# 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

![Ischemic core and penumbra with collateral circulation](images/stroke-penumbra.png)

## 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

| Time Target | Goal | Intervention |
|------------|------|-------------|
| Door-to-CT | <25 minutes | Rule out hemorrhage |
| Door-to-needle (tPA) | <45 min (guideline <60 min) | IV thrombolysis |
| Door-to-groin puncture | <90 min (transfer <120 min) | Mechanical thrombectomy |

- **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

![Time-based stroke intervention algorithm](images/stroke-treatment-timeline.png)

## 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)

![Post-acute stroke management checklist](images/post-stroke-management.png)

## 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.