Ischemic Stroke

Approach Considerations
The central goal of therapy in acute ischemic stroke is to preserve tissue in the ischemic penumbra,
where perfusion is decreased but sufficient to stave off infarction. Tissue in this area of oligemia can
be preserved by restoring blood flow to the compromised area and optimizing collateral flow.
Recanalization strategies, including the administration of intravenous (IV) recombinant tissue-type
plasminogen activator (rt-PA) and intra-arterial approaches, attempt to establish revascularization so
that cells in the penumbra can be rescued before irreversible injury occurs. Restoring blood flow can
mitigate the effects of ischemia only if performed quickly.
Many surgical and endovascular techniques have been studied in the treatment of acute ischemic
stroke. Carotid endarterectomy has been used with some success in the acute management of
internal carotid artery occlusions, but no evidence supports its use acutely in ischemic stroke.
In addition to limiting the duration of ischemia, an alternative strategy is to limit the severity of
ischemic injury (ie, neuronal protection). Neuroprotective strategies are intended to preserve the
penumbral tissues and to extend the time window for revascularization techniques. At the present
time, however, no neuroprotective agents have been shown to impact outcomes in ischemic stroke.

Palliative care
Palliative care is an important component of comprehensive stroke care. Some stroke patients will
simply not recover, and others will be in a state of debilitation such that their comfort is the most
humane and appropriate therapeutic concern. Some patients have advance directives providing
instructions for medical providers in the event of severe medical illness or injury.

Clinical education
Prehospital care providers are essential to timely stroke care. Course curricula for prehospital care
providers are beginning to include more information on stroke than ever before. Through certification
and Acute Cardiac Life Support (ACLS) instruction, as well as continuing medical education classes,
prehospital care providers can remain current on stroke warning signs, prehospital stroke tools, and
triage protocols in their region, and can promote stroke awareness in their own communities.
Physician and nursing staff involved in the care of stroke patients, in the emergency department (ED)
and in the hospital, should participate in scheduled stroke education. This will help them to maintain
the skills required to treat stroke patients effectively and to remain current on medical advances for all
stroke types.

Emergency Response and Transport

Recognition that a stroke may have occurred, activation of 911, and rapid transport to the appropriate
receiving facility are necessary to provide stroke patients with the best chance for acute interventions.
Of patients with signs or symptoms of stroke, 29-65% utilize some facet of the emergency medical
services (EMS) system.[75, 76]
Most of the patients who call EMS are those who present within 3 hours of symptom onset. Calls to
911 and the use of EMS are associated with shorter time periods from symptom onset to hospital
arrival.[77, 78]
Stroke should be a priority dispatch with prompt EMS response. EMS responders should provide
advance notice to their ED destination in as timely a manner as possible so as to allow preparation
and marshaling of personnel and resources. With the development of stroke center designation,
which is currently in progress, such centers would then become the preferred destination for patients
with acute stroke symptoms who utilize EMS.
Data supporting the use of emergency air transport for patients with acute stroke symptoms are
limited. Further evaluation of this transportation modality is necessary to minimize the potentially high
number of stroke mimics and to maximize the appropriate use of transport resources. Telemedicine is
also a technology that has the potential to provide timely expert advice to rural and underserved
clinics and hospitals.[3]

Acute Management of Stroke

The goal for the emergent management of stroke is to assess the patients airway, breathing, and
circulation (ABCs); stabilize the patient as necessary; and complete initial evaluation and assessment,
including imaging and laboratory studies, within 60 minutes of patient arrival. [3] A Finnish study
demonstrated that time to treatment with fibrinolytics can be decreased with changes in EMS and ED
coordination and in ED procedures for treating acute stroke patients. [79]
A US study in which a multidisciplinary team used value stream analysis to assess the steps required
to treat acute ischemic stroke with IV rt-PA found several inefficiencies in the protocol (eg, in patient
routing) that were slowing treatment. Use of a revised protocol that targeted those inefficiencies
reduced door-to-needle times from 60 to 39 minutes and increased the percentage of patients treated
in 60 minutes or less after hospital arrival from 52% to 78%, with no change in symptomatic
hemorrhage rate.[80]
Critical decisions focus on the need for airway management, establishment of optimal blood pressure
control, and identification of potential reperfusion therapies (IV fibrinolysis with rt-PA or intra-arterial
approaches). Involvement of a physician with a special interest in stroke is ideal. Stroke care units
with specially trained personnel exist and improve outcomes.

Comorbidities
Comorbid medical conditions also need to be addressed. Hyperthermia is infrequently associated with
stroke but can increase morbidity. Administration of acetaminophen, by mouth or per rectum, is
indicated in the presence of fever (temperature >100.4F). (>37.5 C}

Oxygen supplementation
Supplemental oxygen is recommended when the patient has a documented oxygen requirement (ie,
oxygen saturation < 95%). In the small proportion of patients with stroke who are relatively
hypotensive, administration of IV fluid, vasopressor therapy, or both may improve flow through critical
stenoses.

Hypoglycemia and hyperglycemia

Hypoglycemia needs to be identified and treated early in the evaluation. In contrast, the management
of hyperglycemia in acute stroke remains an area of uncertainty.[81]
Hyperglycemia is common after acute ischemic stroke, even in patients without diabetes. A Cochrane
review found that the use of IV insulin to maintain serum glucose in the range of 4-7.5 mmol/L (72-135
mg/dL) in the first 24 hours of ischemic stroke did not improve functional outcome, death rates, or final
neurologic deficit and significantly increased the risk of hypoglycemia. [82]

Fibrinolytic Therapy
The only fibrinolytic agent that has been shown to benefit selected patients with acute ischemic stroke
is rt-PA. While streptokinase may benefit patients with acute MI, in patients with acute ischemic stroke
it has been shown to increase the risk of intracranial hemorrhage and death.
Fibrinolytics (ie, rt-PA) restore cerebral blood flow in some patients with acute ischemic stroke and
may lead to improvement or resolution of neurologic deficits. Unfortunately, fibrinolytics may also
cause symptomatic intracranial hemorrhage. Other complications include potentially hemodynamically
significant hemorrhage and angioedema or allergic reactions.[3]

Inclusion/exclusion criteria
Therefore, if the patient is a candidate for fibrinolytic therapy, a thorough review of the inclusion and
exclusion criteria must be performed. The exclusion criteria largely focus on identifying risk of
hemorrhagic complications associated with fibrinolytic use. The American Heart Association/American
Stroke Association (AHA/ASA) inclusion guidelines for the administration of rt-PA are as follows[3] :

Diagnosis of ischemic stroke causing measurable neurologic deficit

Neurologic signs not clearing spontaneously to baseline
Neurologic signs not minor and isolated

Symptoms not suggestive of subarachnoid hemorrhage

No head trauma or prior stroke in past 3 months
No myocardial infarction (MI) in past 3 months
No gastrointestinal/genitourinary hemorrhage in previous 21 days
No arterial puncture in a noncompressible site during the past 7 days
No major surgery in past 14 days
No history of prior intracranial bleeding
Systolic blood pressure under 185 mm Hg, diastolic blood pressure under 110 mm Hg
No evidence of acute trauma or bleeding
Not taking an oral anticoagulant, or if so, international normalized ratio (INR) under 1.7
If taking heparin within 48 hours, a normal activated prothrombin time (aPT)
Platelet count of more than 100,000/L
Blood glucose greater than 50 mg/dL (2.7 mmol)
No seizure with residual postictal impairments
CT scan does not show evidence of multilobar infarction (hypodensity over one third hemisphere) or
intracerebral hemorrhage
The patient and family understand the potential risks and benefits of therapy
Whereas these inclusion/exclusion criteria are from the original FDA approval, subsequent data and
experience have allowed some patients with what were previously considered relative
contraindications to be safely treated. Involvement of a physician with stroke expertise is critical for
assessing the risk/benefit consideration for these groups of patients.

Time to therapy
An rt-PA stroke study group from the National Institute of Neurologic Disorders and Stroke (NINDS)
first reported that the early administration of rt-PA benefited carefully selected patients with acute
ischemic stroke.[5] The FDA subsequently approved the use of rt-PA in patients who met NINDS
criteria. In particular, rt-PA had to be given within 3 hours of stroke onset and only after CT scanning
had ruled out hemorrhagic stroke.
Subsequently, fibrinolytic therapy administered 3-4.5 hours after symptom onset was found to
improve neurologic outcomes in the European Cooperative Acute Stroke Study III (ECASS III),
suggesting a wider time window for fibrinolysis.[83]On the basis of these and other data, in May 2009
the AHA/ASA revised the guidelines for the administration of rt-PA after acute stroke, expanding the
window of treatment from 3 hours to 4.5 hours to provide more patients with an opportunity to benefit
from this therapy.[83, 84, 85, 86]
Eligibility criteria for treatment during this later period are similar to those for earlier treatment but are
more stringent, with any 1 of the following serving as an additional exclusion criterion:

Age older than 80 years

Use of oral anticoagulants, regardless of the INR
Baseline score on the National Institutes of Health Stroke Scale (NIHSS) greater than 25
History of stroke and diabetes
A 10-center European study of nearly 6900 patients found IV rt-PA to be most effective when given
within 90 minutes of the onset of stroke symptoms.[87, 88]Patients scoring in the 7-12 range on the
NIHSS had better outcomes when thrombolytic therapy was provided within 90 minutes of symptom
onset than when it was provided 90-270 minutes after onset. For patients with minor stroke or
moderate-to-severe stroke, however, treatment within the initial 90-minute window provided no
additional advantage.

Hemorrhage risk
Although antiplatelet therapy may increase the risk for symptomatic intracerebral hemorrhage with
fibrinolysis, a study by Diedler et al that included 3782 patients who had received 1 or 2 antiplatelet
drugs found that the risk of intracerebral hemorrhage was small compared with the documented
benefit of fibrinolysis.[89]These researchers concluded that antiplatelet treatment should not be
considered a contraindication to fibrinolysis, although caution is warranted in patients receiving the
combination of aspirin and clopidogrel.

Data regarding the safety of fibrinolytic therapy in patients taking dabigatran, rivaroxaban, or apixaban
are not available. Extreme caution should be used when considering fibrinolytic therapy in such
patients.
Caution should also be exercised in the administration of rt-PA to patients with evidence of low
attenuation (edema or ischemia) involving more than a third of the distribution of the middle cerebral
artery (MCA) on their initial noncontrast CT scan; such patients are less likely to have a favorable
outcome after fibrinolytic therapy and are at higher risk for hemorrhagic transformation of their
ischemic stroke.[52]

Ultrasound therapy
Researchers have studied the use of transcranial ultrasound as a means of assisting rt-PA in
fibrinolysis.[90, 91] By delivering mechanical pressure waves to the thrombus, ultrasound can
theoretically expose more of the thrombuss surface to the circulating fibrinolytic agent. Further
research is necessary to determine the exact role of transcranial Doppler ultrasound in assisting
fibrinolytics in acute ischemic stroke.
For more information, see Thrombolytic Therapy in Stroke and Reperfusion Injury in Stroke.

Intra-arterial Reperfusion
There have been no completed human trials comparing intravenous versus intra-arterial
administration of fibrinolytics. Theoretically, intra-arterial delivery may produce higher local
concentrations of the fibrinolytic agent at lower total doses (and thus possibly lower the risk of a
systemic bleed) and allow a longer therapeutic window. However, the longer time for initiating intraarterial administration may mitigate some of this advantage.[3]
The Interventional Management of Acute Stroke Study (IMS-III) was halted for futility after showing no
additional benefit from intra-arterial therapies (rt-PA, mechanical thrombectomy, or both) compared
with intravenous rt-PA in patients with large-vessel occlusions. Additional analyses of the IMS III data
are under way to better understand the results and potentially identity subsets of patients who may
benefit from the combined approach.[92]
Intra-arterial fibrinolysis has been the traditional approach for patients with stroke from basilar artery
occlusion. However, results of the Basilar Artery International Cooperation Study (BASICS), a
prospective registry study in 592 patients, did not support unequivocal superiority of intra-arterial
fibrinolysis over intravenous fibrinolysis.[93]
A meta-analysis of case studies involving a total of 420 patients with basilar artery occlusion did
indicate that recanalization was achieved more frequently with intra-arterial fibrinolysis than with
intravenous fibrinolysis (65% vs 53%), but the report also found that death and long-term disability
were equally common with the 2 techniques.[94] These researchers concluded that intravenous
fibrinolysis represents probably the best treatment that can be offered to these patients in hospitals
without a 24-hour interventional neuroradiologic service.[94]

Antiplatelet Agents
AHA/ASA guidelines recommend giving aspirin, 325 mg orally, within 24-48 hours of ischemic stroke
onset. The benefit of aspirin is modest but statistically significant and appears principally to involve
the reduction of recurrent stroke.[86]
The International Stroke Trial and the Chinese Acute Stroke Trial (CAST) demonstrated modest
benefit from the use of aspirin in the setting of acute ischemic stroke. The International Stroke Trial
randomized 19,435 patients within 48 hours of stroke onset to treatment with aspirin 325 mg,
subcutaneous heparin in 2 different dose regimens, aspirin with heparin, and a placebo. The study
found that aspirin therapy reduced the risk of stroke recurrence within 14 days (2.8% vs 3.9%), with
no significant excess of hemorrhagic strokes.[95, 96]
In CAST, which included 21,106 patients, aspirin treatment (160 mg/day) that was started within 48
hours of the onset of suspected acute ischemic stroke and was continued in hospital for up to 4
weeks reduced mortality to 3.3%, compared with 3.9% with placebo. A separate study also found that

the combination of aspirin and lowmolecular-weight heparin did not significantly improve
outcomes.[95]
Other antiplatelet agents have also been under evaluation for use in the acute presentation of
ischemic stroke. In a preliminary pilot study, abciximab given within 6 hours showed a trend toward
improved outcome at 3 months.[97] However, the phase 3 Abciximab in Emergency Treatment of
Stroke Trial (AbESTT-II) was terminated prematurely after 808 patients because of lack of efficacy
and an increased rate of symptomatic or fatal intracranial hemorrhage in patients receiving
abciximab.[98]

Blood Pressure Control

Although hypertension is common in acute ischemic stroke and is associated with poor outcome,
studies of antihypertensive treatment in this setting have produced conflicting results. A theoretical
drawback of blood pressure reduction is that elevated blood pressure may counteract dysfunctional
cerebral autoregulation from stroke, but limited evidence suggests that antihypertensive treatment in
acute stroke does not change cerebral perfusion.[99]
Calcium channel blockers did not alter outcome after ischemic stroke in some trials. Possible adverse
effects of antihypertensive treatment have been reported in certain trials, especially those using
intravenous calcium channel blockers or oral beta blockers. In the Controlling Hypertension and
Hypotension Immediately Post-Stroke (CHHIPS) trial, early lowering of blood pressure with labetalol
and lisinopril slightly improved outcome and did not increase serious adverse events. However,
CHHIPS had a small sample size.[100]
A study in 339 patients with ischemic stroke found that oral candesartan reduced combined vascular
events but had no effect on disability.[99] However, the Scandinavian Candesartan Acute Stroke Trial
(SCAST), a randomized, placebo-controlled, double-blind study involving 2029 patients, found no
indication of benefit from candesartan but did find some suggestion of harm. [101]
In the single-blind, randomized China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) study,
which included 4,071 patients with acute ischemic stroke and elevated blood pressure, immediate
blood pressure reduction with antihypertensive medication within 48 hours of symptom onset did not
reduce the risk for death or major disability. CATIS excluded patients who received thrombolytic
therapy. Mean systolic blood pressure was reduced from 166.7 to 144.7 mm Hg within 24 hours in the
antihypertensive treatment group.[102, 103]
Among the 2,038 patients who received antihypertensive treatment, 683 reached the primary
endpoint of death or major disability at 14 days or hospital discharge, compared with 681 of the 2,033
patients who received no antihypertensive treatment. At 3-month follow-up, 500 patients in the
antihypertensive treatment group and 502 patients in the control group reached the secondary
endpoint of death or major disability.[102, 103]
For patients who are not candidates for fibrinolytic therapy, current guidelines recommend permitting
moderate hypertension in most patients with acute ischemic stroke. Most patients will experience
spontaneous reduction in blood pressure over the first 24 hours without treatment. [86] The exceptions
would be patients who have comorbidities (eg, aortic dissection, acute myocardial infarction [MI],
decompensated heart failure, hypertensive emergency) that require emergent blood pressure
management.
Thresholds for antihypertensive treatment in acute ischemic stroke patients who are not fibrinolysis
candidates, according to the 2013 ASA guidelines, are systolic blood pressure higher than 220 mm
Hg or diastolic blood pressure above 120 mm Hg.[86]In those patients, a reasonable goal is to lower
blood pressure by 15% during the first 24 hours after onset of stroke. Care must be taken to not lower
blood pressure too quickly or aggressively, since this could worsen perfusion in the penumbra.

Mechanical Thrombectomy
Mechanical clot disruption is an alternative for patients in whom fibrinolysis is ineffective or
contraindicated. Currently, 4 devices are approved by the FDA for the endovascular treatment of
acute ischemic stroke, as follows:

Merci Retriever (Concentric Medical, Mountain View, CA): Corkscrew-shaped device that captures
and engages clots
Penumbra System (Penumbra, Alameda, CA): Employs both aspiration and extraction
Solitaire FR Revascularization Device (Covidien, Dublin, Ireland): Stent-retriever system; combines
the ability to restore blood flow and retrieve clot
Trevo (Concentric Medical, Mountain View, CA): Stent-retriever system
Successful recanalization occurred in 12 of 28 patients in the Mechanical Embolus Retrieval in
Cerebral Ischemia (MERCI) 1 pilot trial, a study of the Merci Retrieval System.[104] In a second MERCI
study, recanalization was achieved in 48% of patients in whom the device was deployed. Clot was
successfully retrieved from all major cerebral arteries; however, the recanalization rate for the MCA
was lowest.[105]
The Multi MERCI trial used the newer-generation Concentric retrieval device (L5). Recanalization was
demonstrated in approximately 55% of patients who did not receive t-PA and in 68% of those to
whom t-PA was given. Seventy-three percent of patients who failed intravenous t-PA therapy had
recanalization following mechanical embolectomy.[106] On the basis of these results, the FDA cleared
the use of the MERCI device in patients who are either ineligible for or who have failed intravenous
fibrinolytics.
In a trial of the Penumbra System in 23 patients who presented within 8 hours of symptom onset,
revascularization to a Thrombolysis in Myocardial Infarction (TIMI) grade of 2 or 3 was accomplished
in all 21 treated vessels. Vessel tortuosity prevented access by the device in 3 patients. [107]
More recent trials of the stent-retriever systems demonstrated superiority in reperfusion over the
original Merci systems. In the Solitaire Flow Restoration Device Versus the Merci Retriever in Patients
with Acute Ischaemic Stroke (SWIFT) study, which enrolled 113 subjects with moderate or severe
strokes within 8 hours after symptom onset, the Solitaire FR system demonstrated successful
revascularization (TIMI 2-3 flow) in 61% of patients, compared with 24% of patients treated with the
Merci system. Patients in the Solitaire FR group also had a higher rate of good 90-day clinical
outcomes than did those in the Merci group (58% versus 33%, respectively). [108]
A similar study, the Trevo Versus Merci Retrievers for Thrombectomy Revascularisation of Large
Vessel Occlusions in Acute Ischaemic Stroke (TREVO 2) trial, reported successful reperfusion (TIMI
2-3 flow) in 86% of patients using the Trevor stent retriever, compared with 60% in the Merci group.
The rate of good clinical outcomes at 90 days was also higher in the Trevo group than in the Merci
group (40% vs 22%, respectively).[109] Ongoing studies will better define the role of intra-arterial
therapies with and without intravenous fibrinolysis.
Long-term results of the Stenting and Aggressive Medical Management for Preventing Recurrent
Stroke in Intracranial Stenosis (SAMMPRIS) study confirm the superiority of aggressive medical
management alone to aggressive medical management with stenting in patients with a stroke or
transient ischemic attack resulting from stenosis of a major intracranial artery. [110, 111, 112] Long-term
follow-up results were available for 227 patients in the medical management group and 224 patients
in the stenting group.
Occurrence rates for primary endpoint events (stroke or death within 30 days after enrollment or after
either a revascularization procedure for the qualifying lesion during follow-up or a stroke in the
territory of the qualifying artery beyond 30 days) in the medical group and the stenting group were
14.1% and 20.6%, respectively, at year 2 and 14.9% and 23.9% at year 3.[111] Rates of any stroke and
of any major hemorrhage were also significantly lower in the medical group than in the stenting group.
For more information, see Mechanical Thrombolysis in Acute Stroke.

Fever Control
Antipyretics are indicated for febrile stroke patients, since hyperthermia accelerates ischemic
neuronal injury. Substantial experimental evidence suggests that mild brain hypothermia is
neuroprotective. The use of induced hypothermia is currently being evaluated in phase II clinical
trials.[113, 114, 115]
High body temperature in the first 12-24 hours after stroke onset has been associated with poor
functional outcome. However, results from the Paracetamol (Acetaminophen) in Stroke (PAIS) trial did

not support the routine use of high-dose acetaminophen (6 g daily) in patients with acute stroke,
although post-hoc analysis suggested a possible beneficial effect on functional outcome in patients
admitted with a body temperature of 37-39 C.[116]

Cerebral Edema Control

Significant cerebral edema after ischemic stroke is thought to be somewhat rare (10-20%). Maximum
severity of edema is reached 72-96 hours after the onset of stroke.
Early indicators of ischemia on presentation and on noncontrast CT (NCCT) scans are independent
indicators of potential swelling and deterioration (see the image below). Mannitol and other therapies
to reduce intracranial pressure (ICP) may be used in emergency situations, although their usefulness
in swelling secondary to ischemic stroke is unknown. No evidence exists supporting the use of
corticosteroids to decrease cerebral edema in acute ischemic stroke. Prompt neurosurgical
assistance should be sought when indicated.[3]

Axial noncontrast computed tomography (NCCT) scan demonstrates diffuse

hypodensity in the right lentiform nucleus with mass effect upon the frontal horn of the right lateral ventricle in a 70-yearold woman with a history of left-sided weakness for several hours.

Patient position, hyperventilation, hyperosmolar therapy, and, rarely, barbiturate coma may be used,
as in patients with increased ICP secondary to closed head injury. Hemicraniectomy has been shown
to decrease mortality and disability among patients with large hemispheric infarctions associated with
life-threatening edema.[117, 118, 119, 120]
The American Heart Association and the American Stroke Association have released a guideline for
the management of cerebral and cerebellar infarction with brain swelling; recommendations include
the following[121, 122] :

Selected patients, including those able to handle an aggressive rehabilitation program, may benefit
from decompressive craniectomy; younger patients may benefit most, and surgery is not
recommended for patients older than 60 years
Clinical evidence of deterioration in swollen supratentorial hemispheric ischemic stroke includes new
or further impairment of consciousness, cerebral ptosis, and changes in pupillary size
In patients with swollen cerebellar infarction, level of consciousness decreases because of
brainstem compression; this decrease may include early loss of corneal reflexes and the
development of miosis
Standardized definitions are needed to facilitate studies of incidence, prevalence, risk factors, and
outcomes
Identification of high-risk patients should include both clinical and neuroimaging data
Complex medical care of these patients includes airway management and mechanical ventilation,
blood pressure control, fluid management, and glucose and temperature control
In patients with swollen supratentorial hemispheric ischemic stroke, routine intracranial pressure
monitoring or cerebrospinal fluid diversion is not indicated, but in patients who continue to
deteriorate neurologically, decompressive craniectomy with dural expansion should be considered
In patients with swollen cerebellar stroke who deteriorate neurologically, suboccipital craniectomy
with dural expansion should be performed
After a cerebellar infarct, performance of ventriculostomy to relieve obstructive hydrocephalus
should be accompanied by decompressive suboccipital craniectomy to avoid deterioration from
upward cerebellar displacement

As many as one third of patients with swollen hemispheric supratentorial infarcts will be severely
disabled and fully dependent on care even after decompressive craniectomy, whereas most patients
with cerebellar infarct will have acceptable functional outcomes after surgery

Seizure Control
Seizures occur in 2-23% of patients within the first days after ischemic stroke. These seizures are
usually focal, but they may be generalized. Although primary prophylaxis for poststroke seizures is not
indicated, secondary prevention of subsequent seizures with standard antiepileptic therapy is
recommended.[3]
A fraction of patients who have experienced stroke develop chronic seizure disorders. Seizure
disorders secondary to ischemic stroke should be managed in the same manner as other seizure
disorders that arise as a result of neurologic injury.[3]

Acute Decompensation
In the case of the rapidly decompensating patient or the patient with deteriorating neurologic status,
reassessment of the ABCs as well as hemodynamics and reimaging are indicated. Many patients who
develop hemorrhagic transformation or progressive cerebral edema will demonstrate acute clinical
decline. Rarely, a patient may have escalation of symptoms secondary to increased size of the
ischemic penumbra. Careful observation for hemorrhagic transformation (especially in the first 24
hours postreperfusion) and cerebral edema in patients with hemispheric or posterior fossa strokes in
the first 24-36 hours is warranted.

Anticoagulation and Prophylaxis

Currently, data are inadequate to justify the routine use of heparin or other anticoagulants in the acute
management of ischemic stroke.[123] Patients with embolic stroke who have another indication for
anticoagulation (eg, atrial fibrillation) may be placed on anticoagulation therapy nonemergently, with
the goal of preventing further embolic disease; however, the potential benefits of that intervention
must be weighed against the risk of hemorrhagic transformation.[3] For more information, see Stroke
Anticoagulation and Prophylaxis.
Immobilized stroke patients in particular are at increased risk of developing deep venous thrombosis
(DVT) and should receive early efforts to reduce the occurrence of DVT. The use of low-dose,
subcutaneous unfractionated or lowmolecular-weight heparin may be appropriate in these
cases.[3] The CLOTS (Clots in Legs Or sTockings after Stroke) trial demonstrated that intermittent
pneumatic compression of the lower extremities, started in the first 3 hospital days, reduced the risk of
DVT in immobile patients with acute stroke.[124]

Neuroprotective Agents
The rationale for the use of neuroprotective agents is that reducing the release of excitatory
neurotransmitters by neurons in the ischemic penumbra may enhance the survival or these neurons.
Despite very promising results in several animal studies, however, no single neuroprotective agent in
ischemic stroke has as yet been supported by randomized, placebo-controlled human studies.
Nevertheless, substantial research is under way evaluating different neuroprotective strategies.
Hypothermia is fast becoming the standard of care for the ongoing treatment of patients surviving
cardiac arrest from ventricular tachycardia or ventricular fibrillation. However, no major clinical study
has demonstrated a role for hypothermia in the early treatment of ischemic stroke.[3]
For more information, see Neuroprotective Agents in Stroke.

Stroke Prevention
Primary prevention refers to the treatment of individuals with no history of stroke. Measures may
include the use of platelet antiaggregants, statins, and exercise. The 2011 AHA/ASA guidelines for
the primary prevention of stroke emphasize the importance of lifestyle changes to reduce welldocumented modifiable risk factors, citing an 80% lower risk of a first stroke in people who follow a
healthy lifestyle compared with those who do not.[23]
Secondary prevention refers to the treatment of individuals who have already had a stroke. Measures
may include the use of platelet antiaggregants,[125]antihypertensives, statins,[126] and lifestyle

interventions. A study by the Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators

concluded that in stroke patients who have significant intracranial arterial stenosis, aspirin should be
used in preference to warfarin for secondary prevention.[127]
Smoking cessation, blood pressure control, diabetes control, a low-fat diet, weight loss, and regular
exercise should be encouraged as strongly as the medications described above. The 2011 AHA/ASA
guidelines recommend ED-based smoking cessation interventions, and consider it reasonable for
EDs to screen patients for hypertension and drug abuse.[23]
Written prescriptions for exercise and medications for smoking cessation (ie, nicotine patch,
bupropion, varenicline) increase the likelihood of success with these interventions. In addition, the
2011 AHA/ASA guidelines for primary stroke prevention indicate that it is reasonable to avoid
exposure to environmental tobacco smoke, despite a lack of stroke-specific data.

Aspirin for primary prevention

Overall, the value of aspirin in primary prevention appears uncertain,[128] and its use for this purpose is
not recommended for patients at low risk. Aspirin is recommended for primary prevention only in
persons with at least a 6-10% risk of cardiovascular events over 10 years.[23]
On the other hand, low-dose aspirin may be beneficial for primary prevention of stroke in women. A
randomized, placebo-controlled trial in 39,876 initially healthy women aged 45 years or older
demonstrated that 100 mg of aspirin on alternate days resulted in a 24% reduction in the risk of
ischemic stroke, with a nonsignificant increase in the risk of hemorrhagic stroke. [129]

Secondary prevention guidelines

Guidelines issued in 2014 by the American Heart Association (AHA)/American Stroke Association
(ASA) on the secondary prevention of stroke emphasize nutrition and lifestyle and include a new
section on aortic atherosclerosis. New recommendations include the following [130, 131] :

Patients who have had a stroke or transient ischemic attack (TIA) should be screened for diabetes
and obesity
Patients should possibly be screened for sleep apnea
Patients should possibly undergo a nutritional assessment and be advised to follow a
Mediterranean-type diet
Patients who have had a stroke of unknown cause should undergo long-term monitoring for atrial
fibrillation (AF)
The new oral anticoagulants dabigatran (class I, level of evidence [LOE] A), apixaban (class I, LOE
B), and rivaroxaban (class IIa, LOE B) are among the drugs recommended for patients with
nonvalvular AF
Based on research results, the guidelines also recommend that, in patients without deep venous
thrombosis (DVT), a patent foramen ovale not be closed. In addition, because there is little data to
suggest that niacin or fibrate drugs, as a means to raise high-density lipoprotein (HDL) cholesterol,
reduce secondary stroke risk, the guidelines no longer recommend their use.

Dual antiplatelet therapy for secondary prevention

A systematic review and meta-analysis of 12 randomized trials involving 3766 patients concluded
that, compared with aspirin alone, dual antiplatelet therapy with aspirin plus either dipyridamole or
clopidogrel appears to be safe and effective in reducing stroke recurrence and other vascular events
(ie, transient ischemic attack [TIA], acute coronary syndrome, MI), in patients with acute ischemic
stroke or TIA.[132] Dual therapy was also associated with a nonsignificant trend toward increased major
bleeding.
The European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) showed that the
combination of aspirin and dipyridamole was preferable to aspirin alone as antithrombotic therapy for
cerebral ischemia of arterial origin.[133] In ESPRIT, secondary prevention was started within 6 months
of a TIA or minor stroke of presumed arterial origin.
The addition of extended-release dipyridamole to aspirin therapy appears to be equally safe and
effective whether started early or late after stroke. A German study in 543 patients found no

significant difference in disability at 90 days, regardless of whether dipyridamole was started within 24
hours of stroke or TIA onset or after 7 days of aspirin monotherapy.[134]
In contrast, the Management of AtheroThrombosis with Clopidogrel in High-risk patients with recent
transient ischaemic attack or ischaemic stroke (MATCH) trial, which included 7599 patients, found
that adding aspirin to clopidogrel did not significantly reduce major vascular events. However, the risk
of life-threatening or major bleeding was increased by the addition of aspirin. [135]

Carotid artery stenosis

For patients at risk for stroke from asymptomatic carotid artery stenosis, the 2011 AHA/ASA primary
prevention guidelines state that older studies that showed revascularization surgery as more
beneficial than medical treatment may now be obsolete because of improvements in medical
therapies. Therefore, individual patient comorbidities, life expectancy, and preferences should
determine whether medical treatment alone or carotid revascularization is selected. [23]

Atrial fibrillation
Atrial fibrillation (AF) is a major risk factor for stroke. The 2011 AHA/ASA primary stroke prevention
guideline recommends that EDs screen for AF and assess patients for anticoagulation therapy if AF is
found.[23]
In the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W),
oral anticoagulation with warfarin proved superior to clopidogrel plus aspirin for prevention of vascular
events in patients with AF who were at high risk of stroke.[136] The study was stopped early because of
clear evidence of superiority of oral anticoagulation therapy.
Interestingly, in ACTIVE W, the rate of vascular events was significantly higher in patients who
switched from warfarin to clopidogrel plus aspirin as a result of randomization than in patients who
had been on warfarin before study enrollment and remained on warfarin during the study. The benefit
of anticoagulation therapy over dual antiplatelet therapy was much more modest in patients who had
not been on warfarin before study initiation and were then randomized to warfarin.
The 2011 ACC Foundation (ACCF)/AHA/Heart Rhythm Society (HRS) AF guideline update states that
the new anticoagulant dabigatran is useful as an alternative to warfarin in patients with AF who do not
have a prosthetic heart valve or hemodynamically significant valve disease.[137] However, a 2012 metaanalysis found an increased risk for MI or acute coronary syndrome with dabigatran. [138]
For patients with AF after stroke or TIA, the 2010 AHA/ASA secondary stroke prevention guidelines
are in accord with the standard recommendation of warfarin, with aspirin as an alternative for patients
who cannot take oral anticoagulants. However, clopidogrel should not be used in combination with
aspirin for such patients, because the bleeding risk of the combination is comparable to that of
warfarin. The guideline states that the benefit of warfarin after stroke or TIA in patients without AF has
not been established.[139]

Specialized Stroke Centers

The concept of the specialized stroke center has evolved in response to the multitude of factors
involved in the care of patients with acute stroke. The Brain Attack Coalition provided
recommendations for the establishment of 2 tiers of stroke centers: primary stroke centers (PSCs)
and comprehensive stroke centers (CSCs).[3] The Joint Commission for the Accreditation of Hospital
Organizations (JCAHO) now provides accreditation for PSCs and CSCs. These centers are
characterized as follows:

PSC: Designed to maximize the timely provision of stroke-specific therapy, including the
administration of rt-PA; the center is also capable of providing care to patients with uncomplicated
stroke
CSC: Shares the commitment that the PSC has to acute delivery of rt-PA and also provides care to
patients with hemorrhagic stroke and intracranial hemorrhage, as well as to all patients with stroke
who require emergent advanced imaging, intra-arterial therapies, neurosurgical interventions, and
management in a neurosurgical intensive care unit (NSICU)
PSCs and CSCs work most effectively when integrated into a regional stroke system of care so that
patients are treated at the most appropriate hospital based on factors such as severity, comorbidities,

and timing. Integrating regional prehospital services (911 and EMS) into this system of care ensures
the most appropriate triage from the field.
Additionally, stroke centers should have personnel versed in the monitoring of stroke vital signs,
which include the following:

Blood pressure
Glucose levels
Temperature
Oxygenation
Change in neurologic status
A further tier, acute stroke ready hospitals, is being defined as hospitals in which most of the
necessary resources are in place to emergently evaluate patients and potentially treat them with
fibrinolytics, with the assistance of remote stroke expertise, typically by telemedicine. Key to the
optimal function of these stroke centers is their interactions within a regional stroke system of care.

Coordination of care
Once patients have been identified as potential stroke patients, their ED evaluation must be fasttracked to allow for the completion of required laboratory tests and requisite noncontrast head CT
scanning, as well as for the notification and involvement of neurologic consultants. These
requirements have led to the development of "code stroke" protocols for the ED. In addition, EMS
personnel are trained to identify possible stroke patients and arrange for their speedy, preferential
transport to a PSC or CSC.[80]
Hospitals with specialized stroke teams have demonstrated significantly increased rates of fibrinolytic
administration and decreased mortality. Cumulatively, the center should identify performance
measures and include mechanisms for evaluating the effectiveness of the system, as well as its
component parts. The acute care of the stroke patient is more than anything a systems-based team
approach requiring the cooperation of the ED, radiology, pharmacy, neurology, and intensive care unit
(ICU) staff.
A stroke system should ensure effective interaction and collaboration among the agencies, services,
and people involved in providing prevention and the timely identification, triage to the most
appropriate hospital, rapid transport, treatment, and rehabilitation of stroke patients. For more
information, see Stroke Team Creation and Primary Stroke Center Certification.

Consultations
A stroke team or an experienced professional who is sufficiently familiar with stroke should be
available within 15 minutes of the patient's arrival in the ED. Other consultations are tailored to
individual patient needs. Often, occupational therapy, physical therapy, speech therapy, and physical
medicine and rehabilitation experts are consulted within the first day of hospitalization.
Consultation of cardiology, vascular surgery, or neurosurgery may be warranted based on the results
of carotid duplex scanning , neuroimaging, transthoracic and transesophageal echocardiography, and
clinical course. During hospitalization, additional useful consultations include the following:

Home health care coordinator

Rehabilitation coordinator
Social worker
Psychiatrist (commonly for depression)
Dietitian

Medication Summary
While only 1 drug, recombinant tissue-type plasminogen activator (rt-PA), has demonstrated efficacy
and effectiveness in treating acute ischemic stroke and is approved by the FDA, other medications
are equally important. National consensus panels have included the use of antihypertensives,
anticonvulsants, and osmotic agents in their recommendations. Additional agents may be required for
comorbid illnesses in many patients with stroke.

Medications for the management of ischemic stroke can be distributed into the following categories:

Anticoagulation
Reperfusion
Antiplatelet
Neuroprotective

Thrombolytics
Class Summary
Thrombolyticmore accurately, fibrinolyticagents convert entrapped plasminogen to plasmin and
initiate local fibrinolysis by binding to fibrin in a clot.
View full drug information

Alteplase (Activase)
Alteplase is a t-PA used in management of acute myocardial infarction (MI), acute ischemic stroke,
and pulmonary embolism. Safety and efficacy with concomitant administration of heparin or aspirin
during the first 24 hours after symptom onset have not been investigated.

Anticonvulsants, Other
Class Summary
While seizures associated with stroke are relatively uncommon, recurrent seizures may be life
threatening. Generally, agents used for treating recurrent convulsive seizures are also used in
patients with seizures after stroke. Benzodiazepines, typically diazepam and lorazepam, are the firstline drugs for ongoing seizures.
View full drug information

Diazepam (Valium)
Diazepam acts on the gamma-aminobutyric acid (GABA) receptor complex in the limbic system and
thalamus, producing a calming effect. The drug is useful in controlling active seizures and should be
augmented by longer-acting anticonvulsants, such as phenytoin or phenobarbital.
View full drug information

Lorazepam (Ativan)
Lorazepam is a short-acting benzodiazepine with a moderately long half-life. It has become the drug
of choice in many centers for treating active seizures.

Antiplatelet Agents
Class Summary
Although antiplatelet agents have proved useful for preventing recurrent stroke or stroke after
transient ischemic attacks (TIAs), efficacy in the treatment of acute ischemic stroke has not been
demonstrated. Early aspirin therapy is recommended within 48 hours of the onset of symptoms but
should be delayed for at least 24 hours after rt-PA administration. Aspirin should not be considered as
an alternative to intravenous fibrinolysis or other therapies aimed at improving outcomes after stroke.
View full drug information

Aspirin (ASA)
Aspirin blocks prostaglandin synthetase action, which in turn inhibits prostaglandin synthesis and
prevents the formation of platelet-aggregating thromboxane A2. It also acts on the hypothalamic heatregulating center to reduce fever.
View full drug information

Dipyridamole and aspirin (Aggrenox)

The combination of extended-release dipyridamole and aspirin reduces the relative risk of stroke,
death, and myocardial infarction (MI). It is used for the secondary prevention of ischemic stroke and
TIAs.

View full drug information

Clopidogrel (Plavix)
Clopidogrel inhibits platelet aggregation and is used for secondary stroke prevention. It is indicated for
the reduction of atherothrombotic events following a recent stroke.

Anticoagulants, Hematologic
Class Summary
Anticoagulants such as warfarin are used for secondary stroke prevention.
View full drug information

Warfarin (Coumadin, Jantoven)

Warfarin is an anticoagulant used to reduce the risk of death, recurrent MI, and thromboembolic
events such as stroke or systemic embolization after MI.
View full drug information

Dabigatran (Pradaxa)
Dabigatran is a competitive, direct inhibitor of thrombin that can prevent thrombus development. This
agent inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. It may be used
as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients
with paroxysmal to permanent atrial fibrillation and risk factors for stroke or systemic embolization.
View full drug information

Rivaroxaban (Xarelto)
Rivaroxaban is a Factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation. The dose is adjusted according to estimated creatinine
clearance.
View full drug information

Apixaban (Eliquis)
Apixaban is a factor Xa inhibitor that inhibits platelet activation by selectively and reversibly blocking
the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It inhibits free
and clot-bound factor Xa and prothrombinase activity. Although this agent has no direct effect on
platelet aggregation, it does indirectly inhibit platelet aggregation induced by thrombin. Apixaban is
indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation.

Analgesics, Other
Class Summary
Hyperthermia in acute stroke is potentially harmful and should be treated. Agents with potential
bleeding risk should be avoided, if possible.
View full drug information

Acetaminophen (Tylenol, Feverall, Aspirin Free Anacin)

Acetaminophen reduces fever by acting directly on hypothalamic heat-regulating centers, which
increases the dissipation of body heat via vasodilation and sweating.

Beta Blockers, Alpha Activity

Class Summary
Optimal blood pressure management in acute stroke remains subject to some debate. Treatment
parameters depend largely on whether the patient is a candidate for fibrinolytic therapy. While the
target blood pressures may differ, the therapeutic agents are primarily the same.
View full drug information

Labetalol (Normodyne, Trandate)

Labetalol is an adrenergic receptor-blocking agent with nonselective beta-adrenergic and selective

alpha1 competitive receptor-blocking actions. It produces dose-related decreases in blood pressure
without inducing reflex tachycardia.

ACE Inhibitors
Class Summary
Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to
angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
View full drug information

Enalapril (Vasotec)
An ACE inhibitor, enalapril decreases circulating angiotensin II levels and suppresses the reninangiotensin-aldosterone system, lowering overall blood pressure.

Calcium Channel Blockers

Class Summary
Optimal blood pressure management in acute stroke remains subject to some debate. Treatment
parameters depend largely on whether the patient is a candidate for fibrinolytic therapy. While the
target blood pressures may differ, the therapeutic agents are largely the same.
View full drug information

Nicardipine (Cardene)
A calcium channel blocker, nicardipine inhibits calcium ion influx into vascular smooth muscle and
myocardium.[90]

Vasodilators
Class Summary
Vasodilators lower blood pressure through direct vasodilation and relaxation of the vascular smooth
muscle. They are used more for blood pressure lowering in severe or refractory situations and should
be used with caution.
View full drug information

Nitroprusside sodium (Nipride, Nitropress, Sodium Nitroprusside)

Nitroprusside sodium is a vasodilator that decreases peripheral vascular resistance by relaxing
arteriolar smooth muscle. It also decreases venous return through venous dilation.