Patients with acute stroke should be treated with the same sense of urgency as patients with an acute myocardial infarction (MI). Just as a heart attack indicates the need for emergency action because of a lack of blood supply to the heart muscle, an ischemic stroke (cerebral infarction) is a brain attack indicating an abrupt lack of blood supply to a region of the brain. Urgent medical or surgical intervention may be critical to long-term outcome. Most patients who present with cerebral infarction should be hospitalized for urgent evaluation and treatment.

The initial evaluation of a patient who presents with cerebral infarction is similar to that outlined for transient ischemic attack (TIA) and minor cerebral infarction (MCI) (see Chapter 12). Computed tomography (CT) without contrast or magnetic resonance imaging (MRI) is indicated to quickly distinguish between nonhemorrhagic and hemorrhagic cerebrovascular disease. As management options for acute cerebral infarction have continued to evolve, patients with a significant deficit related to the infarction will often undergo computed tomography angiography (CTA) to assess for the presence of intracranial large vessel occlusion (LVO). In addition, computed tomography perfusion (CTP) is now often performed in the acute ischemic stroke setting to clarify the amount of brain tissue that is potentially still salvageable (ischemic penumbra) as opposed to tissue that is irreparably damaged (infarct core). Automated processes are commonly used to define the infarct core and ischemic penumbra, providing rapidly available information in the emergency setting (see Chapter 7). If CT without contrast is performed initially, MRI or CT with contrast may be required if the initial scan indicates a possible arteriovenous malformation, meningioma, or other mass lesion. Other baseline studies should include complete blood cell count, activated partial thromboplastin time, international normalized ratio (INR), blood glucose, creatinine, liver function tests, electrolytes, and erythrocyte sedimentation rate. Lipid analyses, including high-density lipoprotein, low-density lipoprotein, and cholesterol levels, should be performed but do not need to be performed acutely. Cardiac biomarkers such as troponin and creatine kinase should be drawn acutely to rule out MI, given the frequent co-occurrence of coronary artery disease with cerebral infarction. A chest radiograph, an electrocardiogram, and a rhythm strip should also be obtained. The chest radiograph does not need to be available prior to starting thrombolytic therapy.

Treatment of patients with acute cerebral infarction differs somewhat from that of patients with TIA and minor stroke and includes (1) consideration of thrombolytic therapy or mechanical thrombectomy, (2) consideration of antiplatelet agents or anticoagulants, (3) intensive general medical care, (4) treatment of the neurologic deficit, (5) prevention of subsequent neurologic event, and
(6) prevention and treatment of secondary complications such as pneumonia, urinary tract infection, and deep vein thrombosis (DVT); see Appendix E-3. As with TIA and MCI, cardiac evaluation should also include cardiac history (with special attention to ischemic symptoms, arrhythmia, and murmurs) and cardiac examination.

Subsequent evaluation is typically based on the magnitude of the deficit, the patient’s age and medical status, and candidacy for therapeutic intervention, including either a surgical or endovascular procedure, or medical intervention.

The initial therapeutic approach to ischemic infarction has continued to evolve and is dependent on the time from the onset of symptoms to presentation for emergency medical care and on results of the urgent imaging studies. If the history and examination verify that the probable cause of the symptoms is an ischemic stroke and if the onset of symptoms was less than 3 hours (<4.5 hours in selected patients) before the treatment can be started, then emergent intravenous thrombolytic therapy is initiated. In addition, for patients without a rapid clinical response to thrombolysis or up to 6 hours after the onset of symptoms, mechanical thrombectomy is considered. Beyond 6 hours and up to 24 hours after onset, advanced imaging studies (CTP or perfusion-diffusion MRI) are used to determine the size of the infarct core and ischemic penumbra. Selected patients with a relatively small infarct core and large ischemic penumbra may benefit from mechanical thrombectomy up to 24 hours after onset (treatment effects are better for earlier thrombectomy). Likewise, there are clinical data suggesting that thrombolytic therapy may improve functional outcome in advanced imaging-selected patients seen 4.5-9 hours after onset.

Thrombolytic agents, such as recombinant tissue plasminogen activator (tPA), given intravenously are designed to reopen arteries that are occluded by emboli or a primary thrombus and induce reperfusion of an ischemic area of the brain. Although such reperfusion may be associated with a return of neurologic function of the affected area, clinical improvement may not occur, and administration may be complicated by intracerebral hemorrhage (ICH).

The time of onset of the infarction must be sought from the patient or the family. If the onset of symptoms is known to occur less than 3 hours prior to the potential initiation of intravenous (IV) thrombolytic therapy, and the CT head and other clinical issues do not suggest a contraindication, then IV tPA should be considered. Beyond 3 hours after onset, data from the European Cooperative Acute Stroke Study III (ECASS III) trial suggest that selected patients treated between 3 and 4.5 hours after symptom onset may benefit from IV tPA. Patients more than 80 years of age, patients taking warfarin regardless of INR, those with a history of diabetes mellitus and previous ischemic stroke, and those with a very severe stroke (National Institutes of Health Stroke Scale [NIHSS] score >25) were excluded from this extended time window in the clinical trials. However, guidelines including those published by the American Stroke Association suggest that the patients who are otherwise eligible for treatment with tPA in 3 to 4.5 hours may benefit from treatment even if these exclusion criteria exist. The exception involves patients with very severe stroke, NIHSS score more than 25, for whom the benefit of treatment from 3 to 4.5 hours is unclear. The Food and Drug Administration in the United States has not approved tPA for use in the 3- to 4.5-hour time window but the available guidelines support such use. The result of the initial
CT head scan is very important in selecting patients for possible thrombolysis. The CT should not reveal any evidence of intracranial hemorrhage, mass effect, midline shift, or significant early infarction. For patients with known unruptured intracranial aneurysm of less than 10 mm diameter, particularly those with no history of prior aneurysmal rupture, use of tPA is reasonable. Similarly, the risks in those with a known unruptured arteriovenous malformation are unknown, but in those with a severe neurologic deficit related to the evolving cerebral infarction, the potential benefit likely outweighs the risk. In patients with prior imaging revealing 1 to 10 cerebral microbleeds, the use of IV tPA is reasonable. The benefit in those with more than 10 microbleeds is uncertain but treatment with IV tPA can be considered in those with a severe deficit. Treatment with tPA is reasonable in those with an extraaxial neoplasm, but is contraindicated in the presence of an intraaxial neoplasm. Clinical criteria that may exclude patients from IV tPA in addition to the time cut-off are (1) rapid improvement to a nondisabling status; if improvement has occurred but a disabling deficit remains, then IV tPA is reasonable, (2) mild, nondisabling deficits (patients with mild, yet potentially disabling deficits should be considered for treatment), (3) obtundation or coma, (4) history of intracranial hemorrhage or bleeding diathesis, (5) blood pressure (BP) increase persistently greater than 185/110 mm Hg despite aggressive treatment, (6) recent ischemic stroke within 3 months, (7) recent severe head trauma within 3 months, (8) intracranial/spinal surgery within 3 months, and (9) presence of infective endocarditis or aortic arch dissection. Presentation with seizure is no longer considered to be a contraindication to use of tPA if the residual deficit is likely related to stroke and not a postictal process. Similarly, the risk of bleeding in the setting of past gastrointestinal hemorrhage or urinary tract hemorrhage is low, so IV tPA is reasonable.

Laboratory abnormalities that may preclude treatment are (1) heparin use within 48 hours with increased activated partial thromboplastin time or low-molecular-weight heparin (LMWH) use within 24 hours, (2) warfarin use with INR greater than 1.7, (3) serum glucose less than 50 mg/dL, and (4) platelet count less than 100,000 mm³ (treatment does not need to be delayed pending the platelet count but should be discontinued if the platelet count is found to be low). Use of a direct oral anticoagulant, either a direct thrombin inhibitor or direct factor Xa inhibitor, is a contraindication to the use of IV tPA unless the patient has not received a dose for more than 48 hours, in the setting of normal renal function, and/or appropriate normal laboratory tests. Long-term aspirin, clopidogrel, or dipyridamole use is not a contraindication to the use of IV tPA.

If the patient is a candidate for thrombolytic therapy, then the patient and the family should be counseled regarding the risks and benefits of such therapy. In the National Institutes of Health-funded treatment trial of IV tPA published in 1995, the efficacy in improving neurologic status at 3 months was defined for tPA compared with placebo, with the agent administered within 3 hours of symptom onset. There was a greater proportion (12% absolute increase) of people with minimal or no deficit in the tPA group at 3 months after the event, and there was no increase in patients with severe deficits or disability. This finding is particularly important because there was a 6% occurrence of symptomatic hemorrhage within 36 hours of treatment in the tPA group compared with 0.6% in the placebo group. In the IV tPA trial, despite the increased occurrence of symptomatic hemorrhage, the 90-day mortality rate was not different comparing those who were treated with IV tPA (17% mortality) and those who were treated with placebo (21% mortality).

There are data that suggest that IV tPA should be considered in selected patients with unknown time of onset or who awaken with stroke-related
symptoms. In the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) study, in patients with unknown time of onset or who had awakened with stroke symptoms, with a positive diffusion-weighted imaging (DWI) MRI but no abnormality on the MRI fluid-attenuated inversion recovery sequence, those treated with IV tPA did better than those receiving standard treatment. A modified Rankin Score of 0 to 1 was achieved in 53% of the IV tPA group compared to 42% of the standard treatment group. The risk of symptomatic ICH was not significantly increased (2.0% in the IV tPA group and 0.4% in those receiving standard treatment). There are also clinical trial data suggesting that patients with a relatively small infarct core and large ischemic penumbra detected on advanced imaging studies with CTP or perfusion-diffusion MRI may have a better functional outcome when treated with IV tPA between 4.5-9 hours.

An intracranial hemorrhage in the setting of thrombolytic therapy should be suspected if neurologic deterioration occurs or if there is new severe headache, acute hypertension, nausea, or vomiting. Use of tPA should be discontinued immediately if the infusion is ongoing, and a CT scan without contrast should be obtained. In the meantime, INR/prothrombin time, partial thromboplastin time, platelet count, hemoglobin, and fibrinogen level should be determined emergently, and cryoprecipitate-containing factor VIII (10 units) should be prepared and infused over 10 to 30 minutes. An additional dose may be given if the fibrinogen level remains less than 200 mg per dL. An antifibrinolytic agent may also be used, such as tranexamic acid 10 to 15 mg per kg IV infused over 10 minutes or epsilon-aminocaproic acid 5 g IV followed by 1 g IV if needed, until bleeding is controlled. If the CT scan confirms hemorrhage, then neurosurgical consultation should be obtained. A hematologist may aid in outlining optimal replacement therapy with platelets and cryoprecipitate. Another CT scan can be obtained 6 hours later, or sooner if the deficit worsens.

Orolingual edema is an uncommon complication following tPA use. Increased occurrence of orolingual edema is observed in those with prior use of an angiotensin-converting enzyme inhibitor. Airway status should be closely monitored. Those with involvement of the anterior tongue and lips may not require endotracheal intubation but those with involvement of the larynx, oropharynx, palate, or floor of the mouth may progress to the need for intubation. Once noted, IV tPA should be stopped, and diphenhydramine 50 mg IV, ranitidine 50 mg IV, and methylprednisone 125 mg IV or dexamethasone 10 mg IV should be administered. If the angioedema worsens, then epinephrine (0.1%) should be used, with administration of 0.3 mL subcutaneously or 0.5 mL via nebulizer.