In an adult patient with an acute ischemic stroke, what is the recommended protocol for intravenous alteplase (recombinant tissue‑type plasminogen activator) regarding eligibility, dosing, timing, contraindications, monitoring, and subsequent management?

Acute Brain Infarct: Thrombolysis Protocol Update

Intravenous alteplase (0.9 mg/kg, maximum 90 mg) should be administered to eligible acute ischemic stroke patients within 4.5 hours of symptom onset, with 10% given as a bolus over 1 minute and 90% infused over 60 minutes, prioritizing treatment within 3 hours for strongest benefit. 1, 2, 3

Time Windows and Strength of Recommendation

0-3 Hour Window (Strongest Evidence)

• IV alteplase SHOULD BE OFFERED to all eligible patients presenting within 3 hours of symptom onset who meet NINDS inclusion/exclusion criteria (Level A recommendation). 1
• This represents the FDA-approved window with the most robust evidence, showing a 12% absolute increase in patients achieving minimal or no disability (modified Rankin Scale 0-1: 39% vs 26% placebo). 1
• Number needed to treat is 8.3 for one additional patient to achieve favorable outcome. 1

3-4.5 Hour Window (Moderate Evidence)

• IV alteplase SHOULD BE CONSIDERED for patients meeting ECASS III criteria in this extended window (Level B recommendation). 1, 4
• Additional exclusion criteria apply: age >80 years, oral anticoagulant use regardless of INR, NIHSS >25, or history of both stroke and diabetes. 2, 5
• Same dosing protocol (0.9 mg/kg) applies. 3

4.5-24 Hour Window (Emerging Evidence)

• The 2025 HOPE trial demonstrated that alteplase administered 4.5-24 hours after onset in patients with salvageable brain tissue on perfusion imaging increased functional independence (40% vs 26%, P=0.004), though symptomatic ICH increased (3.8% vs 0.51%). 6
• This extended window requires perfusion imaging to identify salvageable tissue and is not yet guideline-endorsed for routine practice. 6
• The ATLANTIS trial (1999) showed no benefit and increased harm when treating 3-5 hours without advanced imaging selection, underscoring the importance of patient selection. 7

Dosing Protocol (Critical to Avoid Errors)

Standard Dosing

• Total dose: 0.9 mg/kg (maximum 90 mg absolute) 1, 2, 3
• Initial bolus: 10% of total dose (0.09 mg/kg) IV push over exactly 1 minute 1, 3
• Continuous infusion: 90% of total dose (0.81 mg/kg) over 60 minutes 1, 3

Common Pitfall to Avoid

• Never use the myocardial infarction dosing protocol for stroke—this is a critical error that can cause harm. 3
• Always verify you are using stroke-specific dosing before administration. 3

Eligibility Criteria

Absolute Requirements Before Treatment

• Blood pressure must be <185/110 mmHg before initiating alteplase. 1, 2, 5
• CT or MRI must exclude intracranial hemorrhage. 1, 2, 5
• Only blood glucose assessment must precede administration—do not delay for other laboratory results. 2, 3
• Blood glucose must be ≥50 mg/dL. 5

Absolute Contraindications

• Intracranial hemorrhage on imaging or prior history of ICH 5
• Suspected subarachnoid hemorrhage 5
• Extensive early ischemic changes (>1/3 MCA territory) 5
• Severe head trauma or intracranial/spinal surgery within 3 months 5
• Ischemic stroke within preceding 3 months 5
• Warfarin with INR >1.7 5
• Direct oral anticoagulants within 48 hours if coagulation tests abnormal 5
• Heparin within 48 hours with elevated aPTT 5
• Platelet count <100,000/mm³ 5
• GI malignancy or bleeding within 21 days 5

Special Populations (Can Receive Alteplase)

• Patients >80 years within 3-hour window (excluded in 3-4.5 hour window) 2, 5
• Mild but potentially disabling deficits despite low NIHSS 5
• Seizure at stroke onset if imaging confirms acute ischemia 1, 5
• Monotherapy or dual antiplatelet therapy (though dual therapy may increase ICH risk) 5
• Cervical artery dissection after careful risk-benefit assessment 5
• End-stage renal disease on hemodialysis with normal aPTT 5
• 1-10 cerebral microbleeds on prior MRI 5

Time Targets for Administration

Door-to-needle time should be <60 minutes in 90% of patients, with median target of 30 minutes. 2, 3, 5

• Initiate alteplase immediately after CT confirms absence of hemorrhage. 3
• Time is brain—every 15-minute delay reduces favorable outcomes. 1
• Treatment should be initiated as quickly as possible as outcomes are strongly time-dependent. 2

Integration with Mechanical Thrombectomy

Critical Decision Algorithm

• Eligible patients should receive IV alteplase even if mechanical thrombectomy is being considered. 2
• Do NOT delay IV thrombolysis to assess for thrombectomy eligibility. 2, 3
• Do NOT evaluate response to IV alteplase before proceeding with catheter angiography for thrombectomy. 2, 3
• For suspected large vessel occlusion (LVO), obtain non-invasive angiography (CTA) but do not delay alteplase administration. 2

Combined Approach Benefits

• Combined IV and endovascular therapy provides superior outcomes for large vessel occlusions, with recanalization rates of 72-88% with modern stent retrievers. 2
• Symptomatic ICH rates are similar between combined therapy (6.3%) and IV rtPA alone (6.6%). 2
• Number needed to treat with thrombectomy is approximately 3-4 patients for one additional good outcome. 2

Monitoring Protocol Post-Administration

Neurological Monitoring

• Neurological assessments every 15 minutes during infusion 1
• Every 30 minutes for next 6 hours 1
• Hourly until 24 hours after treatment 1
• If severe headache, acute hypertension, nausea, or vomiting develop, discontinue infusion and obtain emergency CT. 1

Blood Pressure Monitoring

• Every 15 minutes for first 2 hours 1
• Every 30 minutes for next 6 hours 1
• Hourly until 24 hours after treatment 1
• Maintain BP ≤180/105 mmHg post-treatment 1

Post-Treatment Management

• Delay nasogastric tubes, indwelling bladder catheters, or intra-arterial pressure catheters 1
• Obtain follow-up CT at 24 hours before starting anticoagulants or antiplatelet agents 1
• Delay anticoagulants and antiplatelet agents for 24 hours after treatment 1

Safety Considerations

Hemorrhage Risk

• Symptomatic ICH rates range from 2.4% to 6.4% across major trials. 2
• Hyperglycemia (>11.1 mmol/L) significantly increases ICH risk to 36%. 2
• NIHSS >20 is a stronger predictor of symptomatic hemorrhage than age alone. 2
• Be aware of angioedema as potential side effect causing partial airway obstruction. 1

Mortality

• Alteplase does not increase 90-day mortality despite increased ICH risk. 8
• Patients remain at least 30% more likely to have minimal or no disability at 3 months compared with placebo. 8

Institutional Requirements

The effectiveness of tPA has been less well established in institutions without systems in place to safely administer the medication. 1

This requires:

• Rapid CT availability 24/7 2
• Stroke team availability 2
• Neurological monitoring capabilities 1
• Blood pressure management protocols 1
• Access to neurosurgical consultation if needed 1