Residency · Residency · Internal Medicine

Acute Ischemic Stroke: Time-Based Interventions

Introduction

Acute ischemic stroke is a neurologic emergency where rapid diagnosis and time-based treatment are paramount. The concept of "time is brain" reflects the loss of approximately 1.9 million neurons per minute during a large vessel occlusion. Advances in intravenous thrombolysis and mechanical thrombectomy have dramatically improved outcomes, but these therapies are profoundly time-dependent. Internal medicine residents must recognize stroke presentations, initiate rapid evaluation, and facilitate timely treatment.

Pathophysiology

• Acute ischemic stroke results from occlusion of a cerebral artery by thrombus or embolism
• Ischemic core: irreversibly infarcted tissue
• Ischemic penumbra: hypoperfused but salvageable tissue surrounding the core; the therapeutic target
• The penumbra is sustained by collateral blood flow, which varies among patients and determines the speed of infarct progression
• Mismatch concept: advanced imaging can identify patients with large penumbra (small core, large perfusion deficit) who benefit from intervention even in extended time windows

Rapid Assessment

Prehospital and Emergency Department

• Stroke recognition scales: Cincinnati Prehospital Stroke Scale (facial droop, arm drift, speech abnormality)
• Last known well (LKW) time: critical for determining treatment eligibility; not the same as symptom discovery time
• NIHSS (National Institutes of Health Stroke Scale): standardized 15-item neurologic examination; quantifies deficit severity (0-42)
• NIHSS >= 6: likely large vessel occlusion (LVO); consider thrombectomy evaluation
• Immediate non-contrast CT head: rule out hemorrhagic stroke (must be obtained before thrombolysis)
• CT angiography (CTA): identify large vessel occlusion; should be obtained simultaneously or immediately after non-contrast CT

• Door-to-CT time: target < 25 minutes
• Door-to-needle time (for IV thrombolysis): target < 45 minutes (national guideline < 60 minutes)

Stroke Mimics

• Hypoglycemia (check glucose immediately), seizure with Todd paralysis, migraine with aura, conversion disorder, brain tumor
• Mimics account for up to 25% of initial stroke activations

Intravenous Thrombolysis

Alteplase (tPA)

• Standard window: within 4.5 hours of LKW
• Dose: 0.9 mg/kg (max 90 mg); 10% as IV bolus, remainder infused over 60 minutes
• NINDS trial: 30% relative increase in good functional outcome at 3 months; NNT = 8
• ECASS III: extended window to 4.5 hours; NNT = 14 in the 3-4.5 hour window

Tenecteplase

• Single IV bolus (0.25 mg/kg, max 25 mg); simpler administration than alteplase
• AcT trial and TASTE trial: non-inferior to alteplase for functional outcomes
• Increasingly adopted as the preferred thrombolytic due to ease of administration, especially before thrombectomy transfer
• Now recommended by AHA/ASA 2024 as an alternative to alteplase

Extended Window Thrombolysis

• WAKE-UP trial: alteplase for stroke of unknown onset with DWI-FLAIR mismatch on MRI (penumbral tissue present)
• EXTEND trial: alteplase at 4.5-9 hours using CT or MRI perfusion-based mismatch selection

Contraindications to IV Thrombolysis

• Active internal bleeding, recent intracranial surgery/trauma (3 months), intracranial hemorrhage
• Platelet count < 100,000, INR > 1.7, aPTT > 40 seconds
• Blood pressure > 185/110 mmHg (must be controlled before administration)
• Recent DOAC use within 48 hours (unless specific reversal or low drug level confirmed)

Mechanical Thrombectomy

Standard Window (0-6 Hours)

• Indicated for: large vessel occlusion (ICA, M1 MCA, basilar artery) with NIHSS >= 6 and ASPECTS >= 6
• MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT: five landmark 2015 trials demonstrating profound benefit; NNT = 2.6 for reduced disability
• Thrombectomy should be performed in addition to IV thrombolysis when eligible (bridging therapy)

Extended Window (6-24 Hours)

• DAWN trial (6-24 hours): clinical-core mismatch selection (small infarct core with significant clinical deficit); NNT = 2.8
• DEFUSE 3 (6-16 hours): perfusion imaging mismatch selection; NNT = 3.6
• These trials fundamentally changed stroke care by demonstrating benefit far beyond traditional time windows

Large Core Infarcts

• RESCUE-Japan LIMIT, SELECT2, ANGEL-ASPECT: thrombectomy benefit even with large ischemic cores (ASPECTS 3-5)
• Expanded thrombectomy eligibility to patients previously excluded

Blood Pressure Management

• Pre-thrombolysis: lower to < 185/110 mmHg with IV labetalol or nicardipine
• Post-thrombolysis: maintain < 180/105 mmHg for 24 hours
• No thrombolysis or thrombectomy: permissive hypertension up to 220/120 mmHg (autoregulation of penumbral perfusion); treat if > 220/120
• Avoid hypotension: MAP should not fall below baseline

Post-Stroke Management

• Antiplatelet therapy: aspirin 325 mg within 24-48 hours (hold 24 hours post-thrombolysis)
• CHANCE/POINT trials: dual antiplatelet therapy (aspirin + clopidogrel) for 21 days in minor stroke/TIA reduces recurrent stroke
• Atrial fibrillation: initiate anticoagulation at 4-14 days post-stroke depending on infarct size (1-3-6-12 day rule)
• Statin therapy: high-intensity statin for all ischemic stroke patients
• DVT prophylaxis: intermittent pneumatic compression; pharmacologic prophylaxis after 24-48 hours if no hemorrhagic transformation
• Dysphagia screening: before any oral intake to prevent aspiration pneumonia
• Decompressive craniectomy: consider for malignant MCA territory infarction in patients < 60 years (DESTINY II)

Key Clinical Pearls

• Tenecteplase is replacing alteplase as the preferred thrombolytic due to single-bolus dosing and comparable efficacy
• Mechanical thrombectomy has the lowest NNT of any acute intervention in medicine (approximately 2.6); do not delay transfer to a thrombectomy-capable center
• The treatment window extends to 24 hours for selected patients with favorable imaging (DAWN/DEFUSE 3); "time is brain" but "imaging is brain" matters too
• Dual antiplatelet therapy (aspirin + clopidogrel for 21 days) reduces recurrent stroke after minor stroke or TIA

References

1. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients with Acute Ischemic Stroke: 2019 Update (AHA/ASA). Stroke. 2019;50(12):e344-e418.
2. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct (DAWN). N Engl J Med. 2018;378(1):11-21.
3. Menon BK, Buck BH, Singh N, et al. Intravenous Tenecteplase Compared with Alteplase for Acute Ischaemic Stroke (AcT). Lancet. 2022;400(10356):161-169.
4. Goyal M, Menon BK, van Zwam WH, et al. Endovascular Thrombectomy after Large-Vessel Ischaemic Stroke: A Meta-Analysis (HERMES). Lancet. 2016;387(10029):1723-1731.

For the intern

When stroke arrives at 3am, move fast: check fingerstick glucose immediately (hypoglycemia mimics stroke), establish last known well time, and get non-contrast head CT within 25 minutes. Call the attending and stroke team simultaneously—don't wait for imaging results. If the patient is thrombolysis-eligible (within 4.5 hours, no hemorrhage, no contraindications), give tenecteplase as a single bolus and get CT angiography for large vessel occlusion. Blood pressure over 185/110? Lower it before thrombolysis with IV labetalol. If you see a large vessel occlusion on CTA, initiate thrombectomy transfer immediately—this has the best outcomes of any acute intervention in medicine (number needed to treat around 3). What can wait: aspirin can be given anytime in the first 24-48 hours, secondary prevention workup happens after stabilization, and swallow evaluation happens before first oral intake but isn't a 3am emergency unless the patient is asking for food.

Common pitfalls

• Using symptom discovery time instead of last known well time: if a patient wakes with deficits, last known well is when they went to sleep, not when they woke up—this often excludes patients from thrombolysis incorrectly
• Delaying thrombectomy transfer for "stability": patients with large vessel occlusion need transfer immediately, even if simultaneously receiving thrombolysis; every 15-minute delay worsens outcomes
• Lowering blood pressure too aggressively in non-thrombolysis candidates: permissive hypertension up to 220/120 maintains penumbral perfusion—overtreating extends infarct size
• Forgetting glucose check: hypoglycemia perfectly mimics stroke and is immediately reversible; check before anything else

Make it stick

It’s 3 AM, and the ED calls: "Stroke alert, right-sided weakness, aphasia, arrived 10 minutes ago." Your heart races, but you remember the drill. You run to the ED, grab the chart, and immediately ask the nurse for a fingerstick glucose. While waiting, you talk to the family: "When was she last acting completely normal?"—this is her "last known well" time, the most crucial piece of information. The non-contrast CT is already being done. You page the stroke attending and neurology simultaneously. Glucose is 90. CT is negative for hemorrhage. The patient is within 3 hours. Blood pressure is 190/100. "Let's give IV labetalol," you tell the nurse, "and prepare tenecteplase. I'll order the CT angiogram stat." This focused, rapid sequence of actions directly impacts her ability to talk, walk, and live independently. You are literally saving brain cells.

If you remember one thing

Time is brain, but imaging also matters, especially for extended window interventions. The most impactful thing you can do for a stroke patient is to act quickly to facilitate rapid imaging and treatment.

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