Stroke, Ischemic

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Author

Joseph U Becker, MD, Fellow, Global Health and International Emergency Medicine, Stanford University

Nothing to disclose.

Coauthor(s)

Charles R Wira, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale School of Medicine

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Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

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Specialty Editor(s)

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine

eMedicine Salary Employment

J Stephen Huff, MD, Associate Professor, Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center

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John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

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Richard S Krause, MD, Senior Faculty, Department of Emergency Medicine, State University of New York at Buffalo School of Medicine

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Chief Editor

Rick Kulkarni, MD, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital

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Background

Stroke is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. Also previously called cerebrovascular accident (CVA) or stroke syndrome, stroke is a nonspecific term encompassing a heterogeneous group of pathophysiologic causes, including thrombosis, embolism, and hemorrhage.

Click here to view a slideshow on Acute Stroke.

Strokes are broadly classified as either hemorrhagic or ischemic. Acute ischemic stroke refers to stroke caused by thrombosis or embolism and is more common than hemorrhagic stroke. Prior literature indicates that only 8-18% of strokes were hemorrhagic. However, a recent retrospective review from a stroke center found that 40.9% of 757 strokes were hemorrhagic. However, the authors state that the increased percentage of hemorrhagic stroke may be due to improvement of CT scan availability and implementation unmasking a previous underestimation of the actual percentage, or it may be due to an increase in therapeutic use of antiplatelet agents and warfarin causing an increase in the incidence of hemorrhage.[1]

Emergency physicians (EPs) play a central role in the initial evaluation and management of patients with acute stroke. In 1992, a National Institute of Neurologic Disorders and Stroke (NINDS) t-PA Pilot Trial succeeded at enrolling patients within 90 minutes, which led to the NINDS requirement that investigators from emergency medicine be involved in the larger randomized trial. The NINDS recombinant tissue-type plasminogen activator (rt-PA) stroke study group first reported that the early administration of rt-PA benefited carefully selected patients with acute ischemic stroke.[2]

The trial had a positive outcome leading to the long-standing goal of t-PA administration within a 3-hour window for a patient deemed likely to benefit from thrombolytic intervention. This window has recently been expanded after recent evidence suggested benefit out to 4.5 hours. The collaboration between emergency physicians and neurologists was visionary and enabled the early enrollment of patients, which was an integral component of the positive results. Encouraged by this breakthrough study and the subsequent approval of t-PA for use in acute ischemic stroke by the US Food and Drug Administration (FDA), many medical professionals now newly consider acute ischemic stroke to be a medical emergency—one that may be amenable to treatment.

Building on the success of the NINDS trial and other studies, the European Cooperative Acute Stroke Study III (ECASS III) examined the use of thrombolytic therapy between 3 and 4.5 hours after the onset of symptoms. Thrombolytic therapy was again found to be efficacious in improving neurologic outcomes, suggesting a wider time window for the administration of thrombolytics.[3] Based on this and other data, in May 2009, the American Heart Association and the American Stroke Association guidelines for the administration of rt-PA were revised to expand the treatment window from 3 to 4.5 hours.[4] This indication has not yet been FDA approved.

Since EPs play a central role in the initial evaluation and treatment of patients with acute ischemic stroke, our understanding of its pathophysiology, clinical presentation, and ED evaluation is essential. The EP also must be completely familiar with the entire therapeutic armamentarium currently available to treat acute ischemic stroke, which includes supportive care, treatment of neurologic complications, antiplatelet therapy, glycemic control, blood pressure control, prevention of hyperthermia, and thrombolytic therapy.

In recent years, significant advances have also been made in stroke prevention, supportive care, and rehabilitation. With emerging evidence that the brief counsel of emergency physicians may impact primary and secondary prevention of disease processes, the emergency medicine specialty is also challenged to be vigilant in utilizing "teachable moments" or "brief negotiated interviews" to impact patient education, awareness, and compliance with established preventative treatments. Overall, when the direct costs (care and treatment) and the indirect costs (lost productivity) of strokes are considered together, the cost to US society is $43.3 billion per year.[5]

Pathophysiology

On the macroscopic level, ischemic stroke most often is caused by extracranial embolism or intracranial thrombosis, but it may also be caused by decreased cerebral blood flow. On the cellular level, any process that disrupts blood flow to a portion of the brain unleashes an ischemic cascade, leading to the death of neurons and cerebral infarction. Understanding this chain of events is important for understanding current therapeutic approaches.

Embolism

Emboli may arise from the heart, the extracranial arteries or, rarely, the right-sided circulation (paradoxical emboli) with subsequent passage through a patent foramen ovale. The sources of cardiogenic emboli include valvular thrombi (eg, in mitral stenosis, endocarditis, prosthetic valve), mural thrombi (eg, in myocardial infarction [MI], atrial fibrillation [AF], dilated cardiomyopathy, severe congestive heart failure [CHF]), and atrial myxoma. MI is associated with a 2-3% incidence of embolic stroke, of which 85% occur in the first month after MI.[6]

Thrombosis

Thrombotic stroke can be divided into large vessel, including the carotid artery system, or small vessel comprising the intracerebral arteries, including the branches of the Circle of Willis and the posterior circulation. The most common sites of thrombotic occlusion are cerebral artery branch points, especially in the distribution of the internal carotid artery. Arterial stenosis can cause turbulent blood flow, which can increase risk for thrombus formation, atherosclerosis (ie, ulcerated plaques), and platelet adherence; all cause the formation of blood clots that either embolize or occlude the artery.

Less common causes of thrombosis include polycythemia, sickle cell anemia, protein C deficiency, fibromuscular dysplasia of the cerebral arteries, and prolonged vasoconstriction from migraine headache disorders. Any process that causes dissection of the cerebral arteries also can cause thrombotic stroke (eg, trauma, thoracic aortic dissection, arteritis). Occasionally, hypoperfusion distal to a stenotic or occluded artery or hypoperfusion of a vulnerable watershed region between two cerebral arterial territories can cause ischemic stroke.

Flow disturbances

Stroke symptoms can result from inadequate cerebral blood flow due to decreased blood pressure (and specifically decreased cerebral perfusion pressure) or due to hematologic hyperviscosity due to sickle cell disease or other hematologic illnesses such as multiple myeloma and polycythemia vera. In these instances, cerebral injury may occur in the presence of damage to other organ systems.

Ischemic cascade

Within seconds to minutes of the loss of perfusion to a portion of the brain, an ischemic cascade is unleashed that, if left unchecked, causes a central area of irreversible infarction surrounded by an area of potentially reversible ischemic penumbra.

On the cellular level, the ischemic neuron becomes depolarized as ATP is depleted and membrane ion-transport systems fail. The resulting influx of calcium leads to the release of a number of neurotransmitters, including large quantities of glutamate, which, in turn, activates N -methyl-D-aspartate (NMDA) and other excitatory receptors on other neurons. These neurons then become depolarized, causing further calcium influx, further glutamate release, and local amplification of the initial ischemic insult. This massive calcium influx also activates various degradative enzymes, leading to the destruction of the cell membrane and other essential neuronal structures.[7]

Free radicals, arachidonic acid, and nitric oxide are generated by this process, which leads to further neuronal damage. Within hours to days after a stroke, specific genes are activated, leading to the formation of cytokines and other factors that, in turn, cause further inflammation and microcirculatory compromise.[7] Ultimately, the ischemic penumbra is consumed by these progressive insults, coalescing with the infarcted core, often within hours of the onset of the stroke.

The central goal of therapy in acute ischemic stroke is to preserve the area of oligemia in the ischemic penumbra. The area of oligemia can be preserved by limiting the severity of ischemic injury (ie, neuronal protection) or by reducing the duration of ischemia (ie, restoring blood flow to the compromised area).

The ischemic cascade offers many points at which such interventions could be attempted. Multiple strategies and interventions for blocking this cascade are currently under investigation. The timing of the restoration of cerebral blood flow appears to be a critical factor. Time also may prove to be a key factor in neuronal protection. Although still being studied, neuroprotective agents, which block the earliest stages of the ischemic cascade (eg, glutamate receptor antagonists, calcium channel blockers), are expected to be effective only in the proximal phases of presentation.

Epidemiology

Frequency

United States

Incidence for first-time stroke is more than 700,000 per year, of which 20% of these patients will die within the first year after stroke. At current trends, this number is projected to jump to 1 million per year by the year 2050.[8]

International

Global incidence of stroke is unknown.

Mortality/Morbidity

Stroke is the third leading cause of death and the leading cause of disability in the United States.[9]

Sex

Men are at higher risk for stroke than women. Additionally, women seem to respond better than men to interventions such as rt-PA.

Age

Although stroke often is considered a disease of elderly persons, one third of strokes occur in persons younger than 65 years.[8]

History

Physical

Causes

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Prehospital Care

The recommendations herein for the acute management of the stroke patient are derived from the American Heart Association (AHA) "Guidelines for the Early Management of Adults with Ischemic Stroke" 2007.[12]

Recognition that a stroke may have occurred and rapid transport to the appropriate receiving facility are necessary after addressing the ABCs. Of patients with signs or symptoms of stroke, 29-65% utilize some facet of the EMS system.[37, 38] Further, most patients who call EMS are those who present within 3 hours of symptom onset. EMS use is associated with shorter time periods from symptom onset to hospital arrival.[39, 40]

Stroke should be a priority dispatch with prompt EMS response. EMS responders should provide in as timely a manner as possible advance notice to their emergency department destination so as to allow preparation and marshaling of personnel and resources. There is now ongoing development of stroke center designation that would then become the preferred destination for patients with acute stroke symptoms utilizing EMS.

There appears to be limited data supporting the use of emergency air transport for patients with acute stroke symptoms. 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.[12]

Emergency Department Care

The goal for the acute management of patients with stroke is to stabilize the patient and complete initial evaluation and assessment including imaging and laboratory studies within 60 minutes of patient arrival.[12] Critical decisions focus on need for intubation, blood pressure control, and determining risk/benefit for thrombolytic intervention.

Airway and breathing

Circulation

Patients with acute stroke require intravenous access and cardiac monitoring in the ED. Patients with acute stroke are at risk for cardiac arrhythmias and elevated cardiac biomarkers. In addition, atrial fibrillation may be associated with acute stroke as either the cause (embolic disease) or as a complication.[43, 44]

Blood glucose control

Recent data suggest that severe hyperglycemia is independently associated with poor outcome and reduced reperfusion in thrombolysis as well as extension of the infarcted territory.[45, 46, 47] Additionally, normoglycemic patients should not be given excessive glucose-containing intravenous fluids, as this may lead to hyperglycemia and may exacerbate ischemic cerebral injury. Blood sugar control should be tightly maintained with insulin therapy with the goal of establishing normoglycemia (90-140 mg/dL). Additionally, close monitoring of blood sugar level should continue throughout hospitalization to avoid hypoglycemia.[12]

Head positioning

Studies have shown that cerebral perfusion pressure is maximized when patients are maintained in a supine position. However, lying flat may serve to increase intracranial pressure and thus is not recommended in cases of subarachnoid or other intracranial hemorrhage. Because prolonged immobilization may lead to its own complications, including deep venous thrombosis, pressure ulcer aspiration, and pneumonia, patients should not be kept flat for longer than 24 hours.[48]

Blood pressure control

In poor flow states as occurs with thrombotic and embolic ischemic stroke as well as in increased intracranial pressure due to cerebral edema, the cerebral vasculature is without vasoregulatory capability and thus relies directly on mean arterial pressure (MAP) and cardiac output for maintenance of cerebral blood flow. Therefore, aggressive efforts to lower blood pressure may decrease perfusion pressure and may prolong or worsen ischemia. Both elevated and low blood pressure are associated with poor outcomes in patients with acute stroke.[49, 50]

Recent studies have demonstrated that blood pressure typically drops in the first 24 hours after acute stroke whether or not antihypertensives are administered. Further, studies reveal poorer outcomes in patients with lower pressures, and these poorer outcomes correlated with the degree of pressure decline.[49] However, other data suggest that blood pressure control, particularly when systolic or diastolic pressures are extreme and when thrombolytics are planned, can be an important treatment intervention. As a result, the control of hypertension in the setting of acute stroke is controversial.[20] Because a systolic blood pressure greater than 185 mm Hg or a diastolic pressure of greater than 110 mm Hg is a contraindication to thrombolytics, emergency blood pressure control is indicated in order to allow for thrombolytic administration.

Outside of the consideration of thrombolytic administration, in the absence of hypertension-related complications or organ dysfunction, no data support the administration of emergency antihypertensives in acute stroke.

The consensus recommendation is to lower blood pressure only if systolic pressure is in excess of 220 mm Hg or if diastolic pressure is greater than 120 mm Hg.[12] However, rapid reduction of blood pressure, no matter the degree of hypertension may in fact be harmful.

The management of blood pressure in patients with acute ischemic stroke is divided into those who are candidates for thrombolytics and those who are not.

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 I clinical trials.[51, 52]

High body temperature in the first 12-24 hours after stroke onset has been associated with poor functional outcome. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial assessed whether early treatment with paracetamol improves functional outcome in patients with acute stroke by reducing body temperature and preventing fever. Patients (n=1400) were randomly assigned to receive acetaminophen (6 g daily) or placebo within 12 hours of symptom onset. After 3 months, improvement on the modified Rankin scale was not beyond what was expected. These results do not support routine use of high-dose acetaminophen in patients with acute stroke.[53]

Cerebral edema control

Cerebral edema occurs in up to 15% of patients with ischemic stroke, reaching maximum severity 72-96 hours after the onset of stroke. Hyperventilation and mannitol are used routinely to decrease intracranial pressure quickly and temporarily. No evidence exists supporting the use of corticosteroids to decrease cerebral edema in acute ischemic stroke. Prompt neurosurgical assistance should be sought when indicated.[12]

Seizure control

Seizures occur in 2-23% of patients within the first days after stroke. Although seizure prophylaxis is not indicated, prevention of subsequent seizures with standard antiepileptic therapy is recommended.[12]

Acute decompensation or escalation

In the case of the rapidly decompensating patient or the patient with deteriorating neurologic status, reassessment of 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. Some advocate resetting the time window to zero in this circumstance and encourage consideration of reperfusion strategies.

Medication Summary

Medications for the management of ischemic stroke can be distributed into the following categories: (1) anticoagulation, (2) reperfusion, (3) antiplatelet, and (4) neuroprotective.

Anticoagulation

Although heparin prevents recurrent cardioembolic stroke and may help inhibit ongoing cerebrovascular thrombosis, current guidelines do not recommend anticoagulation for any subset of patients with stroke because of insufficient data. Both randomized prospective trials evaluating t-PA for acute ischemic stroke (ECASS and NINDS) excluded patients who were receiving anticoagulants. Heparin is known to prolong the lytic state caused by t-PA. Immobilized stroke patients who are not receiving anticoagulants, such as IV heparin or an oral anticoagulant, may benefit from low-dose subcutaneous unfractionated or low molecular weight heparin, which reduces the risk of deep vein thrombosis.[12]

The use of low molecular weight heparin as treatment of acute ischemic stroke has not yet been studied adequately. However, multiple past studies have failed to show any beneficial effect of anticoagulation in acute ischemic stroke. Although trials of anticoagulants in the treatment of acute ischemic stroke are ongoing, no current data exist to support their use in acute ischemic stroke.[12]

Reperfusion agents (thrombolytics)

Thrombolytics restore cerebral blood flow among some patients with acute ischemic stroke and may lead to improvement or resolution of neurologic deficits. Unfortunately, thrombolytics can also cause symptomatic intracranial hemorrhage, defined as radiographic evidence of hemorrhage combined with escalation of NIHSS by 4 or more points.

Major clinical trials evaluating the use of intravenous thrombolysis have included the MASK-E, MASK-I, ASK, ECASS I, ECASS II, ECASS III, NINDS trial, and ATLANTIS A and B. While both streptokinase and rt-PA have been shown to benefit patients with acute MI, only alteplase (rt-PA) has been shown to benefit selected patients with acute ischemic stroke. Among the rt-PA trials, ECASS I and II and ATLANTIS A and B enrolled patients up to 6 hours after symptom onset, while the NINDS rt-PA trial treated patients within a 3-hour window.[20, 54, 55, 56, 22, 3]

ECASS III evaluated patients presenting with stroke between 3 and 4.5 hours after symptom onset. Current practice guidelines originate from the NINDS data, and meta-analyses of the above listed clinical trials in the first 3 hours of presentation. However, the ECASS III trial, published in September 2008, provides evidence of the efficacy and safety of thrombolytics out to 4.5 hours after symptom onset and along with other studies may lead to revisions of current practice guidelines.[3] A pooled analysis by Lees et al reinforces the results of the ECASS III trial.[57]

The NINDS t-PA trial study group in 1995 reported that recombinant t-PA reduced disability in patients with acute ischemic stroke. NINDS enrolled 624 patients in 39 centers during the period 1991-1994. To be enrolled, patients must have had onset of stroke symptoms within 3 hoursof presentation; only patients with no evidence of hemorrhage by cranial CT scan were eligible.[20]

Excluded patients were those who had rapidly improving or minor symptoms, significant pretreatment hypertension (BP >185/110 or BP requiring aggressive therapy), symptoms suggestive of subarachnoid hemorrhage, previous history of intracranial hemorrhage, recent stroke or head injury (within 3 mo), or recent major surgery (within 14 d). Also excluded were patients who had received heparin or other anticoagulants within the past 48 hours, had elevated prothrombin time (PT) or activated partial thromboplastin time (aPTT); or were thrombocytopenic (platelet count < 100 X 109/L), hypoglycemic (glucose level < 50 mg/dL), or hyperglycemic (glucose level >400 mg/dL).[20]

Patients in the rt-PA group were given 0.9 mg/kg total dose of rt-PA: 10% as a bolus and 90% over 60 minutes. The maximal dose was 90 mg. All patients were admitted to an ICU, and antiplatelet and anticoagulation therapies were withheld for the first 24 hours after treatment.[20]

NINDS reported a statistically significant increase in full recovery in patients given t-PA (39% vs 26% by dichotomized modified Rankin scale). Of the various scales used to measure disability in the NINDS study, the modified Rankin scale is probably the most useful clinically, since it measures functional neurologic outcome. Patients were considered to be completely recovered from stroke if, 90 days after treatment, they scored less than 2 on the modified Rankin Scale (either no residual deficits or deficits without disability). The beneficial neurologic outcomes were sustained at 1 year and published in 1999.[20]

NINDS also had a 6.4% rate of symptomatic intracranial hemorrhage in the rt-PA group that was higher than in the placebo group. In spite of this, an overall trend toward decreased mortality in the treatment group at 3 months (17% vs 21%) was noted. Subsequent number needed to treat (NNT) analysis of the NINDS stroke trial revealed that 1 of 8 patients given t-PA had complete neurologic recovery at 90 days, while 1 of 17 suffered symptomatic intracranial hemorrhage within the first 36 hours.[20]

ECASS enrolled 620 patients in 75 hospitals in 14 European countries during the period 1992-1994. Eligible patients were those who presented within 6 hoursof stroke symptom onset and had no hemorrhage by cranial CT scan. Excluded patients had severe hemispheric stroke symptoms (eg, hemiplegia with impaired level of consciousness or forced head or eye deviation) or improving symptoms, had recent trauma or surgery, were receiving anticoagulants, or had signs of early infarct on cranial CT scan, such as hypodensity or sulcal effacement in more than 33% of the MCA territory. Patients in the t-PA group were given 1.1 mg/kg of t-PA to 100 mg total over 1 hour (10% of the total dose was given over the first 1-2 min). Anticoagulation was not allowed for the first 24 hours after treatment.[22]

Although ECASS, like the NINDS study, found an equivocally significant increase in full recovery by modified Rankin scale 90 days after treatment in the t-PA group (36% vs 29%), it also documented a statistically significant increase in mortality rate at 90 days (22% vs 16%). NNT analysis of the equivocal ECASS data revealed that 1 in 14 patients given t-PA had full neurologic recovery.[22]

Proponents of rt-PA have argued that the results of ECASS and NINDS cannot be compared directly, because in ECASS, a higher dose of t-PA was given (1.1 vs 0.9 mg/kg), t-PA was given during a longer window of time after symptom onset (6 vs 3 h), and patients may have received different supportive care in the participating centers (Europe vs US).[20, 56, 22]

ECASS III sought to evaluate the efficacy of thrombolytic therapy between 3 and 4.5 hours. The rationale for ECASS III is based on a pooled analysis of prior studies involving a range of symptom duration times. ECASS III enrolled a total of 821 patients (418 to intervention and 403 to control groups) with a median time for alteplase (0.9 mg/kg of body weight) administration of 3 hours 59 minutes. Analysis of disability (modified Rankin scale) and global outcome (composite measure of multiple neurologic and disability scores) revealed significantly favorable outcomes in the alteplase group (52.4% vs 45.2% P= 0.04, and OR 1.28, 95% CI 1 to 1.65, P< 0.05). As with the prior studies, there was a statistically significant association between alteplase and intracranial hemorrhage (P=0.001). The conclusions of the ECASS III trial along with other data may provide the necessary evidence to expand the treatment window for thrombolytic therapy to 4.5 hours.[3]

Despite the potential benefit of rt-PA extending out to 4.5 hours, both ECASS and NINDS indicate that, the earlier rt-PA can be administered, the better the outcome. Evidence suggesting a widened therapeutic window should not be used to justify retarding the rapid triage and assessment necessary for patients with acute stroke.[12, 3]

In May 2009, the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the administration of recombinant tissue plasminogen activator (rt-PA) following acute stroke were revised to expand the window of treatment from 3 hours to 4.5 hours to provide more patients with an opportunity to receive benefit from this effective therapy.[4] Recent studies have provided new data on rt-PA treatment in the 3-to-4.5-hour window.[3, 58]

Patients who are eligible for treatment with rt-PA within 3 hours of onset of stroke should be treated as recommended in the 2007 guidelines.[12] Although a longer time window for treatment with rt-PA has been tested formally, delays in evaluation and initiation of therapy should be avoided because the opportunity for improvement is greater with earlier treatment. rt-PA should be administered to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke (Class I recommendation, level of Evidence B). Eligibility criteria for treatment in the 3 to 4.5 hours after acute stroke are similar to those for treatment at earlier time periods, with any one of the following additional exclusion criteria:

Risks of thrombolytics

Meta-analysis of studies published thus far revealed an overall rate of symptomatic hemorrhage to be 5.2%.[59] However, studies evaluating protocol violations of the inclusion/exclusion criteria derived from the NINDS trial have had higher rates of symptomatic cerebral hemorrhage. Current American Heart Association (AHA)/American Stroke Association (ASA) inclusion guidelines for the administration of rt-PA are as follows:[12]

Patients with evidence of low attenuation (edema or ischemia) involving more than a third of the distribution of the middle cerebral artery on their initial noncontrast CT scan were less likely to have favorable outcome after thrombolytic therapy and are thought to be at higher risk for hemorrhagic transformation of their ischemic stroke.[21] Furthermore, it appears that hemorrhagic complications after thrombolytic administration occurs most frequently when the inclusion/exclusion criteria of the initial NINDs trial are violated.[12, 59]

The 2007 AHA guidelines allow the administration of rt-PA to patients with seizure and stroke as long as neurologic deficits are attributable to the stroke syndrome and not the postictal state.[12]

In addition to the risk of symptomatic intracranial hemorrhage (6.4% in the NINDS trial), other complications include potentially hemodynamically significant hemorrhage and angioedema or allergic reactions.[12]

There is some evidence for an increased risk of symptomatic intracerebral hemorrhage in patients given a thrombolytic who are taking aspirin and clopidogrel.[60] However, this is not a contraindication to thrombolysis, as the benefit is still seen to exceed the risk.

Streptokinase has not been shown to benefit patients with acute ischemic stroke, but it has been shown to increase their risk of intracranial hemorrhage and death. Of 3 major randomized controlled trials, all were terminated prematurely because streptokinase was associated with unacceptable rates of mortality.[61, 62] The failure of streptokinase as a thrombolytic agent for acute ischemic stroke has been attributed to its long action and lack of clot specificity. While alteplase specifically activates plasminogen already bound to a thrombus, streptokinase activates unbound circulating plasminogen.

Intra-arterial thrombolysis

No human trials comparing the intravenous versus intra-arterial administration of thrombolytics exist. However, several authors have posited potential benefits from the intra-arterial approach. These advantages include the higher local concentrations of thrombolytic possibly allowing lower total doses (and theoretically less risk of systemic bleed) and a suggested longer therapeutic window, potentially out to 6 hours. However, the longer time to administration via the intra-arterial approach versus the intravenous approach may mitigate some of this advantage.

One agent in particular, prourokinase, administered intra-arterially was found to have benefit when administered in less than 6 hours' duration since the development of symptoms in patients with MCA strokes.[12] This agent is not currently available for use in the United States, and further studies regarding its effectiveness intra-arterially are warranted. The time window for intra-arterial thrombolysis is 6 hours, but it may be extended up to 12 hours in unique circumstances. As such, the administration of intra-arterial thrombolytics has been most common in situations when intravenous thrombolysis is expected to be limited, as in major vascular occlusions, presentation between 3-6 hours since symptom onset and severe neurologic deficit.[12]

In addition, there appears to be some benefit of intra-arterial administration of thrombolytics (urokinase) in patients with vertebral or basilar artery occlusion treated within 24 hours of symptom onset.[63, 64, 65] Furthermore, intra-arterial thrombolysis may be indicated in patients with contraindications to intravenous thrombolytic administration such as recent surgery.[12, 63, 64, 65]

Ultrasonographic-assisted thrombolysis

Given that a substantial proportion of patients treated with rt-PA have persistent disability and that one of the major reasons for this therapeutic failure is incomplete or slow thrombolysis, researchers have studied the use of transcranial ultrasonography in assisting rt-PA in thrombolysis. By delivering mechanical pressure waves to the thrombus, ultrasound can theoretically expose more of its surface to the circulating thrombolytic agent.

In one study, patients were randomly assigned to either rt-PA with placebo or rt-PA along with continuous ultrasonography. A significant improvement occurred in the rate of recanalization, and a trend toward increased rate of stroke recovery was noted in the transcranial Doppler group.[66]

A meta-analysis of studies of ultrasound-enhanced thrombolysis in ischemic stroke found that the likelihood of complete recanalization was higher in patients receiving the combination t-PA with transcranial Doppler or transcranial color-coded duplex versus intravenous t-PA alone (pooled odds ratio, 2.99; 95% confidence index, 1.70-5.25; P=0.0001).[67] The use of high-frequency ultrasound did not increase the risk of symptomatic intracerebral hemorrhage. The endpoints reported in the review did not include clinical improvement. This is a promising technology for further study.

Further research is necessary to determine the exact role of transcranial Doppler ultrasonography in assisting thrombolytics in acute ischemic stroke.

Experimental agents

Class Summary

These agents convert entrapped plasminogen to plasmin and initiate local fibrinolysis by binding to fibrin in a clot.

Alteplase (Activase)

Clinical Context:  Tissue plasminogen activator (t-PA) used in management of acute MI, acute ischemic stroke, and pulmonary embolism. Safety and efficacy with concomitant administration of heparin or aspirin during first 24 h after symptom onset have not been investigated.

Class Summary

Although antiplatelet agents have been shown useful for preventing recurrent stroke or stroke after TIAs, efficacy in the treatment of acute ischemic stroke has not been demonstrated. The International Stroke Trial and Chinese Acute Stroke Trial demonstrated modest benefit of aspirin in the setting of acute ischemic stroke. The International Stroke Trial randomized 20,000 patients within 24 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 early stroke recurrence.[74, 75]

The Chinese Acute Stroke Trial evaluated 21,106 patients and had a 4-week mortality reduction of 3.3% contrasted to 3.9%. A separate study also found that the combination of aspirin and low molecular weight heparin did not significantly improve outcomes.[76] 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 thrombolysis or other therapies aimed at improving outcomes after stroke.

The precise time to initiate dipyridamole following ischemic stroke or transient ischemic attack (TIA) was evaluated in 46 stroke units in Germany.[77] Patients presenting with an NIH stroke scale score ≤ 20 were randomly assigned to receive aspirin 25 mg plus extended-release dipyridamole 200 mg bid (early dipyridamole regimen) (n=283) or aspirin monotherapy (100 mg once daily) for 7 days (n=260). Therapy in either group was initiated within 24 hours of stroke onset. After 2 week, all patients received aspirin plus dipyridamole for up to 90 days. At day 90, 154 (56%) patients in the early dipyridamole group and 133 (52%) in the aspirin plus later dipyridamole group had no or mild disability (P=0.45). The authors concluded that early initiation of aspirin plus extended-release dipyridamole is likely to be as safe and effective in preventing disability as is later initiation after 7 days following stroke onset.

Other antiplatelet agents are also under evaluation for use in the acute presentation of ischemic stroke. In a preliminary pilot study, abciximab was given within 6 hours to establish a safety profile. A trend toward improved outcome at 3 months for the treatment versus the placebo group was noted.[78] Further clinical trials are necessary.

Aspirin (Bayer Aspirin, Anacin, Bufferin)

Clinical Context:  Blocks prostaglandin synthetase action, which, in turn, inhibits prostaglandin synthesis and prevents formation of platelet-aggregating thromboxane A2. Also acts on hypothalamic heat-regulating center to reduce fever.

Ticlopidine (Ticlid)

Clinical Context:  Second-line antiplatelet therapy for patients who cannot tolerate aspirin or in whom aspirin not effective.

Further Inpatient Care

Referral to a physician with special interest in stroke is ideal. Stroke care units exist and are said to show improved outcomes with specially trained personnel. See the discussion on Stroke Centers in Special Concerns. Comorbid medical problems need to be addressed. Assessments of swallow function, prior to the reinstitution of oral feeding is recommended.[12] Patients should receive deep venous thrombosis prophylaxis, although the timing of institution of this therapy is unknown. Serial monitoring and interventions when necessary early in the clinical course and eventual stroke rehabilitation and physical and occupational therapy are the ideals.

Milionis et al showed a 10-year risk reduction for recurrent stroke when statin therapy was added after a first stroke. Statin use also reduced the risk of mortality, even after adjustment for potential confounders, such as blood pressure control, reported investigators. The study was a retrospective observational analysis of 794 patients hospitalized for a first-time ischemic stroke that linked hospitalization and death records from the Athenian Stroke Registry. The analysis included a period, from January 1997 onward, during which poststroke statin therapy was not common practice.[79]

Complications

The most common and important complications of ischemic stroke include cerebral edema, hemorrhagic transformation, and seizures.

References

  1. Shiber JR, Fontane E, Adewale A. Stroke registry: hemorrhagic vs ischemic strokes. Am J Emerg Med. Mar 2010;28(3):331-3.[View Abstract]
  2. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. Dec 14 1995;333(24):1581-7.[View Abstract]
  3. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. Sep 25 2008;359(13):1317-29.[View Abstract]
  4. [Guideline] Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr. Expansion of the Time Window for Treatment of Acute Ischemic Stroke With Intravenous Tissue Plasminogen Activator. A Science Advisory From the American Heart Association/American Stroke Association. Stroke. May 28 2009;[View Abstract]
  5. American Heart Association. Economic Cost of Cardiovascular Diseases. Available at Http://www.americanheart.org/scientific/Hsstats98/10econom.html. Accessed June 2005.
  6. Witt BJ, Ballman KV, Brown RD Jr, Meverden RA, Jacobsen SJ, Roger VL. The incidence of stroke after myocardial infarction: a meta-analysis. Am J Med. Apr 2006;119(4):354.e1-9.[View Abstract]
  7. Kasner SE, Grotta JC. Emergency identification and treatment of acute ischemic stroke. Ann Emerg Med. Nov 1997;30(5):642-53.[View Abstract]
  8. American Heart Association. 2002 Heart and Stroke Facts Statistical Update. Dallas: American Heart Association; 2001.
  9. U.S. Centers for Disease Control and Prevention and the Heart Disease and Stroke Statistics - 2007 Update, published by the American Heart Association. Available at http://www.strokecenter.org/patients/stats.htm.. Accessed September 2008.
  10. [Guideline] Adams HP Jr. Guidelines for the management of patients with acute ischemic stroke: a synopsis. A Special Writing Group of the Stroke Council, American Heart Association. Heart Dis Stroke. Nov-Dec 1994;3(6):407-11.[View Abstract]
  11. Flynn RW, MacWalter RS, Doney AS. The cost of cerebral ischaemia. Neuropharmacology. Sep 2008;55(3):250-6.[View Abstract]
  12. [Guideline] Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. May 2007;38(5):1655-711.[View Abstract]
  13. Mandelzweig L, Goldbourt U, Boyko V, Tanne D. Perceptual, social, and behavioral factors associated with delays in seeking medical care in patients with symptoms of acute stroke. Stroke. May 2006;37(5):1248-53.[View Abstract]
  14. Huff JS. Stroke mimics and chameleons. Emerg Med Clin North Am. Aug 2002;20(3):583-95.[View Abstract]
  15. Libman RB, Wirkowski E, Alvir J, Rao TH. Conditions that mimic stroke in the emergency department. Implications for acute stroke trials. Arch Neurol. Nov 1995;52(11):1119-22.[View Abstract]
  16. National Institutes of Health Stroke Scale. Available at http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf. Accessed October 2008.
  17. Tintinalli J, Kellen G, Stapczynski J. Emergency Medicine: A Comprehensive Study Guide. 6th ed. New York: American College of Emergency Physicians. McGraw Hill; 2004:1382-1390.
  18. Leira EC, Chang KC, Davis PH, et al. Can we predict early recurrence in acute stroke?. Cerebrovasc Dis. 2004;18(2):139-44.[View Abstract]
  19. Wardlaw JM, Mielke O. Early signs of brain infarction at CT: observer reliability and outcome after thrombolytic treatment--systematic review. Radiology. May 2005;235(2):444-53.[View Abstract]
  20. The NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. Dec 14 1995;333(24):1581-7.[View Abstract]
  21. von Kummer R, Allen KL, Holle R, et al. Acute stroke: usefulness of early CT findings before thrombolytic therapy. Radiology. Nov 1997;205(2):327-33.[View Abstract]
  22. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. Oct 4 1995;274(13):1017-25.[View Abstract]
  23. Klotz E, Konig M. Perfusion measurements of the brain: using dynamic CT for the quantitative assessment of cerebral ischemia in acute stroke. Eur J Radiol. Jun 1999;30(3):170-84.[View Abstract]
  24. Wintermark M, Reichhart M, Thiran JP, et al. Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients. Ann Neurol. Apr 2002;51(4):417-32.[View Abstract]
  25. Wildermuth S, Knauth M, Brandt T, Winter R, Sartor K, Hacke W. Role of CT angiography in patient selection for thrombolytic therapy in acute hemispheric stroke. Stroke. May 1998;29(5):935-8.[View Abstract]
  26. Verro P, Tanenbaum LN, Borden NM, Sen S, Eshkar N. CT angiography in acute ischemic stroke: preliminary results. Stroke. Jan 2002;33(1):276-8.[View Abstract]
  27. Sorensen AG, Buonanno FS, Gonzalez RG, et al. Hyperacute stroke: evaluation with combined multisection diffusion-weighted and hemodynamically weighted echo-planar MR imaging. Radiology. May 1996;199(2):391-401.[View Abstract]
  28. Gonzalez RG, Schaefer PW, Buonanno FS, et al. Diffusion-weighted MR imaging: diagnostic accuracy in patients imaged within 6 hours of stroke symptom onset. Radiology. Jan 1999;210(1):155-62.[View Abstract]
  29. Barber PA, Darby DG, Desmond PM, et al. Identification of major ischemic change. Diffusion-weighted imaging versus computed tomography. Stroke. Oct 1999;30(10):2059-65.[View Abstract]
  30. Lovblad KO, Baird AE, Schlaug G, et al. Ischemic lesion volumes in acute stroke by diffusion-weighted magnetic resonance imaging correlate with clinical outcome. Ann Neurol. Aug 1997;42(2):164-70.[View Abstract]
  31. Neumann-Haefelin T, Wittsack HJ, Wenserski F, et al. Diffusion- and perfusion-weighted MRI. The DWI/PWI mismatch region in acute stroke. Stroke. Aug 1999;30(8):1591-7.[View Abstract]
  32. Lee LJ, Kidwell CS, Alger J, Starkman S, Saver JL. Impact on stroke subtype diagnosis of early diffusion-weighted magnetic resonance imaging and magnetic resonance angiography. Stroke. May 2000;31(5):1081-9.[View Abstract]
  33. Camerlingo M, Casto L, Censori B, Ferraro B, Gazzaniga GC, Mamoli A. Transcranial Doppler in acute ischemic stroke of the middle cerebral artery territories. Acta Neurol Scand. Aug 1993;88(2):108-11.[View Abstract]
  34. Sagar G, Riley P, Vohrah A. Is admission chest radiography of any clinical value in acute stroke patients?. Clin Radiol. Jul 1996;51(7):499-502.[View Abstract]
  35. Sirna S, Biller J, Skorton DJ, Seabold JE. Cardiac evaluation of the patient with stroke. Stroke. Jan 1990;21(1):14-23.[View Abstract]
  36. Adams RJ, Chimowitz MI, Alpert JS, et al. Coronary risk evaluation in patients with transient ischemic attack and ischemic stroke: a scientific statement for healthcare professionals from the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association. Stroke. Sep 2003;34(9):2310-22.[View Abstract]
  37. Handschu R, Poppe R, Rauss J, Neundorfer B, Erbguth F. Emergency calls in acute stroke. Stroke. Apr 2003;34(4):1005-9.[View Abstract]
  38. Williams JE, Rosamond WD, Morris DL. Stroke symptom attribution and time to emergency department arrival: the delay in accessing stroke healthcare study. Acad Emerg Med. Jan 2000;7(1):93-6.[View Abstract]
  39. Zweifler RM, Mendizabal JE, Cunningham S, Shah AK, Rothrock JF. Hospital presentation after stroke in a community sample: the Mobile Stroke Project. South Med J. Nov 2002;95(11):1263-8.[View Abstract]
  40. Lacy CR, Suh DC, Bueno M, Kostis JB. Delay in presentation and evaluation for acute stroke: Stroke Time Registry for Outcomes Knowledge and Epidemiology (S.T.R.O.K.E.). Stroke. Jan 2001;32(1):63-9.[View Abstract]
  41. Milhaud D, Popp J, Thouvenot E, Heroum C, Bonafe A. Mechanical ventilation in ischemic stroke. J Stroke Cerebrovasc Dis. Jul-Aug 2004;13(4):183-8.[View Abstract]
  42. Krieger D, Hacke W. The intensive care of the stroke patient. In: Stroke: Pathophysiology, Diagnosis and Management. 3rd ed. New York, NY: Churchill Livingstone; 1998.
  43. Oppenheimer SM, Hachinski VC. The cardiac consequences of stroke. Neurol Clin. Feb 1992;10(1):167-76.[View Abstract]
  44. Kolin A, Norris JW. Myocardial damage from acute cerebral lesions. Stroke. Nov-Dec 1984;15(6):990-3.[View Abstract]
  45. Bruno A, Levine SR, Frankel MR, et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology. Sep 10 2002;59(5):669-74.[View Abstract]
  46. Bruno A, Biller J, Adams HP Jr, et al. Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology. Jan 15 1999;52(2):280-4.[View Abstract]
  47. Baird TA, Parsons MW, Phanh T, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke. Sep 2003;34(9):2208-14.[View Abstract]
  48. Paula WK. Heads down: flat positioning improves blood flow velocity in acute ischemic stroke. Neurology. Nov 8 2005;65(9):1514; author reply 1514.[View Abstract]
  49. Castillo J, Leira R, Garcia MM, Serena J, Blanco M, Davalos A. Blood pressure decrease during the acute phase of ischemic stroke is associated with brain injury and poor stroke outcome. Stroke. Feb 2004;35(2):520-6.[View Abstract]
  50. Johnston KC, Mayer SA. Blood pressure reduction in ischemic stroke: a two-edged sword?. Neurology. Oct 28 2003;61(8):1030-1.[View Abstract]
  51. Marion DW. Controlled normothermia in neurologic intensive care. Crit Care Med. Feb 2004;32(2 Suppl):S43-5.[View Abstract]
  52. Olsen TS, Weber UJ, Kammersgaard LP. Therapeutic hypothermia for acute stroke. Lancet Neurol. Jul 2003;2(7):410-6.[View Abstract]
  53. [Best Evidence] den Hertog HM, van der Worp HB, van Gemert HM, Algra A, Kappelle LJ, van Gijn J, et al. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial. Lancet Neurol. May 2009;8(5):434-40.[View Abstract]
  54. Albers GW, Clark WM, Madden KP, Hamilton SA. ATLANTIS trial: results for patients treated within 3 hours of stroke onset. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. Stroke. Feb 2002;33(2):493-5.[View Abstract]
  55. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. Oct 17 1998;352(9136):1245-51.[View Abstract]
  56. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. Mar 6 2004;363(9411):768-74.[View Abstract]
  57. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. May 15 2010;375(9727):1695-703.[View Abstract]
  58. Wahlgren N, Ahmed N, Davalos A, Hacke W, Millan M, Muir K, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. Oct 11 2008;372(9646):1303-9.[View Abstract]
  59. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke. Dec 2003;34(12):2847-50.[View Abstract]
  60. [Best Evidence] Diedler J, Ahmed N, Sykora M, Uyttenboogaart M, Overgaard K, Luijckx GJ, et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset. Stroke. Feb 2010;41(2):288-94.[View Abstract]
  61. Donnan GA, Hommel M, Davis SM, McNeil JJ. Streptokinase in acute ischaemic stroke. Steering Committees of the ASK and MAST-E trials. Australian Streptokinase Trial. Lancet. Jul 1 1995;346(8966):56.[View Abstract]
  62. The Multicenter Acute Stroke Trial-Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial--Europe Study Group. N Engl J Med. Jul 18 1996;335(3):145-50.[View Abstract]
  63. Chalela JA, Katzan I, Liebeskind DS, et al. Safety of intra-arterial thrombolysis in the postoperative period. Stroke. Jun 2001;32(6):1365-9.[View Abstract]
  64. Ducrocq X, Bracard S, Taillandier L, Anxionnat R, Lacour JC, Guillemin F, et al. Comparison of intravenous and intra-arterial urokinase thrombolysis for acute ischaemic stroke. J Neuroradiol. Jan 2005;32(1):26-32.[View Abstract]
  65. Macleod MR, Davis SM, Mitchell PJ, et al. Results of a multicentre, randomised controlled trial of intra-arterial urokinase in the treatment of acute posterior circulation ischaemic stroke. Cerebrovasc Dis. 2005;20(1):12-7.[View Abstract]
  66. Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. Nov 18 2004;351(21):2170-8.[View Abstract]
  67. Tsivgoulis G, Eggers J, Ribo M, Perren F, Saqqur M, Rubiera M, et al. Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke. Feb 2010;41(2):280-7.[View Abstract]
  68. Wright WL, Geocadin RG. Postresuscitative intensive care: neuroprotective strategies after cardiac arrest. Semin Neurol. Sep 2006;26(4):396-402.[View Abstract]
  69. Muir KW, Lees KR, Ford I, Davis S. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet. Feb 7 2004;363(9407):439-45.[View Abstract]
  70. Gobin YP, Starkman S, Duckwiler GR, et al. MERCI 1: a phase 1 study of Mechanical Embolus Removal in Cerebral Ischemia. Stroke. Dec 2004;35(12):2848-54.[View Abstract]
  71. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. Jul 2005;36(7):1432-8.[View Abstract]
  72. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. Dec 1 1999;282(21):2003-11.[View Abstract]
  73. Berlis A, Lutsep H, Barnwell S, et al. Mechanical thrombolysis in acute ischemic stroke with endovascular photoacoustic recanalization. Stroke. May 2004;35(5):1112-6.[View Abstract]
  74. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. May 31 1997;349(9065):1569-81.[View Abstract]
  75. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. Jun 7 1997;349(9066):1641-9.[View Abstract]
  76. Padma V, Fisher M, Moonis M. Role of heparin and low-molecular-weight heparins in the management of acute ischemic stroke. Expert Rev Cardiovasc Ther. May 2006;4(3):405-15.[View Abstract]
  77. [Best Evidence] Dengler R, Diener HC, Schwartz A, Grond M, Schumacher H, Machnig T, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. Feb 2010;9(2):159-66.[View Abstract]
  78. Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, dose-escalation study. The Abciximab in Ischemic Stroke Investigators. Stroke. Mar 2000;31(3):601-9.[View Abstract]
  79. Milionis HJ, Giannopoulos S, Kosmidou M, Panoulas V, Manios E, Kyritsis AP, et al. Statin therapy after first stroke reduces 10-year stroke recurrence and improves survival. Neurology. May 26 2009;72(21):1816-22.[View Abstract]
  80. Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial. Stroke. Apr 2005;36(4):880-90.[View Abstract]
  81. [Guideline] Adams H, Adams R, Del Zoppo G, Goldstein LB. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. Apr 2005;36(4):916-23.[View Abstract]
  82. [Guideline] Adams HP Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke. Apr 2003;34(4):1056-83.[View Abstract]
  83. [Guideline] Adams HP Jr, Brott TG, Crowell RM, et al. Guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. Sep 1994;25(9):1901-14.[View Abstract]
  84. Albers GW. Medical treatment for acute ischemic stroke. Am J Med. 1996;3-9.
  85. Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology. Apr 24 2001;56(8):1015-20.[View Abstract]
  86. Barsan WG, Kothari R. Stroke. In: Emergency Medicine Concepts and Practices. Vol 3. 1998:2184-98.
  87. Bronner LL, Kanter DS, Manson JE. Primary prevention of stroke. N Engl J Med. Nov 23 1995;333(21):1392-400.[View Abstract]
  88. Brott T, Bogousslavsky J. Treatment of acute ischemic stroke. N Engl J Med. Sep 7 2000;343(10):710-22.[View Abstract]
  89. Chan YF, Kwiatkowski TG, Rella JG, Rennie WP, Kwon RK, Silverman RA. Tissue plasminogen activator for acute ischemic stroke: a New York city emergency medicine perspective. J Emerg Med. Nov 2005;29(4):405-8.[View Abstract]
  90. Christensen H, Fogh Christensen A, Boysen G. Abnormalities on ECG and telemetry predict stroke outcome at 3 months. J Neurol Sci. Jul 15 2005;234(1-2):99-103.[View Abstract]
  91. Cocho D, Belvis R, Marti-Fabregas J, et al. Reasons for exclusion from thrombolytic therapy following acute ischemic stroke. Neurology. Feb 22 2005;64(4):719-20.[View Abstract]
  92. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. Jan 1998;29(1):4-11.[View Abstract]
  93. Fieschi C, Hacke W, Kaste M, Toni D, Lesaffre E. Thrombolytic therapy for acute ischaemic stroke. ECASS Study Group. Lancet. Nov 15 1997;350(9089):1476; author reply 1477.[View Abstract]
  94. Grotta J, Bratina P. Subjective experiences of 24 patients dramatically recovering from stroke. Stroke. Jul 1995;26(7):1285-8.[View Abstract]
  95. Gubitz G, Sandercock P, Counsell C. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. 2004;CD000024.[View Abstract]
  96. Jones MM, Nogajski JH, Faulder K, Harrington T, Ng P, Storey CE. Intra-arterial thrombolysis in acute ischaemic stroke. Intern Med J. May 2005;35(5):300-2.[View Abstract]
  97. Kase CS, Wolf PA, Chodosh EH, et al. Prevalence of silent stroke in patients presenting with initial stroke: the Framingham Study. Stroke. Jul 1989;20(7):850-2.[View Abstract]
  98. Kwiatkowski TG, Libman RB, Frankel M, et al. Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. N Engl J Med. Jun 10 1999;340(23):1781-7.[View Abstract]
  99. Lewandowski C, Barsan W. Treatment of acute ischemic stroke. Ann Emerg Med. Feb 2001;37(2):202-16.[View Abstract]
  100. Lyden PD, Lau GT. A critical appraisal of stroke evaluation and rating scales. Stroke. Nov 1991;22(11):1345-52.[View Abstract]
  101. National Institute of Neurological Disorders Stroke rt-PA Stroke Study Group. Recombinant tissue plasminogen activator for minor strokes: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study experience. Ann Emerg Med. Sep 2005;46(3):243-52.[View Abstract]
  102. National Stroke Association Consensus Group. Stroke: the first hours - emergency evaluation and treatment. Stroke Clin Updates. 1997;5-14.
  103. Noor R, Wang CX, Shuaib A. Hyperthermia masks the neuroprotective effects of tissue plaminogen activator. Stroke. Mar 2005;36(3):665-9.[View Abstract]
  104. Parnetti L, Caso V, Santucci A, et al. Mild hyperhomocysteinemia is a risk-factor in all etiological subtypes of stroke. Neurol Sci. Apr 2004;25(1):13-7.[View Abstract]
  105. Raco, et al. Management of acute cerebellar infarction: One institution's experience. Neurosurgery vol 53(5). Nov 2005;1061-1065.
  106. Ribo M, Molina CA, Rovira A, et al. Safety and efficacy of intravenous tissue plasminogen activator stroke treatment in the 3- to 6-hour window using multimodal transcranial Doppler/MRI selection protocol. Stroke. Mar 2005;36(3):602-6.[View Abstract]
  107. Savitz SI, Caplan LR. Vertebrobasilar disease. N Engl J Med. Jun 23 2005;352(25):2618-26.[View Abstract]
  108. [Guideline] Schwamm LH, Pancioli A, Acker JE 3rd, et al. Recommendations for the establishment of stroke systems of care: recommendations from the American Stroke Association's Task Force on the Development of Stroke Systems. Circulation. Mar 1 2005;111(8):1078-91.[View Abstract]
  109. Tomson J, Lip GY. Blood pressure changes in acute haemorrhagic stroke. Blood Press Monit. Aug 2005;10(4):197-9.[View Abstract]
  110. Wechsler LR, Roberts R, Furlan AJ, et al. Factors influencing outcome and treatment effect in PROACT II. Stroke. May 2003;34(5):1224-9.[View Abstract]
  111. Wilterdink JL, Bendixen B, Adams HP Jr, Woolson RF, Clarke WR, Hansen MD. Effect of prior aspirin use on stroke severity in the trial of Org 10172 in acute stroke treatment (TOAST). Stroke. Dec 1 2001;32(12):2836-40.[View Abstract]
  112. Wyer PC, Osborn HH. Recombinant tissue plasminogen activator: in my community hospital ED, will early administration of rt-PA to patients with the initial diagnosis of acute ischemic stroke reduce mortality and disability?. Ann Emerg Med. Nov 1997;30(5):629-38.[View Abstract]
  113. Yundt KD, Diringer MN. The use of hyperventilation and its impact on cerebral ischemia in the treatment of traumatic brain injury. Crit Care Clin. Jan 1997;13(1):163-84.[View Abstract]
  114. Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96(4):380-5.[View Abstract]