Emergency Medicine Reports October 13, 1997

Stroke: Comprehensive Guidelines for Clinical Assessment and Emergency Management (Part II)

Authors: John E. Duldner, Jr., MD, Emergency Physician, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland, OH.

Charles L. Emerman, MD, Chairman, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland, OH; Associate Professor, Case Western Reserve University, Cleveland, OH.

Peer Reviewers: Edward Jauch, MD, MS, Assistant Professor, Department of Emergency Medicine, University of Cincinnati Medical Center; Member, Greater Cincinnati/Northern Kentucky Stroke Team, Cincinnati, OH.

Sydney Starkman, MD, FACEP, Associate Clinical Professor of Emergency Medicine and Neurology, UCLA Medical Center; Chairman, Stroke Group, UCLA Stroke Center, Los Angeles, CA.

Put simply, acute stroke care is a treacherous, unpredictable enterprise that is just now coming out of its infancy. And, if anything is certain, we know this treatment arena will witness growing pains. In fact, few life-threatening conditions are linked to interventions that require the emergency physician to balance on a tightrope between pharmacotherapies that have the potential to produce, on the upside, so much good, but on the downside, so much potential irreversible damage to vital neurological structures.

Not surprisingly, the management of acute ischemic stroke has become a team effort that combines the skills of prehospital personnel, emergency physicians, and neurological specialists. This intensive multi-disciplinary effort is required because stroke management is no longer a primarily "passive" exercise simply requiring an appropriate triage decision, but now demands a careful assessment of treatment options, including aspirin therapy, blood pressure-lowering medications, anticoagulation, and, in a very small percentage of eligible patients, treatment with thrombolytic drugs.

Because pharmacotherapy directed against the clotting system has the potential of producing undesirable, life- and neurological function-compromising complications—specifically, the conversion of bland, thrombotic cerebral infarctions into hemorrhagic stroke—the most challenging aspect of stroke management is identifying patient subgroups who will benefit from anticoagulation or thrombolytic therapy without incurring the substantial complications associated with their use.

The patient selection process frequently falls within the province of the emergency physician, who must make rapid, time-pegged decisions in collaboration with the consulting neurologist, radiologist, primary care physician, as well as the patient and his or her family. This process requires precise documentation of onset of symptoms, a careful review of exclusionary and inclusionary criteria for thrombolytic protocols, and a determination of the likely risks of therapy based on patient factors, location of the stroke, early radiographic findings, and presentation.

In part I of this two-part series, the authors outlined a systematic approach for recognizing acute ischemic stroke syndromes and determining the vascular distribution of the insult based on the clinical presentation, including the constellation of neurological deficits. Part II presents an up-to-date approach for managing these patients, with a special emphasis on indications for CT scanning, strategies and target parameters for blood pressure reduction, and a discussion of the current status of thrombolytic therapy in this patient population.

—The Editor

Management of Acute Ischemic Syndromes

General Comments. Until recently, emergency physicians managing patients who were suffering an acute stroke had little to offer other than supportive measures. Over the past decade, however, we have seen significant advances in the management and treatment of stroke as well as a new focus on this devastating disease.1 Since the approval of tissue plasminogen activator (t-PA) for use in treating acute ischemic stroke, there has been an increasing awareness of new stroke therapies by both the public and the medical community. Emergency physicians are the first medical contact for a large percentage of stroke victims, and they can play an important role in initiating therapy.

A Systems Approach. The management of the acute stroke patient involves a multidisciplinary approach requiring participation of prehospital personnel, emergency nurses, emergency physicians, primary care providers, neurologists, and, in some cases, intensive care and rehabilitation specialists. The National Institutes of Neurological Disorders and Stroke(NINDS)/t-PA Stroke Study group recently outlined a "systems approach" for evaluation and management of stroke.2 In outlining a methodology to improve clinical outcomes in acute stroke patients, this group of investigators stated that, "It is critical to develop efficient hospital-based methods for hyperacute stroke patient screening, evaluation, and intervention at both community-based and tertiary care academic centers."2 Ideally, this stroke awareness and quality improvement program would include community education and public awareness campaigns, education of prehospital providers, systematic protocols for rapid ED evaluation—including a noncontrast head CT, accurate establishment of time of symptom onset, review of thrombolytic inclusion and exclusion criteria, and prompt treatment. In the eight centers included in this report, each had well-developed plans and protocols with defined goals. Each of the leading enrollment centers in the NINDS stroke trial incorporated the use of a "stroke team." Several other stroke programs have demonstrated success using stroke protocols and specialized systems for the care of the stroke patient.3-7

Stroke Teams. The number and the training background of personnel participating in a hospital-based stroke team depend on the availability of human and financial resources. At some institutions, the stroke team may consist of an emergency physician, who serves as the primary coordinator of care and uses phone consultation to communicate issues to a number of other team members (research coordinators, cerebrovascular nurse clinicians, neurologists, and intensive care specialists). Regardless of the size of a stroke team, the emergency physician should be able to lead the group, initiate a systematic diagnostic assessment plan, and manage the patient with appropriate medications or resuscitative interventions.

ED Evaluation. The ED evaluation of the acute stroke patient should adhere to a systematic treatment algorithm. (See Figure 1.) In this regard, it should be stressed that, although the FDA has approved the use of t-PA in selected patients with acute ischemic stroke, it has been postulated that fewer than 10% of patients with an acute ischemic neurological event will qualify for thrombolytic treatment. However, the presence of stroke critical pathways or protocols will improve care for all stroke patients.

Initial Evaluation. Although there is a tendency to focus on neurologic disability, the clinician should focus on airway and circulatory stabilization. It is important to rule out other diseases that may mimic an acute stroke, including seizure disorder, hypoglycemia, complex migraine, dysrhythmia, or syncope. The assessment should include a thorough history and physical examination and an appropriate neurological exam. The time of symptom onset also needs to be accurately determined for consideration of thrombolytic therapy. In patients whose symptoms were present upon awakening, their time of symptom onset is estimated from the last time that the patient’s neurological status was known to be normal, or the time just prior to going to sleep. Vital signs should be monitored at least every 10-15 minutes, and a noncontrast cranial computed tomography (CCT) scan should be obtained quickly if thrombolytics are considered.

Moreover, an NIH Stroke Scale (NIHSS) should be included as part of the physician evaluation. (See Table 1.) A clinical examination scale that was developed to assess neurological function,8 the NIHSS score is linked to severity of neurological deficit; the higher the score, the worse the neurological deficit, with scores ranging from 0-42. The NIHSS is frequently used in acute stroke trials and may be used to supplement the neurological exam. The NIHSS is available as a training video that requires less than two hours to complete.

The NIHSS, like the Glasgow Coma Scale, standardizes the assessment of stroke severity and allows treating physicians to document and communicate the severity of neurological insult according to a standardized "severity of illness" scale. Moreover, it permits clinicians to compare the status of the patient by performing repeat evaluations to measure either the improvement or worsening of a patient’s clinical condition. A comprehensive form for recording patient information includes more detailed instructions for scoring the patient examination. The complete scale with instructions can be obtained from the NINDS.

Thrombolytic therapy inclusion and exclusion criteria should be reviewed. (See Table 2.) Vital signs, particularly blood pressure should be monitored frequently and treated when appropriate. For all acute stroke patients, therapy to minimize cerebral injury should be administered according to hospital-based critical pathways.

Transient Ischemic Attacks

Evaluation. The primary objective when evaluating a patient with a transient ischemic attach (TIA) is to determine whether the ischemic insult has occurred in the anterior or posterior circulation and whether the patient falls into a high-risk category. The first point to stress is that most TIAs are, in fact, very transient. Almost 25% of patients will have resolution of their symptoms within five minutes, and 50% of patients will have resolution within 30 minutes of noticing symptoms.9 If the patient’s deficit still persists after one hour, there is only a 15% chance that the neurological symptoms will abate over the next 24 hours. Since the patient may be neurologically normal by the time they arrive in the ED, a careful history is essential in establishing the diagnosis. Not infrequently, the emergency physician will have to seek information from EMS personnel, family members, or observers who may have observed the deficit.

Distinguishing between TIAs that involve the anterior circulation from those involving the posterior circulation has important diagnostic and treatment implications. Symptoms associated with anterior circulation ischemia usually include motor or sensory deficits of the extremities or face, amaurosis fugax, aphasia, and/or homonymous hemianopia. In contrast, patients with symptoms involving the posterior circulation ischemia may complain of motor or sensory dysfunction, but commonly such symptoms will occur in association with diplopia, dysphasia, dysarthria, ataxia, and/or vertigo.

The patient should be questioned about co-existing vascular or cardiac disease. For example, a careful inquiry may reveal that the patient may have experienced neurological symptoms but did not seek medical attention. The patient may have symptoms suggesting vasculopathies, connective tissue disorders, or intracranial mass lesions. Patients under 40 years of age should be questioned about family history of early stroke, drug use, or symptoms suggestive of a hypercoagulable state.

The physical examination should be directed at uncovering subtle signs of neurological deficit. Attention should also be focused on determining whether the patient has evidence of cardiovascular disease. In this regard, a carotid bruit is not specific for high-grade stenosis, although, in the setting of a TIA, a carotid bruit is 85% specific for at least moderate stenosis.

Almost all patients should undergo a non-contrast enhanced CT. About 20% of patients who have a TIA will have abnormalities on CT scanning.10,11 Additionally, the CT may be helpful in ruling out mass lesions or intracranial hemorrhage. An MRI is generally not be part of the ED evaluation. Patients who suffer a TIA are at increased risk for a stroke. After the first year, the risk of subsequent stroke decreases to around 8% per year. There is no difference in stroke rate between patients with an anterior or posterior circulation TIA, but the combination of TIAs in both vascular territories does carry a higher risk.

Patients should be considered to be at high-risk for subsequent stroke if they have had multiple TIAs within the two weeks prior to arrival in the ED, if the deficit associated with the TIA was very severe, or if the patient had crescendo symptoms. In addition, patients should be considered to be at high risk if the TIA was caused by cardioembolic events. Patients who have had a history of recurrent TIAs should be questioned to determine whether symptoms experienced during the attack occurred within the same arterial distribution, indicating a vascular source, or whether symptoms reflect variable circulatory territories suggesting a cardioembolic source.

Risk factors for cardioembolism include atrial fibrillation, mitral stenosis, bioprosthetic and mechanical heart valves, myocardial infarction within the previous six months, documented left ventricular thrombus, known atrial myxoma, and dilated cardiomyopathy.12 Other cardiac abnormalities that may be minor risk factors for transient ischemic attack include sick sinus syndrome, foramen ovale, aortic stenosis, and atrial septal aneurysm.12,13

Patients in the high-risk group should be hospitalized as should those individuals with TIA who cannot undergo a rapid outpatient assessment. If cardioembolism is the suspected etiology for TIA, consideration should be given to heparinization, starting with a loading dose of 5000-10,000 IU followed by 1000-1200 units per hour guided by the PTT. Anticoagulation should be withheld until the CT scan is available in order to rule out a hemorrhagic stroke. In addition, consultation with a neurologist or the patient’s primary care physician is strongly advised since the evidence in favor of heparinization in TIA is not definitively established.

Patients in the low-risk group may be discharged to home as long as adequate follow-up is available and an expeditious outpatient work-up can be completed within one week.14 Patients with symptoms of anterior circulation ischemia should undergo either duplex carotid ultrasound or oculoplethysmography. Duplex Doppler ultrasound is very accurate for detection of carotid stenosis. Ocular plethysmography will detect lesions of at least 50% stenosis with about 90% sensitivity.15,16 Magnetic resonance angiography (MRA) is a non-invasive means of assessing both the extra- and intracranial circulation. MRA is limited by difficulty in distinguishing between very high grade stenosis and complete occlusion. Patients considered for surgery will generally require conventional angiography. Patients with symptoms consistent with posterior circulation ischemia may be evaluated using a transcranial Doppler ultrasonography. This test is about 75% sensitive for detecting significant stenosis.17 Alternatively, MRA again can be used to assess the posterior circulation.

Patients who are going to be discharged to home should be started on aspirin therapy, which has been shown to decrease the risk of stroke by about 23%.18 There is considerable controversy about the appropriate doses of aspirin with recommendations ranging from 75-1300 mg/d. At the present time, 75 mg/d of aspirin appears to be an adequate dose.19 Patients who cannot tolerate aspirin or who have had a TIA while already on aspirin therapy for another purpose may be started on ticlopidine. Ticlopidine is generally initiated at 250 mg bid. The use of ticlopidine is limited by such side effects as diarrhea and occasional neutropenia, which occur in the first three months of use. Some patients may require anticoagulation with warfarin; however, these patients usually will be admitted, rather than discharged from the emergency department on oral anticoagulants.20 Patients with symptoms of posterior circulation TIA may also be started on either aspirin or ticlopidine.

Acute Stroke: Management Considerations

ED evaluation of a stroke patient includes a complete blood count (CBC) including platelets, prothrombin time (PT), activated partial thromboplastin time (aPTT), and serum electrolytes. A rapid blood glucose should also be obtained. A noncontrast cranial computed tomography scan, ECG, and chest x-ray should be ordered. If the patient is a candidate for thrombolytic therapy, then the patient should be typed and cross-matched. Arterial blood gas and lumbar puncture should be obtained when indicated.21,22

Computed Tomography in Acute Stroke. CT scan is the diagnostic image of choice for acute neurological disease under evaluation in the ED. Previously, it was thought that infarction is not visible on CT scan until 24 hours after the onset of symptoms. However, subtle CT signs of early infarction may be seen within the first six hours after symptom onset with attenuation of brain tissue secondary to cytotoxic edema. Early CT manifestations of acute stroke have prognostic significance in that patients with early infarct changes on CT scan are more likely to have cerebral hemorrhage after t-PA.23,24 The major signs of early infarction include peri-infarct edema, mass effect, sulcal effacement, or hemorrhage. Patients with early infarct signs on CT should not receive thrombolysis.

Blood Pressure. Acute stroke produces an increase in blood pressure in approximately 80% of patients.8 Regardless of the treatment for stroke, blood pressure should be monitored frequently. Control of blood pressure is especially important in the setting of thrombolytic therapy for several reasons. First, significant elevation in blood pressure is an exclusion criteria for t-PA. In addition, management of blood pressure after administration of t-PA is important because elevated BP is associated with an increased risk of intracerebral hemorrhage.2,25

Minimal or moderate elevations in blood pressure do not require urgent pharmacological treatment, since there generally is a spontaneous decline in blood pressure over time.8,26 As a guideline, antihypertensive intervention is not required unless the calculated mean arterial blood pressure is greater than 130 mmHg or the systolic blood pressure is greater than 230 mmHg. Systolic blood pressures between 180-230 mmHg or diastolic pressures 105-120 mmHg may be treated with labetalol hydrochloride. This dose may be repeated or doubled every 10-20 minutes up to a dose of 150 mg. If adequate reductions in blood pressure are not achieved, intravenous sodium nitroprusside may be infused at a starting dose of 0.5 mcg/kg/min. Remember that a rapid reduction in the blood pressure is unnecessary and may be harmful.25 Although there is no definitive data to support an "ideal" blood pressure, a reduction to systolic blood pressures of 200-230 mmHg and to diastolic pressures of 100-120 mmHg is probably adequate. Other agents that may be effective for reduction of blood pressure include intravenous nitroglycerin, sodium nitroprusside, esmolol, and intravenous ACE inhibitors.26,27 The use of sublingual nifedipine should be avoided because of its rapid and unpredictable hypotensive effect. Hypotension is a rare phenomenon in acute ischemic stroke. If present, the etiology (e.g., volume depletion) should be sought.25

Anticoagulation. Although studies are ongoing, the efficacy of heparin in acute ischemic stroke is not well-established. Despite this, heparin is used commonly in the setting of acute stroke. The role of antithrombotic agents in acute stroke now also includes the use of low molecular weight heparins (LMWH) and heparinoids. Initial studies suggest that LMW heparins reduce disability and death even six months after stroke.28 Two other trials, the International Stroke Trial (IST) 29 and the TOAST trial (Trial of Org 10172 in Acute Stroke Treatment) may lend additional information to support the use of these agents. The use of intravenous heparin should be considered only in consultation with a neurologist or other physicians experienced in stroke management.

A noncontrast CT should be obtained prior to the initiation of heparin therapy. Specifically, heparin has been recommended in: 1) patients who have suffered minor strokes; 2) patients who do not have hemorrhages with their strokes but have evolving signs and symptoms; 3) patients whose stroke is caused by large vessel atherothrombosis; and, 4) patients with cardioembolic stroke.30 A history of bleeding disorders, recent surgery or trauma, and gastrointestinal bleeding disorders are usually contraindications to the use of heparin. A rectal exam including stool guaiac should be performed prior to heparin administration.

The use of antiplatelet agents in the acute setting of stroke is not well studied. There are two trials that have investigated the role of aspirin in acute stroke. In the IST, patients received 300 mg of aspirin vs. no-aspirin.29 The mortality reduction was .3% and the reduction in recurrent stroke was .7% in the aspirin group. In the Chinese Aspirin Stroke Trial (CAST), the use of aspirin vs. placebo resulted in decreased mortality, but the overall disability rate was not improved. These studies suggest a role for aspirin or other antiplatelet agents, but the data must be interpreted carefully because patients were enrolled as late as 24 hours after stroke onset.

Hyperglycemia. There has been considerable discussion regarding the effect of elevated serum glucose in the setting of acute stroke. Animal data suggest that hyperglycemia enlarges infarct size; however, clinical studies have not supported this finding.25,27 Nevertheless, it is important to recognize and treat hyperglycemia and hypoglycemia, as these disorders may present with focal neurological findings.

Antipyretics. Although there is experimental data to support the protective effects of hypothermia in reducing infarct size, clinical data are lacking.31 Hyperthermia is likely to indicate co-morbid disease, with one study indicating that acute infection may constitute a risk factor for ischemic stroke.32

Seizures. The frequency of seizures during an acute stroke approaches 43% and are more likely to occur in the setting of hemorrhagic infarction.33-35 If seizure occurs, it is more likely to manifest within the first 24 hours and usually presents as a partial seizure.33,36 In a recent study, patients who had more severe strokes were more likely to have a seizure during the early phase of a stroke. Even when other variables were considered, including atrial fibrillation, diabetes, and admission blood glucose, initial stroke severity was the most important variable predictive of seizure activity. Other factors including age, gender, history of ischemic heart disease, or hypertension did not influence likelihood of seizure.37 From a practical perspective, early seizures were more likely to occur in younger patients, in individuals with acute confusional states, in those with involvement of the cortex, and in patients who had suffered large stroke. Patients with lacunar infarction are less likely to experience early seizures.37

The efficacy of prophylactic anticonvulsant therapy in patients with acute stroke has not been established. However, if seizures are present, they may be controlled with benzodiazepines—either lorazepam or diazepam. Phenytoin is recommended in patients with recurrent seizures.21

Corticosteroids. There is currently no role for the use of corticosteroids in the management of acute stroke. Several clinical trials have investigated the use of corticosteroids; however, no improvement in outcome after stroke was demonstrated. Furthermore, the incidence of infection was greater in patients treated with steroids. 21,25,38-40

Cerebral Edema. The use of hypoosmolar fluids should be avoided. Instead, restrict IV fluids as a means of minimizing cerebral edema. Identify and treat factors that may worsen intracranial pressure such as hypoxia, hypercarbia, and hyperthermia. Elevating the head to 20-30° may also be helpful. Osmotic diuresis using mannitol or furosemide is not recommended.21 Decompression or evacuation of large cerebellar infarctions that compress the brain stem may be helpful in selected cases.25

Special Considerations: Thrombolytic Therapy

The recent approval of tissue plasminogen activator (t-PA) for use in acute ischemic stroke now provides the emergency physician with an additional therapeutic option in stroke management. Despite the controversy surrounding the administration of intravenous thrombolysis, the NINDS study demonstrated a benefit for patients with ischemic stroke in the carotid or vertebrobasilar circulation.2 The clinical improvement with thrombolysis was found to be beneficial irrespective of gender.2 It should be stressed that age is not an exclusion criterion for administration of thrombolytic therapy, and, in the NINDS trial, the benefit of therapy was seen in all age groups.25 The incidence of spontaneous intracerebral hemorrhage, however, does increase significantly with age.41 Treatment was beneficial for patients regardless of the etiology of the stroke, including small vessel occlusive disease, large vessel occlusive disease, and cardioembolic stroke. Patients with extensive, severe neurological deficit, or proximal middle cerebral artery occlusion may respond only to intravenous thrombolytic therapy. If followed with precision and prudence, the management guidelines recommended by the trial investigators provide an acceptable degree of benefit vs. risk for the patient. In institutions where thrombolysis for stroke is an accepted arm of the stroke management pathway, a primary focus should be to streamline evaluation of stroke patients to determine their stability for t-PA administration.

Informed Consent. A good faith effort to obtain informed consent should be undertaken. Though it is an accepted treatment, there are risks to the patient and it is important that patients and families are made aware of these risks and are able to make an informed decision.

NIH Stroke Scale Score. The NIH Stroke Scale (NIHSS) can be an important part of the diagnostic evaluation of the stroke patient. The scale can guide the decision analysis for thrombolysis because it is linked to severity of neurological deficit. Though not a formal exclusion criteria, patients with NIHSS scores higher than 22 will likely have extensive deficits and may have an increased risk of intracerebral hemorrhage (ICH).25

Issues in Thrombolysis. Dosage and Administrations. The exclusionary and inclusionary criteria should be reviewed prior to administration of t-PA. (See Table 2.) The dose of t-PA administered for acute ischemic stroke is 0.9 mg/kg with a maximum dose of 90 mg. Ten percent of the dose is given as a bolus dose, and the remainder is given over 60 minutes. The drug should be administered through a dedicated intravenous catheter site.

Temporal Issues. The present guidelines permit the administration of intravenous thrombolytics only within three hours of symptom onset. Accordingly, it is critical to accurately establish time of symptom onset and question the patient, family, or other witnesses to confirm the time of onset accurately. This three-hour window has been chosen to reduce the risk of hemorrhage and to maximize the potential for recovery. In the ECASS trial, which treated patients up to six hours after time of symptom onset, the higher 30-day mortality in the treated cohort outweighed any demonstrated benefit on functional, neurological, and economic outcomes.24

In contrast, the NINDS trial focused on evaluation and treatment only in patients with onset of symptoms that occurred within three hours of presentation to the physician. In this select population, the study demonstrated improved outcome in the thrombolytic-treated group.2 The ATLANTIS trial is presently underway; it is designed to evaluate the administration of t-PA after three hours but within five hours of symptom onset. Results of this study may show that the temporal window can be safely extended. Presently, however, thrombolysis cannot be recommended for individuals with symptoms with onset occurring more than three hours prior to ED presentation.

Blood Pressure Management in Thrombolytic Therapy. Meticulous attention to blood pressure management in the setting of thrombolysis is mandatory in order to minimize the risk of ICH. In this view, blood pressure should be monitored at least every 15 minutes for the first two hours after infusion has started, every 30 minutes thereafter for the next six hours, and then every hour, for a total of 24 hours. The presence of hypertension with systolic blood pressures (SBP) exceeding 185 mmHg or diastolic blood pressures (DBP) exceeding 110 mmHg on two or more readings separated by 10-15 minutes is an exclusion criteria. If thrombolytic therapy is administered, blood pressure must be maintained at a systolic value less than 185 mmHg and a diastolic reading of less than 110 mmHg. If the blood pressure on two consecutive readings 5-10 minutes apart shows a SBP greater than 180 mmHg or DBP 110 mmHg, labetalol hydrochloride should be administered at an initial dose of 10 mg IV over 1-2 minutes. The dose may be repeated or doubled every 10-20 minutes up to a dose of 150 mg. If the response is unsatisfactory, then an infusion of sodium nitroprusside starting at a dose of 0.5 mcg/kg/min is recommended. If the DBP is greater than 140 mmHg, then begin with an infusion of sodium nitroprusside, starting at 0.5 mcg/kg/minute.

Other agents that may be effective for reducing of blood pressure include intravenous nitroglycerin, esmolol, and or ACE inhibitors (such as enalapril 0.625-2.5 mg). These medications may be particularly helpful if labetalol is contraindicated.25

Concomitant Therapy. The administration of intravenous, subcutaneous, or oral anticoagulants for the first 24 hours of thrombolytic therapy is not recommended. Patients taking oral anticoagulants at the time of stroke should be excluded from the thrombolytic therapy if their INR is increased.

In addition, anti-platelet agents should not be used during the first 24 hours. It is important to note that patients who are taking antiplatelet agents at the time of their stroke are not excluded from the administration of t-PA; however antiplatelet agents should be discontinued for 24 hours.25

Complications of Thrombolytic Therapy. The administration of intravenous thrombolysis is not without risk; among possible complications, intracranial hemorrhage is the most worrisome and, potentially, the most devastating. Though more likely to occur within the first few hours of infusion, ICH after t-PA may occur up to 36 hours after administration of therapy.2

Vascular access should be performed only as necessary. Central venous or arterial punctures should be restricted during the first 24 hours. In the event IV sodium nitroprusside is required, the risk must be weighted with respect to bleeding complications and the need for intra-arterial blood pressure measurements. Placement of an indwelling bladder catheter should be avoided during the infusion and for 30 minutes thereafter. Insertion of a nasogastric tube should be avoided for 24 hours after treatment.25

Bleeding complications are generally classified into those involving the central nervous system (CNS) and those involving other organs.25 Hemorrhage, superficial or deep, is the most serious complication, and the treatment of bleeding due to thrombolytic therapy is guided by the location and size of the hematoma, likelihood that bleeding can be controlled with direct pressure the interval between the administration of the drug and onset of the hemorrhage, and the risk of neurological worsening or death.

CNS Hemorrhage. ICH should be suspected if there is a significant change in patient’s neurological status or if vomiting or increasing headache occurs. Patients with acute ICH generally have an elevated blood pressure as part of their clinical course. If ICH is suspected, the patient should have a hematocrit, PT, PTT, platelet count, and fibrinogen levels drawn. Patients should have blood typed and cross-matched including four units of packed red blood cells, 4-6 units of cryoprecipitate or fresh frozen plasma, and 1-2 units of platelets. Immediate neurosurgical consultation should be obtained following the demonstration of ICH on the CT scan.25

Non-CNS Hemorrhage. Direct pressure should be applied for bleeding at compressible sites, including arterial or venous puncture sites. If the bleeding is not stemmed by mechanical compression, the ongoing infusion of drug should be halted. Occult bleeding may occur at noncompressible sites. Subtle signs and symptoms may be present for patients with retroperitoneal or gastrointestinal bleeding. Frequent exams and monitoring of vital signs may provide clues. Unlike CNS hemorrhage, patients with retroperitoneal or GI hemorrhage are more likely to present with hypotension. Fluid resuscitation should be instituted, and appropriate diagnostic studies should be obtained before initiating medical or surgical therapy.

Neurosurgical Consultation. Neurosurgical consultation or support must be available for all patients undergoing thrombolytic therapy.25 However, it should be noted that there has been some controversy whether neurosurgical support must be immediately available at the treating institution. This issue is of considerable importance to the community physicians since neurosurgical consultation may not be as readily available as in the academic setting. In the community or rural setting, patients should not be eliminated from consideration for t-PA for lack of "in-house" neurosurgical backup. Efforts should be made with the regional tertiary centers to accept patients in the event of complications. Rapid transport via aeromedical means or ground ambulance are acceptable strategies.

Thrombolytic Therapy in the Rural or Community ED. At smaller hospitals, local physicians or hospital administrators may be unable to commit the substantial resources required to support a thrombolytic protocol for ischemic stroke. In these situations, the emergency physician should contact a regional tertiary referral center to establish an acute stroke coordinated care track (CCT) for patient transfer.

An aeromedical coordinated care track to transfer patients from surrounding rural hospitals to a referral center facility using a helicopter transport service may be established at the outlying ED. In this case, t-PA can be administered in the evaluating ED, and the infusion is continued while en route assuming that entry criteria can be adequately evaluated.

Emerging Stroke Therapies

Unfortunately, the overwhelming percentage of stroke patients do not meet selection criteria for thrombolytic therapy. The primary focus for new acute stroke therapies is in the area of "neuro-protective" or "cyto-protective" agents. These drugs target the ischemic penumbra, the area where blood supplies are inadequate to main clinical and electrophysiological functions but that represent areas of tissue that may be viable for several hours after the occlusive event. The peri-infarct cellular milieu resulting in tissue death involves depletion of energy stores, ion pump failure, membrane destabilization, and free radical formation.

Free Radical Scavengers. Free radicals are formed in the ischemic penumbra and are believed to be directly toxic to nerve cells.25 One agent, a steroid lipid peroxidation inhibitor, tirilazad mesylate, has been studied; however, it did not improve overall functional outcome at three months in two separate trials.

Membrane-Stabilizing Compounds. The plasma membrane is a barrier to neurotransmitters and ions. In the ischemic setting, the plasma membrane loses its protective capacity. Membrane stabilizing agents, such as a monoganglioside, are believed to enter the plasma membrane and block harmful excitotoxic effects. Three clinical studies, however, failed to show improved outcome three months after stroke; however, subanalysis did suggest that early treatment within 4-6 hours may offer benefit, but this requires further investigation.42

Ion Channel Blockers. Sodium channel blockers are involved with glutamate release. Fosphenytoin, a pro-drug of phenytoin, blocks the sodium receptor and decreases release of glutamate, resulting in diminished excitotoxic side effects. Nimodipine, a calcium channel blocker already recommended for use in subarachnoid hemorrhage, is being investigated for the use of stroke. One study did not show benefit; however, study medication was administered up to 48 hours after the onset of stroke. An ongoing study, the Very Early Nimodipine Use in Acute Stroke (VENUS) trial, is evaluating the effect of oral nimodipine started within six hours after onset of ischemic symptoms.43

Glutamate Receptor Antagonists. Glutamate is considered an excitotoxic amino acid because stimulation of glutamate receptors leads to uncontrolled entry of calcium into the neuron resulting in cell death. The NMDA receptor is located on the cell surface and has a glutamate binding site. NMDA receptor antagonists may be protective to cells reducing glutamate release due to the ischemic insult. Eliprodil was an NMDA antagonist that showed promise, however, a Phase III trial did not demonstrate efficacy. Another compound, Cerestat (aptiganel hydrochloride) is presently under evaluation.

Enhanced Activity of GABA. GABA is the main inhibitory neurotransmitter in the brain. The pharmacological strategy for its use involves counteracting excito-toxicity by enhancing the inhibitory activity of GABA. One compound, chlormethiazole, increases the effect of GABA by working directly at the GABA receptor. The efficacy results are pending from the recent completion of a trial.42

Monoclonal Antibody Therapy. White blood cells are present after ischemic insult and may be destructive to the microcirculation and may release cytokines that enhance neuronal tissue damage. Enlimomab is a murine monoclonal antibody that binds to intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is increased in the setting of focal ischemia and results in an influx of white blood cells. By administering the monoclonal antibody, it is believed to reduce the destructive effects of the white blood cells.

Though there are several neuroprotective strategies under investigation, additional agents are under development that involve opioid receptor antagonists, protein synthesis inhibitors, and growth factor compounds.

Intra-Arterial Thrombolysis. The use of micro-angiographic techniques for the visualization of clot in the cerebral circulation followed by the administration of thrombolytic agents is possible. One ongoing study, PROACT, uses pro-urokinase administered angiographically within six hours of symptom onset. Patient recruitment efforts are still underway, and the efficacy results are pending. Except for the investigational studies, intra-arterial administration of thrombolysis is not indicated or FDA-approved for the treatment of stroke. Until trials are completed, intra-arterial administration of thrombolytic therapy should be considered strictly investigational.

Summary

Maximizing clinical outcomes in stroke patients requires a systematic approach to diagnosis and management. Prompt CT scanning will be required to guide therapy in most cases, and a careful history documenting symptom onset is mandatory for determining which patients will be eligible for thrombolytic intervention. Although thrombolysis is becoming established as primary modality in some major centers, the precise inclusionary and exclusionary criteria for patient selection are still being refined. In patients who are poor candidates for thrombolytic protocols, or who are managed in centers which do not yet include this therapy in their treatment pathways, eligibility for other interventions, including aspirin and anticoagulation with heparin, should be considered.

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Physician CME Questions

57. Contraindications to thrombolytic therapy include:

A. rapidly improving deficits.

B. persistent hypertension.

C. pure sensory strokes.

D. All of the above

58. The correct dose of corticosteroid in acute stroke is:

A. dexamethasone, 10 mg IV.

B. methylprednisone, 120 mg IV.

C. prednisone, 60 mg PO.

D. should not be used

59. An early finding of large infarct on noncontrast CT of the brain is:

A. sulcal effacement.

B. normal CT of the brain.

C. midline shift.

D. well-defined hypodensity.

60. The appropriate dose of t-PA is:

A. 1.0 mg/kg, max dose of 100 mg.

B. 0.7 mg/kg, max dose of 90 mg.

C. 0.9 mg/kg, max dose of 90 mg.

D. 0.8 mg/kg, max dose of 100 mg.

61. In order to use t-PA, the patient’s blood pressure should be below:

A. 150 mmHg systolic.

B. 90 mmHg diastolic.

C. 180 mmHg systolic.

D. 200 mmHg systolic.

62. Patients with TIA should always be admitted if:

A. the patient is in atrial fibrillation.

B. the patient had amaurosis fugax.

C. the patient had arm weakness.

D. the symptoms lasted for 30 minutes.

63. Risk factors for cardioembolism include:

A. second-degree heart block.

B. mitral regurgitation.

C. right bundle branch block.

D. mitral stenosis.

64. The percentage of acute ischemic stroke patients who qualify for thrombolytic treatment is estimated to be:

A. 25%.

B. less than 10%.

C. 50%.

D. 90%.