated and the placebo groups [72].
Glycoprotein IIb/IIIa antagonists also are being evaluated alone
(AbESST, SaTIS, SETIS) and in combination with low-dose intravenous
tPA (the Clear Stroke Trial) [7376]. The ReoPro Retavase Reperfusion
of Stroke Safety StudydImaging Evaluation trial is assessing the use of abciximab alone and in conjunction with escalating doses of reteplase. Preliminary results suggest promise for the combination therapy, but not for
abciximab alone [77].
Although several novel pharmacologic agents hold promise for acute ischemic stroke patients, current care of patients with acute ischemic stroke
still emphasizes NINDS- and FDA-dened use of intravenous tPA dosed
at 0.9 mg/kg with a maximum dose of 90 mg. The risk of symptomatic intracranial hemorrhage is approximately 6% when the NINDS- and FDAapproved guidelines are strictly adhered to (see Box 1).
Intra-arterial thrombolysis
Direct administration of intra-arterial thrombolytic agents into the clot,
while passing the catheter through the clot and mechanically disrupting it,
allows for a lower tPA dose and a decreased risk of systemic hemorrhagic
complications. A disadvantage of intra-arterial thrombolytic therapy is
the time and expertise required for catheterization, restricting this therapeutic modality to medical centers that have interventional neuroradiologists
and critical care services available 24 hours a day.
Prolyse in Acute Cerebral Thromboembolism (PROACT) was a randomized clinical trial evaluating the ecacy of intra-arterial prourokinase plus
intravenous heparin compared with placebo plus intravenous heparin in patients presenting with middle cerebral artery occlusions less than 6 hours old
[78,79]. Mechanical disruption of the clot was not permitted. PROACT I
[78] randomized 46 patients and showed that intra-arterial prourokinase infusion was associated with superior recanalization rates compared with placebo. The symptomatic intracranial hemorrhage rate was 15.4% in the
prourokinase group versus 7.1% in the placebo group. In PROACT II
[79], there was a statistically signicant benet with 40% of prourokinasetreated patients having a good 3-month functional outcome (modied
Rankin score %2) compared with 25% of the control group. Symptomatic
intracranial hemorrhage occurred in 10% of the prourokinase group and
2% of the control group (P .063). Because prourokinase is not available
in the United States for clinical use, tPA and urokinase have been used
instead for intra-arterial thrombolysis with favorable outcomes in selected
patients [53,78,79].

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357

Intra-arterial thrombolytic therapy for acute stroke is not approved by

the FDA, but may be considered in patients with middle cerebral artery occlusions who can be treated within 3 to 6 hours after symptom onset and
who have no (or minimal) signs of infarction on their baseline CT scans
[4,53]. Given the high mortality associated with basilar artery and internal
carotid artery bifurcation (carotid T) occlusions, patients with these lesions
also may be considered for intra-arterial thrombolytic therapy on a caseby-case basis [4,53].
Combined intravenous and intra-arterial thrombolysis
The combination of intravenous and intra-arterial thrombolysis has been
investigated in several pilot studies and may be more eective than either
therapy alone in patients with acute, very large vessel occlusions. The National Institutes of Health Interventional Management of Stroke trial I
(IMS I) investigated the feasibility and safety of a combined intravenous
and intra-arterial approach to recanalization in patients with ischemic
stroke and a substantial neurologic decit (NIHSS R10) [80]. The study enrolled 80 patients, and their outcome was compared with historical intravenous tPA controls. The patients received 0.6 mg/kg of intravenous tPA over
30 minutes within 3 hours from stroke symptom onset followed by intraarterial tPA within 5 hours if a vessel occlusion was still present on angiography. The 3-month mortality rate and the symptomatic intracerebral
hemorrhage rate in IMS patients were similar to intravenous tPAtreated
patients in the NINDS tPA Stroke Trial. IMS subjects showed a nonsignificant trend toward better clinical outcomes than historical intravenous tPA
controls (odds ratio 1.35; 95% condence interval, 0.782.37). The results of
this study and other pilot studies suggest that a combined intravenous plus
intra-arterial approach to recanalization is feasible and safe. Further studies
assessing the ecacy of this combined approach to recanalization are presently ongoing and have incorporated the use of endovascular mechanical
devices.
Mechanical thrombolysis
Several endovascular devices have been developed in recent years to remove clots from the cerebral circulation. These devices have been tested in
patients with acute stroke who are ineligible for or who failed intravenous
tPA treatment [8185]. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) retrieval device has been studied most extensively and
was approved by the FDA for use in acute stroke patients who are ineligible or fail intravenous tPA therapy [85]. The device is deployed just beyond the clot with release of two nitinol helices and pulled back into the
clot with the remainder of the helices deployed (Fig. 3). It is twisted three
to ve times to capture the clot better. A balloon is inated in the internal

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Fig. 3. (A, B) The MERCI retrieval device (Concentric Medical): illustration of the clot removal process. (Courtesy of Concentric Medical, Inc., Mountain View, CA; with permission.
All Rights Reserved. 2008.)

carotid artery temporarily to prevent forward ow, while the clot is recoiled into the positioning catheter and out the body. The MERCI device
was tested in an uncontrolled, nonrandomized trial conducted in two
parts [85]. The trial enrolled 151 patients who had stroke symptom duration of 3 to 8 hours or less than 3 hours with a contraindication for tPA.
Patients also had a substantial neurologic decit (NIHSS R8) and an occlusion of a treatable vessel. Partial or complete recanalization was
achieved in 46% of patients on intention-to-treat analysis, and almost
half (46%) of these had good neurologic outcomes at 90 days (modied
Rankin score of 02). Clinically signicant procedural complications
were reported in 7% of patients. The Multi-MERCI trial tested a newer
device (L5) and allowed pretreatment with intravenous tPA [86]. With
the newer device this trial, although not statistically signicant, seemed
promising for better recanalization rates of 68% versus 60% (P .15),
lower mortality (35% versus 44%, P .12), and higher favorable outcomes (35% versus 28%, P .19) compared with the MERCI trial
[86]. Further studies of the MERCI device are forthcoming in the MRRescue and the IMS III trials.
Primary angioplasty and stenting have been shown to be superior to
thrombolytic therapy in patients with acute myocardial infarction. This
method is most eective in atherosclerotic arteries that have in situ thrombus rather than in blood vessels that are occluded by embolic material
[81,87]. Many strokes are caused by artery-to-artery embolism or cardioembolism, however, and these types of clots tend to rebound into an occlusive position despite angioplasty. With further technologic renements,
angioplasty and stenting may play a more important role in the management of acute ischemic stroke in the future [88,89].

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359

Neuroprotective strategies
Many neuroprotective agents that were promising in laboratory models
of focal ischemia have not shown benet in clinical studies, partly because
of limitations in trial design. Interest in neuroprotective agents for patients
with acute ischemic stroke remains, however, and several phase 3 studies are
presently ongoing. One of the most robust neuroprotective strategies in experimental stroke models is mild-to-moderate hypothermia (2 C5 C below
normal brain temperature) [9092]. Hypothermia consistently has been associated with a marked reduction in ischemic damage and improved behavioral outcomes in these models. The benecial eects seem to be greatest
when hypothermia is initiated early. The therapeutic window of mild hypothermia in patients with acute ischemic stroke is unknown, but likely to be
limited to several hours after ischemia onset. The feasibility of hypothermia
for acute ischemic stroke patients has been tested in several clinical pilot trials. The Cooling for Acute Ischemic brain Damage study was a phase 2 randomized clinical trial using hypothermia in patients less than 12 hours from
stroke onset. There was no signicant clinical benet in 18 patients treated
with hypothermia compared with 22 patients who received standard medical
therapy. The study showed, however, that endovascular cooling at 33 C was
feasible and tolerated by most patients [93]. The Intravascular Cooling for
the Treatment of StrokedLonger window trial is presently ongoing. This
is a multicenter, controlled, randomized trial designed to investigate the feasibility and safety of a combination of therapeutic hypothermia with intravenous tPA in the 0- to 6-hour window in awake stroke patients [94].
The Stroke-Acute Ischemic NXY-059 Treatment (SAINT) trials were designed to evaluate the therapeutic benet of intravenous NXY-059, a nitrone
radical trapping agent, administered within 6 hours of stroke onset [95,96].
The SAINT I trial enrolled more than 1700 patients with acute ischemic
stroke and showed a modest, but statistically signicant (P .038) improved outcome in the treatment group as measured by the modied Rankin
scale at 90 days; however, the denitive SAINT II trial, which enrolled more
than 3300 patients, did not conrm these results [95,96]. Ongoing phase III
trials evaluating neuroprotective agents in acute ischemic stroke include the
Field Administration of Stroke TherapydMagnesium trial assessing the
benet of intravenous magnesium within 2 hours from stroke onset and
the Albumin in Acute Stroke study, a trial of high-dose albumin within
5 hours of symptom onset [9799].
Anticoagulation in acute ischemic stroke
There is no evidence to support urgent anticoagulation to prevent stroke
recurrence or extension in patients with acute stroke [25,53,100]. Intravenous heparin infused for 7 days was evaluated in a small randomized, controlled study with 225 patients with acute ischemic stroke [101]. No

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signicant dierence in stroke progression or neurologic outcome was found

between the treatment and the control groups. Analysis of the combined
heparin groups from International Stroke Trial showed that a decreased recurrent stroke risk at 14 days was oset by an increased risk of intracranial
hemorrhage [55]. The low-dose heparin group (5000 U twice a day) had decreased mortality with only a slight and nonsignicant increase in bleeding
risk. The low-dose heparin in combination with aspirin group had the lowest
rate of stroke recurrence and no signicant increase in bleeding risk compared with patients on only low-dose heparin. A subgroup analysis of patients who presented with atrial brillation and acute ischemic stroke
showed a signicant reduced risk of recurrent ischemic strokes (4.9% versus
2.8%), but the increased risk of intracranial hemorrhage negated any potential benets (2.1% versus 0.4%) at 14 days [53,55].
Studies evaluating low-molecular-weight heparins in acute ischemic
stroke failed to show a benecial eect [102105]. In a subgroup analysis
of the TOAST trial, however, better outcomes were observed in patients
with stroke caused by large artery atherosclerosis [103,105,106]. In a recent
study among Asian stroke patients with large artery occlusive disease (intracranial and extracranial), low-molecular-weight heparin (nadroparin) overall did not support a signicant benet over aspirin in acute stroke patients
[107]. Benets observed in secondary outcome measures, however, may warrant further study of low-molecular-weight heparins in acute stroke patients
attributed to large artery atherosclerosis.

Complications of stroke
Hemorrhagic transformation
A feared complication of thrombolytic therapy in stroke patients is intracranial hemorrhage. Symptomatic intracerebral hemorrhage occurs in approximately 6% of patients receiving intravenous tPA for acute ischemic
stroke and has been associated with high morbidity and mortality [2,108].
Risk factors for symptomatic intracerebral hemorrhage after thrombolytic
therapy include symptom severity, early infarct signs on admission brain
CT, older age, elevated systolic blood pressure, low platelet count, elevated
serum glucose, history of diabetes, history of congestive heart failure, longer
time to treatment, and low levels of plasminogen activator inhibitor
[109120]. The presence of one or more of these risk factors should not be
considered a contraindication to tPA treatment, however, in a patient
who otherwise qualies based on the NINDS criteria.
The biologic half-life of tPA at the clot site is approximately 45 minutes,
and most tPA-related intracranial hemorrhages occur in the rst few hours
after treatment. If a patient has a signicant neurologic change during intravenous tPA administration, the infusion should be stopped, and an emergent head CT scan should be obtained. Laboratory tests should be

MANAGEMENT OF ACUTE ISCHEMIC STROKE

361

performed immediately, including coagulation parameters, brinogen, and

complete blood count with platelets. If a symptomatic intracerebral hemorrhage is diagnosed, emergent infusion of fresh frozen plasma (510 mL/kg)
and cryoprecipitate (0.1 bag/kg) is recommended [121].
Cerebral edema
Patients with ischemic stroke with cerebral edema and mass eect are at
risk for brain herniation, brainstem compression, coma, and death. Examples are patients with large hemispheric infarctions involving the middle cerebral artery territory and patients with large cerebellar infarctions. Mass
eect caused by ischemic infarcts typically peaks 3 to 5 days after symptom
onset. The clinical examination is more sensitive in detecting worsening cerebral edema, local tissue shifts, and impending uncal or transtentorial herniation than continuous ICP monitoring because the clinical deterioration
caused by regional tissue injury and compression precedes a global increase
in ICP in most patients [5,122,123].
In patients with suspected elevated ICP, initial management should consider adequacy of airway, breathing, and circulatory function. The head
should be elevated 30 degrees to decrease ICP and optimize cerebral venous
return [124,125]. Hyperosmolar therapy should be instituted using mannitol,
hypertonic saline, or both [126128]. Mannitol extracts intracellular and
interstitial water from the brain. This agent also is a free radical scavenger,
inhibits programmed cell death, and lowers blood viscosity [129]. It is administered as a 0.5 to 1 g/kg loading dose and can be followed by boluses
of 0.25 g/kg every 6 hours. The main complications associated with mannitol use are hypovolemia, hypotension, and electrolyte disturbances resulting
from osmotic diuresis. Hypertonic saline has been proposed as an alternative to mannitol and may be of particular advantage in hypovolemic patients. Rebound edema may occur after abrupt cessation of mannitol or
hypertonic saline [128]. Experimental and clinical studies suggest potential
benets of hypertonic saline over mannitol in the treatment of stroke-related
brain edema and increased ICP [130,131]. More details on the treatment of
increased ICP and the use of hyperosmolar therapy can be found elsewhere
in this issue. Because of the concern of compromising cerebral blood ow,
hyperventilation should be used only in emergency situations and as a temporizing measure until more denitive therapies can be initiated. Corticosteroid therapy, although eective in decreasing cerebral edema in patients
with brain tumors and brain abscesses, does not improve cerebral edema
associated with ischemic or hemorrhagic stroke and ought to be avoided
because corticosteroids are of no benet and may worsen outcome [132].
Craniectomy has been proposed as a lifesaving measure in patients with
large hemispheric infarction accompanied by mass eect space-occupying
edema (Fig. 4). The goal of surgery is to reverse mass eect and brain tissue
shifts, decrease ICP, improve cerebral perfusion, and prevent secondary

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Fig. 4. Nonenhanced CT scan 3 days after a right middle cerebral artery territory infarction
that required a hemicraniectomy to decrease tissue shifts and prevent transtentorial herniation
and death.

injury. Several observational studies demonstrated a decrease in mortality

and improved neurologic outcome, in particular in young patients (age
!60 years) with hemispheric infarctions who underwent decompressive
hemicraniectomy when compared with historic controls [133135]. Based
on these encouraging reports, three randomized controlled trials were undertaken in Europe to assess the benecial eect of decompressive surgery
in patients with space-occupying hemispheric strokes. A meta-analysis combining data from the three studies was recently published and demonstrated
that decompressive hemicraniectomy reduced mortality and improved
functional outcome [136]. A substantial proportion of survivors (40%)
had a 12-month modied Rankin scale score of 4, however, leading the
authors to conclude that the decision to perform decompressive surgery
should be made on an individual basis in every patient [136]. Decompressive surgery also may benet patients with large cerebellar infarctions, in
particular patients with hydrocephalus, brainstem compression, and neurologic deterioration.
Deep venous thrombosis
Deep venous thrombosis and pulmonary embolism are a cause of early
death in 5% of stroke patients [137]. Low-dose heparin or low-molecularweight heparin may be used for prevention of deep venous thrombosis [53].
In the PROTECT study, citraparin, a low-molecular-weight heparin, was
found to be at least as eective as unfractionated heparin (5000 units

MANAGEMENT OF ACUTE ISCHEMIC STROKE

363

subcutaneous three times a day) in preventing proximal deep venous

thromboembolism, pulmonary embolism, and death related to venous
thromboembolism in patients with acute ischemic stroke [138]. Major
bleeding events were similar between the citraparin (1.1%) and the unfractionated heparin (1.8%) treated groups [138]. In the PREVAIL study,
enoxaparin signicantly reduced the risk of thromboembolism (relative
risk reduction 43%) compared with unfractionated heparin (5000 units
subcutaneous twice a day) (P .0001) [139]. Symptomatic intracranial
hemorrhage and extracranial major hemorrhages were similar between
the two groups [139]. Patients who have received thrombolytic therapy
should not receive anticoagulation therapy for deep venous thrombosis
prophylaxis in the rst 24 hours [2,4,22,25,53]. Sequential compression
devices are indicated in nonambulatory stroke patients who are unable
to receive heparin or low-molecular-weight heparin [53].
Hyperglycemia
Hyperglycemia has been associated with larger cerebral infarct volumes
in animal models [140]. In humans, worsened outcomes have been reported
in patients with elevated admission glucose levels [141]. Hyperglycemia has
also been associated with increased cerebral edema volumes and higher hemorrhagic transformation rates with or without intravenous tPA administration [113,142,143]. Stroke patients often have surges in their blood glucose
levels because of the sympathetic stress response in the acute phase [4].
Based on these observations it is recommended to avoid dextrose-containing
intravenous infusions and serially to check blood glucose and adequately
correct elevated blood sugars with short-acting insulin. Further studies are
needed to investigate the benet of tight blood glucose control on stroke
outcome [144].
Fever
Hyperthermia adversely aects stroke outcome in animal models and
in observational clinical studies [91,145147]. Proposed mechanisms by
which hyperthermia may worsen outcome include promotion of an inammatory response, an increase in release of excitotoxic amino acids,
and an increase in cerebral metabolic demand in an already compromised
cerebral blood ow state [147149]. Pneumonia and urinary tract infections are common in stroke patients and must be worked-up aggressively
in a febrile patient. Deep venous thrombosis also may cause fevers and
should be considered in patients with unexplained fevers. Further studies
are needed to evaluate the therapeutic impact of antipyretic agents and
cooling therapies in acute stroke. A detailed discussion on temperature
management in patients with neurologic injuries can be found elsewhere
in this issue.

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Summary
Intravenous tPA should be administered to all patients with acute ischemic stroke who present within 3 hours of stroke onset and meet the NINDS
inclusion and exclusion criteria. The risk of symptomatic intracranial hemorrhage with intravenous tPA is approximately 6%. Intra-arterial tPA and
mechanical thrombectomy are alternative treatment strategies for acute
stroke patients who are ineligible for or fail intravenous tPA treatment. Further studies are needed to assess the benet of these treatments. Patients
with acute ischemic stroke should be maintained euglycemic, euvolemic,
and normothermic. Permissive hypertension may be benecial, but in patients receiving tPA blood pressures should be maintained at or less than
180/105 mm Hg. Patients with life-threatening cerebral edema from hemispheric infarctions require hyperosmolar therapy and may benet from
early surgical decompression. Novel management strategies under investigation include the use of multimodal imaging to identify patients who might
benet from tPA beyond the 3-hour time window, new thrombolytic agents,
and neuroprotective therapies.
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