Version May 2024
INTRODUCTION — The most important factor in successful reperfusion therapy of acute ischemic stroke is early treatment. Nonetheless, selection of appropriate candidates for reperfusion demands a neurologic evaluation and a neuroimaging study. In addition, reperfusion therapy for acute stroke requires a system that coordinates emergency services, stroke neurology, intensive care services, neuroimaging, and neurosurgery to provide optimal treatment.
This topic will review the administration of intravenous thrombolytic therapy for patients with acute ischemic stroke. The approach to reperfusion therapy and selection of appropriate patients for treatment is discussed elsewhere. (See "Approach to reperfusion therapy for acute ischemic stroke".)
Mechanical thrombectomy is reviewed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke".)
Other aspects of acute ischemic stroke care are discussed elsewhere. (See "Initial assessment and management of acute stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Neuroimaging of acute stroke".)
OVERVIEW OF REPERFUSION THERAPY — The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve outcome by reducing stroke-related disability and mortality. There are two options for reperfusion therapy that are proven effective:
Intravenous thrombolytic therapy — Thrombolytic therapy is the mainstay of treatment for acute ischemic stroke. Because the benefit is time-dependent, it is critical to treat eligible patients as quickly as possible.
●Treatment within 4.5 hours – Intravenous thrombolysis improves functional outcome for patients with acute ischemic stroke, provided that treatment is initiated within 4.5 hours of clearly defined symptom onset time or within 4.5 hours of the time the patient was last known to be well (table 1 and algorithm 1). (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit by time to treatment'.)
●Wake-up stroke or unknown time of symptom onset – For patients with wake-up stroke or unknown time last known well, imaging-based criteria to determine eligibility for intravenous thrombolysis (ie, an MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to determine eligibility for intravenous thrombolysis. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit with imaging selection of patients'.)
●Alteplase – Alteplase, a recombinant tissue plasminogen activator (tPA), initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converting entrapped plasminogen to plasmin. In turn, plasmin breaks up the thrombus. The pivotal randomized trials that established the efficacy of intravenous thrombolytic therapy for acute stroke used alteplase as the thrombolytic agent. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase'.)
●Tenecteplase – Tenecteplase is a thrombolytic agent that is more fibrin-specific and has a longer duration of action compared with alteplase. Although not licensed in the United States for intravenous thrombolysis in acute ischemic stroke treatment, there is evidence that intravenous tenecteplase has similar efficacy and safety outcomes compared with alteplase. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Tenecteplase'.)
Mechanical thrombectomy — Mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who can be treated within 24 hours of the time last known to be well (ie, at neurologic baseline), regardless of whether they receive intravenous thrombolysis for the same ischemic stroke event (algorithm 2). (See "Mechanical thrombectomy for acute ischemic stroke".)
Eligible patients should receive intravenous thrombolysis without delay even if mechanical thrombectomy is being considered [1].
ADMINISTRATION OF THROMBOLYTIC THERAPY — "Time is brain." The sooner intravenous thrombolysis is initiated after ischemic stroke, the more likely it is to be beneficial. The benefits and risks of thrombolytic therapy with alteplase or tenecteplase are discussed in detail separately (see "Approach to reperfusion therapy for acute ischemic stroke"). The selection of appropriate patients for such therapy is summarized in the table (table 1 and algorithm 1).
Preparing for treatment — Prior to treatment, all patients require confirmation of the following:
●The diagnosis is acute ischemic stroke
●Treatment is commencing within the required 4.5-hour time window after the onset of symptoms, defined as the time last seen normal or at baseline
●There is a persistent, measurable, disabling neurologic deficit
●Eligibility criteria are met (table 1)
●Serum glucose must be checked to rule out hypoglycemia as a cause of neurologic deficit
●The noncontrast head computed tomography (CT) or brain magnetic resonance imaging (MRI) is without hemorrhage or other contraindication
●Blood pressure parameters are met (see 'Management of blood pressure' below)
●Two intravenous lines, preferably large bore, are in place
●Accurate body weight has been determined [2]
Management of blood pressure — Strict blood pressure control is critical prior to and during the first 24 hours after thrombolytic therapy.
●The blood pressure must be at or below 185 mmHg systolic and 110 mmHg diastolic before administering thrombolysis. Patients with blood pressure above this range should be treated with intravenous agents such as intravenous labetalol or nicardipine, or clevidipine (table 2) [1]. Alternative agents include hydralazine and enalaprilat. If intravenous treatment does not bring the blood pressure into the acceptable range, the patient should not be treated with thrombolysis because the risk of intracerebral hemorrhage with thrombolytic therapy may be increased.
●Once thrombolytic therapy has been administered, the blood pressure must be maintained below 180/105 mmHg during and for 24 hours following thrombolytic therapy (table 2). Intravenous labetalol, nicardipine, or clevidipine are suggested agents of first choice [1]. Frequent blood pressure monitoring is recommended to ensure that the blood pressure remains in the acceptable range. Current guidelines recommend monitoring every 15 minutes for the first 2 hours after starting thrombolytic treatment, then every 30 minutes for the next 6 hours, then every hour until 24 hours after starting treatment. The frequency of blood pressure monitoring should be increased if the systolic blood pressure is >180 mmHg or if the diastolic blood pressure is >105 mmHg.
For patients with stroke caused by a known large artery occlusion (documented by computed tomography angiography [CTA] or magnetic resonance angiography [MRA]), we suggest keeping systolic blood pressure between 150 to 180 mmHg prior to reperfusion, and targeting systolic blood pressure to <140 mmHg once reperfusion is achieved with intravenous thrombolysis or mechanical thrombectomy (see "Mechanical thrombectomy for acute ischemic stroke", section on 'Blood pressure'). These recommendations regarding blood pressure control are based on consensus, since there are no data supporting the use of any specific antihypertensive agent or regimen for patients with acute ischemic stroke treated with thrombolysis.
The optimal lower end of the range of desired blood pressure is unclear in those requiring antihypertensive treatment for thrombolysis. Maintaining the blood pressure below 180/105 mmHg for at least the first 24 hours after administration of thrombolytic therapy is the only guideline recommendation [1]. In this situation, there is still a risk of worsening blood flow within the ischemic penumbra if blood pressure is driven too low. Therefore, it is important to avoid excessive blood pressure lowering when using intravenous antihypertensive treatment.
Despite concerns about reducing perfusion, more intensive blood pressure reduction might reduce the risk of symptomatic intracerebral hemorrhage and thereby improve outcomes. The blood pressure control assessment arm of the open-label, international ENCHANTED trial tested this strategy and found that a target blood pressure of 130 to 140 mmHg with intravenous thrombolytic therapy did not appear to be beneficial or harmful. The ENCHANTED trial enrolled over 2200 alteplase-eligible patients with acute ischemic stroke and randomly assigned them to intensive blood pressure lowering (to a target systolic blood pressure of 130 to 140 mmHg within one hour) or guideline blood pressure lowering (target <180 mmHg) over 72 hours [3]. The mean systolic blood pressure over 24 hours in the intensive and guideline groups was 144.3 mmHg and 149.8 mmHg, respectively. At 90 days, there was no difference in functional status between groups. Intracranial hemorrhage was less frequent in the intensive group compared with the guideline group (14.8 versus 18.7 percent), but there was no significant difference between groups in rates of symptomatic intracerebral hemorrhage or serious adverse events.
Dosing
Alteplase dose — A dedicated intravenous line is required for alteplase, and all patients should have at least one additional large bore intravenous line.
●The alteplase dose is calculated at 0.9 mg/kg of actual body weight, with a maximum dose of 90 mg
●Ten percent of the dose is given as an intravenous bolus over one minute and the remainder is infused over one hour
It is advisable to remove any excess alteplase from the bottle prior to administration, in order to avoid overdosage if the intravenous pump is inaccurately calibrated.
In Japan, the approved dose of alteplase for acute ischemic stroke is 0.6 mg/kg, based upon the results of a small open-label study suggesting that this dose was associated with a lower risk of intracerebral hemorrhage and similar efficacy compared with the standard alteplase dose of 0.9 mg/kg [4]. However, in the ENCHANTED trial, which enrolled over 3300 subjects (63 percent Asian) with acute ischemic stroke, low-dose alteplase (0.6 mg/kg) did not meet noninferiority criteria compared with standard-dose alteplase (0.9 mg/kg) for the outcome of death and disability at 90 days [5].
Tenecteplase dose — The dose of tenecteplase is 0.25 mg/kg (maximum total dose 25 mg) given in a single intravenous bolus over 5 seconds, followed by a saline flush [6,7].
Monitoring — All patients treated with intravenous thrombolysis for acute ischemic stroke should be admitted to an intensive care unit or dedicated stroke unit for at least 24 hours of close neurologic and cardiac monitoring [1]. Symptomatic intracerebral hemorrhage should be suspected in any patient who develops sudden neurologic deterioration, a decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in blood pressure after thrombolytic therapy is administered, especially within the first 24 hours of treatment. (See 'Management of symptomatic intracerebral hemorrhage' below.)
Important measures during the first 24 hours of treatment with thrombolytic therapy include the following [1]:
●Vital signs and neurologic status should be checked every 15 minutes for two hours, then every 30 minutes for six hours, then every 60 minutes until 24 hours from the start of thrombolysis.
●Blood pressure must be maintained at or below 180/105 mmHg during the first 24 hours. (See 'Management of blood pressure' above.)
●Antithrombotic agents, such as heparin, warfarin, direct oral anticoagulants, or antiplatelet drugs, should not be administered for at least 24 hours after the alteplase infusion or tenecteplase bolus is completed, unless their administration is absolutely necessary.
●Placement of intra-arterial catheters, indwelling bladder catheters, and nasogastric tubes should be avoided for at least 24 hours if the patient can be safely managed without them.
A follow-up noncontrast CT (or MRI) brain scan should be obtained 24 hours after thrombolysis is initiated before starting treatment with antiplatelet or anticoagulant agents [1].
COMPLICATIONS — The most feared complication of thrombolytic therapy is symptomatic intracerebral hemorrhage. Asymptomatic intracerebral hemorrhage, systemic bleeding, and angioedema are additional complications that may arise.
Intracerebral hemorrhage — Treatment with intravenous (IV) thrombolysis within 4.5 hours of acute ischemic stroke onset is associated with an increased early risk of intracerebral hemorrhage, which was in the range of 5 to 7 percent; lower rates have been observed using stricter definitions of symptomatic intracerebral hemorrhage. This risk is offset by later benefit in the form of reduced disability. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase' and "Approach to reperfusion therapy for acute ischemic stroke", section on 'Risk of intracerebral hemorrhage'.)
Management of symptomatic intracerebral hemorrhage — Symptomatic intracerebral hemorrhage should be suspected in any patient who develops sudden neurologic deterioration, a decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in blood pressure after thrombolytic therapy is administered, especially within the first 24 hours of treatment.
In patients with suspected intracerebral hemorrhage, the alteplase infusion should be discontinued and a stat noncontrast head computed tomography (CT) or magnetic resonance imaging (MRI) scan should be arranged (table 3) [1]. Blood should be drawn for typing and cross matching, and measurement of prothrombin time, activated partial thromboplastin time, platelet count, and fibrinogen.
Treatment options for intracerebral hemorrhage related to intravenous thrombolytic treatment are unproven but include the administration of agents to reverse the effects of thrombolytic therapy and antithrombotic therapy [1,8-13]:
●Cryoprecipitate, 10 units immediately (infused over 10 to 30 minutes) and more as needed to achieve a serum fibrinogen level of 150 to 200 mg/dL
●Antifibrinolytic agents: aminocaproic acid 4 to 5 g IV during first hour, followed by 1 g/hour for 8 hours until bleeding is controlled, or tranexamic acid 10 to 15 mg/kg IV over 10 to 20 minutes
●Prothrombin complex concentrate as adjunctive therapy to cryoprecipitate for patients on warfarin prior to thrombolytic treatment
●Fresh frozen plasma as adjunctive therapy to cryoprecipitate for patients on warfarin prior to thrombolytic treatment if prothrombin complex concentrate is not available
●Vitamin K as adjunctive therapy for patients on warfarin prior to thrombolytic treatment
●Six to eight units of platelets for patients with thrombocytopenia (platelet count <100,000/microL)
●In patients receiving unfractionated heparin (UFH) for any reason, it is reasonable to treat with 1 mg of protamine for every 100 units of UFH given in the preceding 4 hours
Urgent neurosurgery and hematology consultations are indicated for patients with symptomatic intracranial hemorrhage associated with thrombolysis [1]. Supportive therapy includes management of blood pressure, intracranial pressure, cerebral perfusion pressure, and glucose control.
The efficacy of neurosurgical evacuation in this setting is unproven. However, in a retrospective analysis of data from the GUSTO-I trial of thrombolysis for myocardial infarction, 30-day survival was significantly higher with neurosurgical hematoma evacuation than without (65 versus 35 percent), and there was a trend towards improved functional outcome due to a higher incidence of nondisabling stroke in those with evacuation compared with those without (20 versus 12 percent) [14]. However, no definitive conclusions can be drawn from this retrospective, nonrandomized study.
Systemic bleeding — Mild systemic bleeding usually occurs in the form of oozing from intravenous catheter sites, ecchymoses (especially under automated blood pressure cuffs), and gum bleeding; these complications do not require cessation of treatment. More serious bleeding, such as from the gastrointestinal or genitourinary system, may require discontinuation of alteplase depending on the severity.
Rarely, patients who suffer stroke after a recent myocardial infarction can develop bleeding into the pericardium, resulting in life-threatening tamponade [15,16]. Consequently, patients who become hypotensive after thrombolytic therapy should be evaluated with urgent echocardiography.
Angioedema — Orolingual angioedema occurs in 1 to 8 percent of patients treated with alteplase or tenecteplase for ischemic stroke [17-20], and it is typically mild, transient, and contralateral to the ischemic hemisphere [18,21]. Patients taking angiotensin converting enzyme inhibitors and those with CT evidence of ischemia in the frontal and insular cortex may be at increased risk.
Severe orolingual angioedema is rare but may cause partial airway obstruction and require emergent airway management [1,18,21,22]. CT of the tongue can distinguish hematoma from angioedema in this setting [23].
The patient with angioedema near or involving the tongue, uvula, soft palate, or larynx must be immediately assessed for signs of airway compromise. If intubation is necessary, the airway should be managed by the most experienced person available, because intubation in the presence of laryngeal angioedema can be difficult due to distortion of the normal anatomy. Angioedema of the lips or mouth sometimes spreads to involve the throat, and frequent monitoring of airway patency is critical throughout treatment. (See "An overview of angioedema: Clinical features, diagnosis, and management".)
Treating centers should be aware of the potential need for stopping the drug infusion, administering antihistamines and glucocorticoids, and intubating patients who develop stridor.
Specific management recommendations for orolingual angioedema include the following [1]:
●Maintain airway:
•Endotracheal intubation may not be necessary if edema is limited to anterior tongue and lips. Edema involving larynx, palate, floor of mouth, or oropharynx with rapid progression (within 30 minutes) poses higher risk of requiring intubation.
•Awake fiberoptic intubation is optimal. Nasotracheal intubation may be necessary but is associated with a risk of epistaxis after treatment with IV thrombolysis. Emergency cricothyrotomy is rarely needed and is also problematic after IV thrombolysis treatment, but in a life-threatening circumstance the need to establish an airway supersedes this concern. (See "Approach to the difficult airway in adults for emergency medicine and critical care" and "The difficult pediatric airway for emergency medicine".)
●Discontinue alteplase infusion and hold angiotensin converting enzyme inhibitor
●Give in rapid sequence:
•IV methylprednisolone 125 mg
•IV diphenhydramine 50 mg
•IV famotidine 20 mg
●If there is further increase in angioedema, give epinephrine (0.1 percent) 0.3 mL subcutaneously or 0.5 mL by nebulizer, but note that epinephrine has a theoretical risk of blood pressure elevation and hemorrhage
Additional treatment options for refractory angioedema include icatibant and plasma-derived C1 inhibitor concentrate, which have been used to treat hereditary angioedema and angiotensin converting enzyme inhibitor-related angioedema [1]. (See "ACE inhibitor-induced angioedema", section on 'Therapies of unproven efficacy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Stroke (The Basics)")
●Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Time is brain – Intravenous thrombolysis is the mainstay of treatment for acute ischemic stroke, provided that treatment is initiated within 4.5 hours of clearly defined symptom onset. Because the benefit of is time-dependent, it is critical to treat patients as quickly as possible. (See 'Overview of reperfusion therapy' above.)
●Patient selection – Prior to treatment, eligibility should be confirmed (table 1 and algorithm 1), two intravenous lines, preferably large bore, should be placed, and accurate body weight determined. (See 'Preparing for treatment' above.)
●Blood pressure management – Strict blood pressure control is critical prior to and during the first 24 hours after thrombolytic therapy. The blood pressure must be at or below 185/110 mmHg before starting treatment. The blood pressure must be maintained at or below 180/105 mmHg for 24 hours following thrombolytic treatment (table 2). (See 'Management of blood pressure' above.)
●Dosing – The alteplase dose is calculated at 0.9 mg/kg of actual body weight, with a maximum dose of 90 mg. Ten percent of the dose is given as an intravenous bolus over one minute and the remainder is infused over one hour. In Japan, however, the approved dose of alteplase for acute ischemic stroke is 0.6 mg/kg.
The tenecteplase dose is 0.25 mg/kg (maximum total dose 25 mg) given in a single intravenous bolus over 5 seconds, followed by a saline flush. (See 'Dosing' above.)
●No antithrombotics for 24 hours – Treatment with anticoagulant or antiplatelet agents should not be started within the first 24 hours of thrombolytic therapy in patients with acute ischemic stroke. Antiplatelet therapy should be started for most patients 24 to 48 hours after thrombolytic therapy. (See 'Monitoring' above and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)
●Adverse effects – The most feared complication of thrombolytic therapy is symptomatic intracerebral hemorrhage. Asymptomatic intracerebral hemorrhage, systemic bleeding, and angioedema are additional complications that may arise. (See 'Complications' above.)
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