eMedicine Specialties > Emergency Medicine > Neurology

Stroke, Ischemic: Treatment & Medication

Author: Joseph U Becker, MD, Fellow, Global Health and International Emergency Medicine, Stanford University
Coauthor(s): Charles R Wira, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale School of Medicine; Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Contributor Information and Disclosures

Updated: Jun 19, 2009

Treatment

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” 2007.11

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.36,37  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.38,39

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.11

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.11 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.40,41

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.42,43

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 infracted territory.44,45,46 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.11

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.47

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.48,49

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.48  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.19 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.11 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.19 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.11
    • 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.11
      • 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.11
      • 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.11
      • Consensus agreement is that these blood pressure guidelines should be maintained in the face of other interventions to restore perfusion such as intra-arterial thrombolyisis.11
      • 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.48

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.50,51

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.52

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.11

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.11

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

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.11

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.11

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.19,53,54,55,21,2

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.2

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.19

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).19

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.19

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 1999.19

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.19

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.21

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.21

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).19,55,21

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.2

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.11,2


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.3 Recent studies have provided new data on rt-PA treatment in the 3-to-4.5-hour window.2,56

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.11 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%.57 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:11

  • 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.20 Furthermore, it appears that hemorrhagic complications after thrombolytic administration occurs most frequently when the inclusion/exclusion criteria of the initial NINDs trial are violated.11,57

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.11

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.11

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.58,59

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.11 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.11

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.60,61,62 Furthermore, intra-arterial thrombolysis may be indicated in patients with contraindications to intravenous thrombolytic administration such as recent surgery.11,60,61,62

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. 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.63 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.64 The IMAGES study recently failed to determine a benefit for intravenous magnesium in stroke.65 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.64
  • 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.66
    • 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%.67,68
    • 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.69
  • 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.11
  • 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.11


Fibrinolytic agents

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


Alteplase (Activase)

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.

Adult

0.9 mg/kg IV over 60 min; not to exceed 90 mg; 10% of total dose administered as initial IV bolus over 1 min; administer only within 3 h of onset of stroke symptoms

Pediatric

Not established

Drugs that alter platelet function (aspirin, dipyridamole, abciximab) may increase risk of bleeding prior to, during, or after alteplase therapy; may give heparin with and after alteplase infusions to reduce risk of rethrombosis; either heparin or alteplase may cause bleeding complications

Documented hypersensitivity; concurrent aspirin or anticoagulant medication; acute intracranial hemorrhage on pretreatment evaluation; seizure at onset of stroke; history of intracranial hemorrhage; suspected subarachnoid hemorrhage; active internal bleeding; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm; arteriovenous malformation or aneurysm; bleeding diathesis; severe uncontrolled hypertension

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for bleeding, especially at arterial puncture sites or with coadministration of vitamin K antagonists; control and monitor BP frequently during and following alteplase administration (when managing acute ischemic stroke); do not use >0.9 mg/kg to manage acute ischemic stroke; doses >0.9 mg/kg may cause ICH

Anti-Platelet Agents

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.70,71

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.72 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.

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.73 Further clinical trials are necessary.


Aspirin (Bayer Aspirin, Anacin, Bufferin)

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.

Adult

1.3 g/d PO divided bid/qid

Pediatric

10-15 mg/kg/dose PO q4-6h; not to exceed 60-80 mg/kg/d

Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease serum levels; anticoagulants may cause additive hypoprothrombinemic effects and increased bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma
Because of association with Reye syndrome, do not use in children (<16 y) with flu

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in severe anemia or coagulation defects, or in patients taking anticoagulants


Ticlopidine (Ticlid)

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

Adult

250 mg PO bid

Pediatric

Not established

Corticosteroids and antacids decrease effects; theophylline, cimetidine, aspirin, and NSAIDs increase toxicity

Documented hypersensitivity; severe neutropenia or thrombocytopenia; liver damage; active bleeding disorders

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Discontinue if absolute neutrophil count decreases to <1200/mm3 or platelet count decreases to <80,000/mm3

More on Stroke, Ischemic

Overview: Stroke, Ischemic
Differential Diagnoses & Workup: Stroke, Ischemic
Treatment & Medication: Stroke, Ischemic
Follow-up: Stroke, Ischemic
References
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References

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Further Reading

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Keywords

ischemic stroke, acute stroke, acute ischemic stroke, CVA, loss of neurologic function, cerebrovascular accident, stroke syndrome, thrombosis, embolism, hemorrhage, hemorrhagic stroke, cerebrovascular disease, neurologic complications, antithrombotic therapy, thrombolytic therapy, recombinant tissue-type plasminogen activator, rt-PA, t-PA, extracranial embolism, intracranial thrombosis, death of neurons, cerebral infarction, paradoxical emboli, cardiogenic emboli, valvular thrombi, mitral stenosis, endocarditis, prosthetic valves, mural thrombi, lipohyalinosis, pure motor strokes, pure sensory strokes, ataxic hemiparetic strokes, thrombotic occlusion, arterial stenosis, atherosclerosis, platelet adherence, polycythemia, sickle cell anemia, protein C deficiency, fibromuscular dysplasia of the cerebral arteries, prolonged vasoconstriction, thoracic aortic dissection, arteritis, acute neurologic deficit, altered level of consciousness, hemiparesis, monoparesis, quadriparesis, monocular visual loss, binocular visual loss

visual field deficits, diplopia, dysarthria, ataxia, vertigo, aphasia, carotid bruits, hypesthesia, hemianopsia, homonymous hemianopsia, agnosia, visual agnosia, receptive aphasia, expressive aphasia, cortical blindness, altered mental status, impaired memory, vertebrobasilar artery occlusions, nystagmus, dysphagia, facial hypesthesia, syncope, loss of pain sensation, loss of temperature sensation, smoking, heart disease, coronary artery disease, left ventricular hypertrophy, chronic atrial fibrillation, hypercholesterolemia, transient ischemic attacks, TIAs

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Contributor Information and Disclosures

Author

Joseph U Becker, MD, Fellow, Global Health and International Emergency Medicine, Stanford University
Joseph U Becker, MD is a member of the following medical societies: American College of Emergency Physicians, Emergency Medicine Residents Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Charles R Wira, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale School of Medicine
Charles R Wira, MD is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians
Disclosure: Nothing to disclose.

Medical Editor

Richard S Krause, MD, Senior Faculty, Department of Emergency Medicine, State University of New York at Buffalo School of Medicine
Richard S Krause, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

J Stephen Huff, MD, Associate Professor, Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center
J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

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
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Rick Kulkarni, MD, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
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