Stroke, Ischemic

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.

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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]

• References

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.

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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]

• Cerebrovascular disease was the second leading cause of death worldwide in 1990, killing more than 4.3 million people.^[10]
• Cerebrovascular disease was also the fifth leading cause of lost productivity, as measured by disability-adjusted life years (DALYs). DALYs include years of productivity lost to either death or varying degrees of disability. In 1990, cerebrovascular disease caused 38.5 million DALYs throughout the world.^[11]

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]

• References

History

• Stroke should be considered in any patient presenting with an acute neurologic deficit (focal or global) or altered level of consciousness.
• No historical feature distinguishes ischemic from hemorrhagic stroke, although nausea, vomiting, headache, and change in level of consciousness are more common in hemorrhagic strokes.
• Common symptoms of stroke include abrupt onset of hemiparesis, monoparesis, or quadriparesis; monocular or binocular visual loss; visual field deficits; diplopia; dysarthria; ataxia; vertigo; aphasia; or sudden decrease in the level of consciousness.
• Although such symptoms can occur alone, they are more likely to occur in combination.
• Establishing the time of onset of these symptoms is of paramount importance when considering patients for possible thrombolytic therapy. An essential question is, "When was the patient last seen normal?" It is advisable for emergency clinicians to rapidly enlist the assistance of family members or relatives to establish time of onset and to identify other pertinent components of the patient's history of presentation. The median time from symptom onset to ED presentation ranges from 4-24 hours in the United States.^[12]
• Multiple factors contribute to delays in seeking care for symptoms of stroke.

  • Many strokes occur while patients are sleeping (also known as "wake-up" stroke) and are not discovered until the patient wakes.
  • Stroke can leave some patients too incapacitated to call for help.
  • Occasionally, a stroke goes unrecognized by the patient or their caregivers.^{[8, 13]}

   

  

   
• Stroke mimics commonly confound the clinical diagnosis of stroke. One study reported that 19% of patients diagnosed with acute ischemic stroke by neurologists before cranial CT scanning actually had noncerebrovascular causes for their symptoms. The most frequent stroke mimics include seizure (17%); systemic infection (17%); brain tumor (15%); toxic-metabolic cause, such as hyponatremia (13%); and positional vertigo (6%). Miscellaneous disorders mimicking stroke include syncope, trauma, subdural hematoma, herpes encephalitis, transient global amnesia, dementia, demyelinating disease, myasthenia gravis, parkinsonism, hypertensive encephalopathy, and conversion disorders. A critical masquerading metabolic derangement not to be missed by providers is hypoglycemia.^{[14, 15]}

• References

Physical

• The goals of the physical examination include detecting extracranial causes of stroke symptoms, distinguishing stroke from stroke mimics, determining and documenting for future comparison the degree of deficit, and localizing the lesion.
• The physical examination always includes a careful head and neck examination for signs of trauma, infection, and meningeal irritation.
• A careful search for the cardiovascular causes of stroke requires examination of the ocular fundi (retinopathy, emboli, hemorrhage), heart (irregular rhythm, murmur, gallop), and peripheral vasculature (palpation of carotid, radial, and femoral pulses, auscultation for carotid bruit).
• Patients with a decreased level of consciousness should be assessed to ensure that they are able to protect their airway.
• Neurologic examination

  • With the availability of thrombolytic therapy for acute ischemic stroke in selected patients, the EP must be able to perform a brief but accurate neurologic examination on patients with suspected stroke syndromes.
  • The goals of the neurologic examination include (1) confirming the presence of a stroke syndrome (to be defined further by cranial CT scanning), (2) distinguishing stroke from stroke mimics, and (3) establishing a neurologic baseline should the patient's condition improve or deteriorate.
  • Essential components of the neurologic examination include evaluation of mental status and the level of consciousness, cranial nerves, motor function, sensory function, cerebellar function, gait, and deep tendon reflexes.
  • The skull and spine also should be examined, and signs of meningismus should be sought.
  • Central facial weakness from a stroke should be differentiated from the peripheral weakness of Bell palsy. With peripheral lesions (Bell palsy), the patient is unable to lift the eyebrows or wrinkle the forehead.
  • The 4 principal neuroanatomic stroke syndromes are caused by disruption of their respective cerebrovascular distributions. Correlating the patient's neurologic deficits with the expected site of arterial compromise may assist in confirming the diagnosis of stroke and interpreting the subsequent cranial CT scan.
  • Middle cerebral artery (MCA) occlusion commonly produces contralateral hemiparesis, contralateral hypesthesia, ipsilateral hemianopsia, and gaze preference toward the side of the lesion. Agnosia is common, and receptive or expressive aphasia may result if the lesion occurs in the dominant hemisphere. Neglect, inattention, and extinction of double simultaneous stimulation may occur in nondominant hemisphere lesions. Since the MCA supplies the upper extremity motor strip, weakness of the arm and face is usually worse than that of the lower limb.
  • Anterior cerebral artery occlusions primarily affect frontal lobe function and can result in dis-inhibition and speech perseveration, producing primitive reflexes (eg, grasping, sucking reflexes), altered mental status, impaired judgment, contralateral weakness (greater in legs than arms), contralateral cortical sensory deficits gait apraxia, and urinary incontinence.
  • Posterior cerebral artery occlusions affect vision and thought, producing contralateral homonymous hemianopsia, cortical blindness, visual agnosia, altered mental status, and impaired memory.
  • Vertebrobasilar artery occlusions are notoriously difficult to detect because they cause a wide variety of cranial nerve, cerebellar, and brainstem deficits. These include vertigo, nystagmus, diplopia, visual field deficits, dysphagia, dysarthria, facial hypesthesia, syncope, and ataxia. A hallmark of posterior circulation stroke is that there are crossed findings: ipsilateral cranial nerve deficits and contralateral motor deficits. This is contrasted to anterior stroke, which produces only unilateral findings.
  • Lacunar strokes result from occlusion of the small, perforating arteries of the deep subcortical areas of the brain. The infarcts are generally from 2-20 mm in diameter. The most common lacunar syndromes include pure motor, pure sensory, and ataxic hemiparetic strokes. Lacunar infarcts are often associated with partial or full occlusion of the parent feeding artery. Lacunar strokes account for 13-20% of all cerebral infarctions. Lacunar infarcts commonly occur in patients with small vessel disease, such as diabetes and hypertension. By virtue of their small size and well-defined subcortical location, lacunar infarcts do not lead to impairments in cognition, memory, speech, or level of consciousness.
  • Stroke scales
    • The National Institutes of Health Stroke Scale (NIHSS) is a rapid and reproducible tool for quantifying neurologic deficits in stroke patients and is useful for following the patient's early course. It is advisable to use this scale because it provides a means of quantitatively following a patient's course (ie, rapidly improving symptoms, or, escalation of symptoms secondary to either a bleed or cerebral edema).
    • The NIHSS is a 42-point scale with minor strokes usually being considered to have a score less than 5. A NIHSS score greater than 10 correlates with an 80% likelihood of visual flow deficits on angiography. Discretion must be also be used in assessing the magnitude of the clinical deficit; for instance, if a patient's only deficit is being mute, then the NIHSS score will be 3. Additionally, the scale does not measure some deficits associated with posterior circulation strokes (ie, vertigo, ataxia).^[16]

   

  

   

• References

Causes

• Risk factors

  • Briefly assessing the risk factors for stroke may provide clues as to its cause and reinforce the clinical gestalt that clinicians may have in uncertain situations. Risk factors for ischemic stroke include advanced age (the risk doubles every decade), hypertension, smoking, heart disease (coronary artery disease, left ventricular hypertrophy, chronic atrial fibrillation), and hypercholesterolemia. Hyperhomocysteinemia has also been identified as an independent risk factor for all forms of stroke.^[17]
  • Diseases associated with increased blood viscosity and the use of oral contraceptives place patients at higher risk for ischemic stroke.
  • Previous cerebrovascular disease is a risk factor for ischemic stroke.

   

  

   
• Transient ischemic attack

  • Transient ischemic attack (TIA) has come to be known as a neurologic deficit that resolves within 24 hours. Roughly 80% resolve within 60 minutes. Tissue-based definitions are being proposed with magnetic resonance imaging.^[17]
  • TIA can result from any of the aforementioned mechanisms of stroke. Data suggest that roughly 10% of patients with TIA suffer stroke within 90 days and half of these patients suffer stroke within 2 days.^{[17, 18]}

   

  

   

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Laboratory Studies

• CBC, basic chemistry panel, coagulation studies, and cardiac biomarkers should be obtained in most patients.

  • CBC serves as a baseline study and may reveal a cause for the stroke (eg, polycythemia, thrombocytosis, thrombocytopenia, leukemia) or provide evidence of concurrent illness (eg, anemia).
  • Chemistry panel serves as a baseline study and may reveal a stroke mimic (eg, hypoglycemia, hyponatremia) or provide evidence of concurrent illness (eg, diabetes, renal insufficiency).
  • Coagulation studies may reveal a coagulopathy and are useful when thrombolytics or anticoagulants are to be used. In patients who are not anticoagulated and in whom there is no suspicion for coagulation abnormality, administration of rt-PA should not be delayed awaiting laboratory studies.
  • Cardiac biomarkers are important because of the association of cerebral vascular disease and coronary artery disease. Additionally, several studies have indicated a link between elevations of cardiac enzyme levels and poor outcome in ischemic stroke.

   

  

   
• Toxicology screening may be useful in selected patients in order to assist in identifying intoxicated patients with symptoms/behavior mimicking stroke syndromes. Urine pregnancy test should be obtained for all women of childbearing age with stroke symptoms. rt-PA is Pregnancy Class C.

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Imaging Studies

• Noncontrast head CT scan

  • Emergent noncontrast head CT scanning is mandatory for rapidly distinguishing ischemic from hemorrhagic infarction and may help determine the anatomic distribution of stroke.
  • Head CT scan is a fundamental branch point in the evaluation of stroke, since patients with acute ischemic stroke may be triaged to receive thrombolytic therapy, whereas patients with hemorrhagic stroke are best served via a completely different diagnostic and therapeutic pathway.
  • CT scan may also rule out other life-threatening processes, such as hematoma, neoplasm, and abscess.
  • The changes in CT scan over the time course of acute cerebral infarction must be understood. The sensitivity of standard noncontrast head CT increases 24 hours after ischemic event.^[12] After 6-12 hours, sufficient edema is recruited into the stroke area to produce a regional hypodensity on CT scan.^[19] A large hypodense area present on CT scan within the first 3 hours of reported symptom onset should prompt careful review regarding the time of stroke symptom onset (eg, determining when the patient was last seen in usual health). The presence of CT evidence of infarction early in presentation has also been associated with poor outcome and increased propensity for hemorrhagic transformation after thrombolytics.^{[20, 21, 22]}
  • Other radiologic clues to acute ischemic infarction include the insular ribbon sign, the hyperdense MCA sign (MCA occlusion), obscuration of the lentiform nucleus, sulcal asymmetry, and loss of gray-white matter differentiation.^[12]
  • Unfortunately, as many as 5% of patients with subarachnoid hemorrhages also have a normal CT scan, making lumbar puncture or other imaging (MR or CTA) imperative when subarachnoid hemorrhage is suspected. CT scan may also fail to demonstrate some parenchymal hemorrhages smaller than 1 cm.^[17]

   

  

   
• CT perfusion: CT perfusion is a novel modality potentially useful in identifying early areas of ischemia. By continuing to scan through the brain after an initial bolus of intravenous contrast dye, perfusion of different brain regions can be measured. Areas of hypoattenuation on CT perfusion imaging correspond well with ischemia and allow some determination of viability and as a result the ischemic penumbra.^{[23, 24]}
• CT angiography

  • Noncontrast CT may be followed by a CT angiography (CTA) in certain centers. CTA may identify a filling defect in a cerebral artery, thus localizing the lesion to a specific portion of the causative vessel. In addition, CTA can provide an estimation of perfusion because poorly perfused cerebral tissue appears as hypodense areas of tissue. Noncontrast head CT in combination with CT angiography and CT perfusion imaging has been shown to have increased sensitivity for detecting small ischemic lesions when compared with any of the individual imaging modalities alone. CTA also has a higher sensitivity than standard noncontrast CT for detecting subarachnoid hemorrhage.^{[12, 25, 26]}
  • CT scanning utilizing all 3 of these CT modalities (CT perfusion, angiography and noncontrast CT) are being studied in acute stroke imaging. This technology may offer improved detection of early stroke signs, small hemorrhagic strokes, and subarachnoid hemorrhages and as well allow for calculation of perfusion. These studies have the disadvantage of requiring further expense, radiation exposure, and the administration of intravenous contrast dye. It is unclear to what extent earlier detection of ischemia via newer imaging modalities will impact current treatment algorithms and the administration of thrombolytics.^[12]

   

  

   
• Magnetic resonance imaging

  • A variety of MRI protocols have utility in acute stroke.
    • Standard MR T1 and T2 sequences may be combined with other imaging protocols such as diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) to yield improved sensitivity for the detection of acute ischemic and hemorrhagic strokes over standard noncontrast CT. Further, subacute intracerebral hemorrhage, while difficult to diagnose via standard noncontrast CT, can be detected with reliability approaching 100%.
    • DWI can detect ischemia much earlier than standard CT or MRI and provides useful data in stroke and TIA patients outside of the initial management window.^{[12, 27, 28]} DWI MRI can detect small areas of ischemia, particularly in regions poorly visualized by noncontrast CT scanning such as the cerebellum and the brain stem.^[12] Acute stroke volume, as measured on DWI MRI, correlates well with final lesion volume and clinical stroke severity scales, suggesting a possible role in prognostication.^{[29, 30]}
  • PWI MRI directly measures perfused areas of brain in a manner similar to CT perfusion. A contrast bolus is given, and multiple images over time are obtained, providing a comparative measure of perfused versus nonperfused tissue regions. PWI MRI may have utility in acute stroke patients.^[31]
  • MR angiography (MRA) has also been shown to have efficacy in the early identification of vascular lesions and blockages in acute stroke.^[32]
  • Disadvantages of MRI imaging in acute stroke include its high cost, lack of ready availability at most centers, complexity, time required for transport and obtaining the study (15-20 minutes minimum with most scanners), and significant contraindication in patients with metallic implants. Despite the significant improvements in CT and MRI technology, differentiation and thus measurement of infarcted core tissue and ischemic and potentially rescuable penumbra tissue is still not possible acutely. It is likely that a combination of CT and/or MRI modalities will be necessary to fully assess the patient with acute stroke for hemorrhage and stroke mimics, and to quantify the area of infarcted versus ischemic tissue. These data will be useful in allowing the extension of the therapeutic window for thrombolysis in certain cases where large areas of rescuable tissue are identified and in preventing symptomatic intracranial hemorrhage in those patients in whom bleeds are identified.

   

  

   
• Further imaging: The ultrasonography studies below are usually reserved for further evaluation outside of the ED.

  • Carotid duplex scanning is reserved for patients with acute ischemic stroke in whom carotid artery stenosis or occlusion is suspected.
  • Transcranial Doppler ultrasonography is useful for evaluating more proximal vascular anatomy, including the MCA, intracranial carotid artery, and vertebrobasilar artery.^[33]
  • Echocardiography is obtained in all patients with acute ischemic stroke in whom cardiogenic embolism is suspected. Transesophageal echocardiography is necessary for detecting thoracic aortic dissection and more accurate for identification of thrombi in the left atrial appendage from atrial fibrillation. A certain proportion of patients with strokes may have underlying systolic dysfunction, diastolic dysfunction, or concentric hypertrophy. Echocardiography is also a modality to identify the presence of a patent foramen ovale.

   

  

   
• Chest radiography: Chest radiography has potential utility for patients with acute stroke; however, obtaining a chest radiograph should not delay the administration of rt-PA, and it has not been shown to alter the clinical course or decision making in most cases.^[34]

• References

Other Tests

• Electrocardiography

  • ECG should be obtained for all patients with acute stroke because as many as 60% of all cardiogenic emboli are associated with atrial fibrillation or acute MI.
  • Some reports have also recommended continuous cardiac monitoring for all patients, since 4% of patients have a life-threatening arrhythmia during the course of their illness and 3% have concurrent MI. Acute ischemic stroke has been associated with acute cardiac dysfunction and arrhythmia, which then correlate with worse functional outcome and morbidity at 3 months.^{[35, 36]}

   

  

   

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Procedures

• Angiography

  • Angiography is useful for patients with acute ischemic stroke in whom characterization of the cerebrovascular anatomy might lead to change in medical or surgical management, such as patients with subtle occlusive diseases (eg, fibromuscular dysplasia, vasculitis) or arterial dissection.
  • Angiography continues to play an important role in the preoperative evaluation of carotid artery disease.

   

  

   

• References

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]

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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

• Patients presenting with Glasgow Coma Scale scores less than or equal to 8, rapidly decreasing Glasgow Coma Scale scores, or inadequate airway protection or ventilation require emergent airway control via rapid sequence intubation.
• When increased intracranial pressure is suspected, rapid sequence induction should be directed at minimizing the potentially adverse effects of intubation.
• In unusual cases of potential imminent brain herniation where the goal of mechanical ventilation is hyperventilation to decrease intracranial pressure by decreasing cerebral blood flow, the recommended endpoint is an arterial pCO₂ of 32-36 mm Hg. Intravenous mannitol can be considered as well.
• Supplemental oxygen use should be guided by pulse oximetry. Patients should receive supplemental oxygen if their pulse oximetry reading or arterial blood gas measurement reveals that they are hypoxic. The most common cause of hypoxia in the patient with acute stroke is partial airway obstruction, hypoventilation, atelectasis, or aspiration of stomach or oropharyngeal contents.^{[41, 42]}

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.

• Non–t-PA candidates

  • For patients who are not rt-PA candidates and whose systolic blood pressure is less than 220 mm Hg and whose diastolic blood pressure is less than 120 mm Hg in the absence of evidence of end-organ involvement (ie, pulmonary edema, aortic dissection, hypertensive encephalopathy), blood pressure should be monitored (without acute intervention) and stroke symptoms and complications should be treated (increased ICP, seizures).
  • For patients with elevated systolic blood pressures above 220 mm Hg or diastolic blood pressures between 120 and 140 mm Hg, labetalol (10-20 mg IV for 1-2 min) should be the initial drug of choice, unless a contraindication to its use exists. Dosing may be repeated or doubled every 10 minutes to a maximum dose of 300 mg. Alternatively, nicardipine (5 mg/h IV initial infusion) titrated to effect via increasing 2.5 mg/h every 5 minutes to a maximum dose of 15 mg/h may be used for blood pressure control. Lastly, nitroprusside at 0.5 mcg/kg/min IV infusion may be used in the setting of continuous blood pressure monitoring. The goal of intervention is a reduction of 10-15% of blood pressure.

   

  

   
• For patients who will be receiving rt-PA, systolic blood pressure greater than 185 mm Hg and diastolic blood pressure greater than 110 mm Hg require intervention. Monitoring and control of blood pressure during and after thrombolytic administration are vital as uncontrolled hypertension is associated with hemorrhagic complication.^[20] The initial drug of choice is labetalol (10-20 mg IV for 1-2 min), and one dose may be repeated. One to two inches of transdermal nitropaste may also be used. As an alternative to these choices nicardipine infusion at 5 mg/h titrated up to a maximum dose of 15 mg/h can be used.^[12]

  • Monitoring of blood pressure is crucial, and, for the first 2 hours, blood pressure should be checked every 15 minutes, then every 30 minutes for 6 hours, and finally every hour for 16 hours. The goal of therapy should be to reduce blood pressure by 15-25% within the first day, with continued blood pressure control during hospitalization. In order to assure adequate blood pressure control during hospitalization, the following agents and doses may be considered:
    • Systolic blood pressure (SBP): 180-230 mm Hg or diastolic blood pressure (DBP) 105-120 mm Hg: Labetalol 10 mg IV over 1-2 minutes may repeat every 10-20 minutes up to 300 mg total or an infusion of labetalol up to 2-8 mg/min.^[12]
    • For SBP >230 mm Hg or DBP 121-140 mm Hg labetalol at the above doses can be considered or nicardipine infusion at 5 mg/h to a maximum of 15 mg/h. For difficult to control blood pressure, sodium nitroprusside can be considered.^[12]
    • Use of sublingual nifedipine to lower blood pressure in the ED is discouraged since extreme hypotension may result. Trials of nimodipine, initially thought to be beneficial given its vasodilatory effect as a calcium channel blocker, have failed to demonstrate any beneficial outcome in comparison to placebo.^[12]
    • Consensus agreement is that these blood pressure guidelines should be maintained in the face of other interventions to restore perfusion such as intra-arterial thrombolysis.^[12]
    • Given the need to maintain adequate cerebral blood flow, severe hypotension should be managed in standard fashion with aggressive fluid resuscitation a search for the etiology of hypotension and, if necessary, vasopressor support. Evidence suggests that baseline SBP < 100 mg Hg and DBP < 70 mm Hg correlate with worse outcome.^[49]

   

  

   

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.

• References

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:

• Patients older than 80 years
• All patients taking oral anticoagulants are excluded regardless of the international normalized ratio (INR)
• Patients with baseline NIH Stroke Scale >25
• Patients with a history of stroke and diabetes

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]

• Diagnosis of ischemic stroke causing measurable neurologic deficit
• Neurologic signs should not be clearing spontaneously
• Neurologic signs should not be minor and isolated
• Caution should be exercised in treating patients with major deficits
• Symptoms should not be suggestive of subarachnoid hemorrhage
• Onset of symptoms < 3 hours before beginning treatment
• No head trauma or prior stroke in past 3 months
• No MI in prior 3 months
• No GI/GU hemorrhage in previous 21 days
• No arterial puncture in noncompressible site during prior 7 days
• No major surgery in prior 14 days
• No history of prior intracranial bleed
• SBP < 185 mm Hg, DBP < 110 mm Hg
• No evidence of acute trauma or bleeding
• Not taking an oral anticoagulant, or if so INR < 1.7
• If taking heparin within 48 hours must have a normal activated prothrombin time (aPT)
• Platelet count >100,000 μL
• Blood glucose level greater than 50 mg/dL (2.7 mmol)
• No seizure with residual postictal impairments
• CT scan does not show evidence of multilobar infarction (hypodensity >1/3 hemisphere)
• The patient and family understand the potential risks and benefits of therapy

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

• Neuroprotective agents

  • Despite very promising results in several animal studies as of yet no single neuroprotective agent in ischemic stroke is supported by randomized placebo-controlled human studies. Nevertheless, substantial research is underway evaluating their use for this indication. Since the ischemic cascade is a dynamic process, the efficacy of interventions to protect the ischemic penumbra also may prove to be time dependent.
  • Theoretically, calcium channel blockers (eg, nimodipine) should have the narrowest window of therapeutic opportunity, since calcium influx is one of the earliest events in the ischemic cascade. A recent study suggests that lubeluzole (an inhibitor of glutamate release) may benefit patients with acute ischemic stroke if given within 6 hours. Aptiganel (noncompetitive inhibitor of the NMDA receptor) also appears promising when given early in the course of ischemia.^[68] The IMAGES study recently failed to determine a benefit for intravenous magnesium in stroke.^[69] Further research is underway utilizing magnesium earlier in the symptom course.
  • Neuroprotectants affecting later events in the ischemic cascade include free-radical scavengers (tirilazad, citicoline, cerovive) and neuronal membrane stabilizers [citicoline]). Cerovive is currently being evaluated in a large placebo-controlled randomized study. Monoclonal antibodies against leukocyte adhesion molecules also are being evaluated as late neuroprotectants (enlimomab). No set classification system yet exists for the many neuroprotectants being investigated, since many agents appear to have more than one mechanism of action.^[68]

   

  

   
• Surgical and endovascular interventions

  • Many surgical and endovascular techniques have been studied in the treatment of acute ischemic stroke. Carotid endarterectomy has been used in the acute management of internal carotid artery occlusions with some success (Gay, Huber, guidelines). Other interventions have included laser, intra-arterial suction, snares, angioplasty, as well as clot retrieval devices.
  • The MERCI 1 pilot trial studied the safety and efficacy of the Merci Retrieval System, an endovascular embolectomy system for use in ischemic stroke. Inclusion criteria included NIHSS greater than 10, treatment commencement within 8 hours of symptom onset, and contraindication to IV thrombolytics. Successful recanalization occurred in 12 of 28 patients. Twelve asymptomatic bleeds and only one procedure-related complication occurred. Among patients who had successful recanalization, the significant recovery rate was 50%, while, in those with no recanalization, none had significant recovery. No cases of downstream embolic events occurred as a result of the procedure.^[70]
  • In a second MERCI study, the same intervention was attempted in 151 patients. All study patients had been excluded from intravenous thrombolytic therapy for various reasons. Recanalization was achieved in 48% of those in which the device was deployed. Clot was successfully retrieved from all major cerebral arteries; however, the recanalization rate for the middle cerebral artery (MCA) was lowest. While the rate of asymptomatic intracerebral bleed was higher than placebo, it was lower than that of the NINDS rt-PA study (5% vs 6%). However, an overall complication rate of 7.1% was found to be comparable to the complication rates for systemic thrombolytic therapy. A further study of clot extraction in the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) study identified a recanalization rate of 66%.^{[71, 72]}
  • While these studies suggest a treatment effect, as of yet, there has been little placebo-controlled comparison. Thus, further research is required to delineate the role of endovascular embolectomy in the management of acute ischemic stroke. However, based on these results, the FDA has cleared the use of the MERCI device in patients who are either ineligible for or who have failed intravenous thrombolytics.
  • Other studies have evaluated the efficacy of mechanical clot disruption in the setting of acute stroke. In most cases, these technologies were used in combination with thrombolysis. In one study by Berlis et al, mechanical disruption via an endovascular photoacoustic device was found to be more effective than thrombolysis alone in recanalization rates.^[73]

   

  

   
• Anticoagulants: Currently, data are inadequate to justify the utilization of heparin or other anticoagulants in the acute management of patients with ischemic stroke. Patients with embolic stroke who have another indication for anticoagulation (eg, atrial fibrillation) may be placed on anticoagulation therapy with the goal of preventing further embolic disease.^[12]
• Induced hypothermia: Hypothermia is another treatment strategy that has received recent consideration. Hypothermia is fast becoming standard of care for the ongoing treatment of patients surviving cardiac arrest due to ventricular tachycardia or ventricular fibrillation. No major clinical study has demonstrated a role for hypothermia in the early treatment of ischemic stroke. It isadvisable to prevent hyperthermia for the first several days after acute ischemic stroke because fever has been independently associated with poor outcome and failure of thrombolysis.^[12]

• References

Class Summary

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

• References

Alteplase (Activase)

• Dosing, Interactions, etc.

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.

• References

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.

• References

Aspirin (Bayer Aspirin, Anacin, Bufferin)

• Dosing, Interactions, etc.

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.

• References

Ticlopidine (Ticlid)

• Dosing, Interactions, etc.

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

• References

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]

• References

Complications

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

• Significant cerebral edema after ischemic stroke is thought to be somewhat rare (10-20%).^[12]
• Early indicators of ischemia on presentation and on noncontrast CT scan are independent indicators of potential swelling and deterioration. Mannitol and other therapies to reduce intracranial pressure may be utilized in emergency situations, although their usefulness in swelling secondary to ischemic stroke are unknown.^[12] Some patients furthermore experience hemorrhagic transformation of their infarct. This is estimated to occur in 5% of uncomplicated ischemic strokes, in the absence of thrombolytics. Hemorrhagic transformation is not always associated with neurologic decline and ranges from small petechial hemorrhages to hematomas requiring evacuation.
• The incidence of seizures ranges from 2-23% in the immediate post-stroke recovery period. Post-ischemia strokes are usually focal but may be generalized. A fraction of patients who have experienced stroke develop chronic seizure disorders. Seizures secondary to ischemic stroke should be managed in the same manner as other seizure disorders that arise as a result of neurologic injury.^[12]

• References