Stroke Management - Harrison's Principles of Internal Medicine 22e (2025)

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MASTER FLOWCHART: STROKE MANAGEMENT

PATIENT PRESENTS WITH ACUTE NEUROLOGICAL DEFICIT
              |
              v
    ┌─────────────────────────────┐
    │   IMMEDIATE STABILIZATION   │
    │   ABC (Airway/Breathing/    │
    │   Circulation)              │
    │   Finger-stick glucose       │
    │   Treat hypo/hyperglycemia  │
    └─────────┬───────────────────┘
              |
              v
    ┌─────────────────────────────┐
    │  EMERGENCY NON-CONTRAST     │
    │       HEAD CT SCAN          │
    │  (within minutes of arrival)│
    └─────────┬───────────────────┘
              |
       ┌──────┴────────┐
       |               |
       v               v
  ISCHEMIC         HEMORRHAGIC
  STROKE           STROKE
  (No blood        (Blood on CT)
  on CT)               |
       |               └────────────────────────┐
       v                                        v
  [See Section A]                          [See Section B]

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SECTION A: ACUTE ISCHEMIC STROKE

A1. IMMEDIATE INVESTIGATIONS

CONFIRMED ISCHEMIC STROKE (CT negative for blood)
              |
  ┌───────────┼───────────────────────┐
  v           v                       v
MANDATORY   CARDIAC               VASCULAR
LABS        WORKUP                IMAGING
  |           |                       |
• CBC        • 12-lead ECG           • CT Angiography
• BMP        • Troponin               (if EVT candidate)
• PT/PTT/    • Echocardiogram        • MRA Brain/Neck
  INR          (TTE or TEE)          • Carotid Doppler
• LFT/RFT   • Holter monitor         (if carotid territory)
• Glucose     (paroxysmal AF)
• HbA1c
• Lipids
• Type & Screen

• Hypercoagulability panel (young stroke, no clear cause): Protein C/S, antithrombin III, factor V Leiden, prothrombin gene mutation, antiphospholipid antibodies
• ESR/CRP (vasculitis workup)
• Toxicology screen (cocaine, amphetamines)
• MRI brain with DWI (most sensitive for early ischemia - restricted diffusion within minutes)
• CT Perfusion: identifies ischemic core vs salvageable penumbra for late-window EVT selection

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A2. SIX PILLARS OF ISCHEMIC STROKE TREATMENT

                    ACUTE ISCHEMIC STROKE
                          |
        ┌────────┬─────────┼──────────┬─────────┬──────────┐
        v        v         v          v         v          v
    MEDICAL   IV-tPA   ENDOVASCULAR  ANTI-    NEURO-    STROKE
    SUPPORT  THROMBO-  THROMBECTOMY THROMBOT  PROTECTN  CENTER &
             LYSIS     (EVT)        THERAPY           REHAB

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A3. MEDICAL SUPPORT (Pillar 1)

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A4. IV THROMBOLYSIS - rt-PA / ALTEPLASE (Pillar 2)

Dosing

Alteplase 0.9 mg/kg IV (maximum 90 mg)

• 10% of dose as IV bolus over 1 minute
• Remaining 90% as IV infusion over 60 minutes

TIME WINDOW FLOWCHART

ONSET OF SYMPTOMS
      |
      |-- ≤3 hours ────> STANDARD WINDOW (all eligible patients)
      |
      |-- 3-4.5 hours ──> EXTENDED WINDOW (most patients, extra exclusions apply)
      |
      |-- >4.5 hours ───> IV tPA NOT indicated
                          (consider EVT if large vessel occlusion)

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INDICATIONS FOR IV tPA

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CONTRAINDICATIONS TO IV tPA

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POST-tPA MONITORING PROTOCOL

tPA INFUSION COMPLETE
        |
        v
• No antithrombotics for 24 hours
• No arterial punctures (use existing lines)
• No NG/Foley for 30 min post-infusion
• BP monitoring q15 min x 2h, then q30 min x 6h, then q1h x 16h
• Repeat CT head at 24h BEFORE starting antithrombotics
• Watch for: angioedema, orolingual edema, hemorrhagic transformation

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A5. ENDOVASCULAR THROMBECTOMY / EVT (Pillar 3)

Indications for Mechanical Thrombectomy

CANDIDATE SCREENING FOR EVT
            |
    ┌───────┼───────────────────────┐
    v       v                       v
 CLINICAL  IMAGING              VESSEL
 CRITERIA  CRITERIA             CRITERIA
    |           |                   |
• NIHSS ≥6  • CT/MRI no          • LVO confirmed
• Premorbid   large infarct        on CTA/MRA:
  mRS 0-1    (ASPECTS ≥6)          - ICA
• Age ≥18   • Penumbra:            - M1 MCA
            • Core <70mL           - M2 MCA (selected)
            • Mismatch >1.8        - Basilar artery
                                   - Vertebral artery
            ALL THREE CRITERIA MET?
                     |
                ┌────┘
                v
          PROCEED TO EVT

Time Windows for EVT

EVT Procedure Note

• Preferred: Stent retriever devices (Merci, Solitaire, Trevo) + aspiration
• Access: Transfemoral or transradial approach
• Anticoagulation during procedure: Heparin 70 units/kg IV bolus
• Target: mTICI ≥2b reperfusion (successful in ~80-90% of cases)

Contraindications to EVT

• CT showing large completed infarct (ASPECTS <6 = poor outcome territory)
• No LVO on vascular imaging
• Premorbid severe disability (mRS 3-5)
• Life expectancy <3 months
• Coagulopathy not correctable (INR >3)

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A6. ANTITHROMBOTIC THERAPY (Pillar 4)

For Non-Cardioembolic Stroke (Atherothrombotic/Lacunar)

ANTIPLATELET THERAPY - CHOOSE ONE:

1. ASPIRIN 325 mg PO loading, then 81-325 mg/day
   - Give within 24-48h of stroke onset
   - If tPA given: wait 24h, confirm no hemorrhage on CT, THEN start

2. ASPIRIN 25 mg + EXTENDED-RELEASE DIPYRIDAMOLE 200 mg (Aggrenox) BID
   - Superior to aspirin alone for secondary prevention
   - SE: headache (common, usually resolves)

3. CLOPIDOGREL 75 mg/day
   - Alternative if aspirin intolerant
   - Preferred in high atherosclerotic burden

4. ASPIRIN + CLOPIDOGREL (DAPT) - SHORT-TERM (21 days)
   - For high-risk TIA (ABCD2 ≥4) or minor stroke (NIHSS ≤3)
   - CHANCE trial: reduces recurrent stroke without major bleeding increase
   - Then switch to monotherapy

For Cardioembolic Stroke (Atrial Fibrillation)

ANTICOAGULATION - CHA₂DS₂-VASc GUIDED:

Score 0: Aspirin or no antithrombotic
Score 1: Aspirin OR OAC (individualize)
Score ≥2: ORAL ANTICOAGULANT (OAC) - MANDATORY

PREFERRED OAC (Non-Valvular AF):
┌─────────────────────────────────────────────────────┐
│  DOAC (Direct Oral Anticoagulants) - PREFERRED      │
│                                                     │
│  Apixaban: 5 mg BID (2.5 mg BID if ≥2 of:         │
│           age ≥80, weight ≤60kg, Cr ≥1.5)          │
│                                                     │
│  Rivaroxaban: 20 mg once daily with evening meal    │
│                                                     │
│  Dabigatran: 150 mg BID (75 mg BID if CrCl 15-30) │
│                                                     │
│  Edoxaban: 60 mg once daily (30 mg if CrCl 15-50, │
│           weight ≤60 kg, P-gp inhibitors)          │
└─────────────────────────────────────────────────────┘

WARFARIN (Valvular AF, mechanical valves):
Target INR: 2.0-3.0 (mitral mechanical: 2.5-3.5)

TIMING OF ANTICOAGULATION AFTER CARDIOEMBOLIC STROKE:
• Small infarct: Start OAC at day 3-5
• Moderate infarct: Start OAC at day 6-8
• Large infarct: Start OAC at day 12-14
• TIA: Start OAC immediately
("1-3-6-12 rule" - days after stroke onset)

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A7. NEUROPROTECTION (Pillar 5)

• Numerous neuroprotective agents tested in trials (NMDA antagonists, calcium channel blockers, free-radical scavengers) have failed to show benefit
• Current "neuroprotection" is indirect: maintain euglycemia, treat fever, maintain BP, optimize oxygenation
• Normobaric oxygen: no proven benefit in unselected patients
• Hypothermia: under investigation; not yet standard

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A8. STROKE CENTERS & REHABILITATION (Pillar 6)

ACUTE MANAGEMENT                    REHABILITATION
        |                                  |
• Dedicated Stroke Unit             • Begin within 24-48h
• Continuous monitoring             • Physiotherapy (mobility)
• Stroke protocol activation        • Occupational therapy (ADLs)
• Multidisciplinary team            • Speech therapy (dysphagia/aphasia)
• Telemedicine (tele-stroke)        • Cognitive rehabilitation
  in non-stroke centers             • Psychological support
                                    • Driving assessment
                                    • Vocational rehabilitation

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SECTION B: INTRACEREBRAL HEMORRHAGE (ICH)

B1. EMERGENCY MANAGEMENT OF ICH

HEMORRHAGIC STROKE CONFIRMED ON CT
              |
    ┌─────────┼────────────────────┐
    v         v                    v
AIRWAY &   BLOOD               REVERSAL OF
NEURO      PRESSURE            ANTICOAGULATION
STATUS     CONTROL
    |         |                    |
• Intubate • Target SBP          • Warfarin: Vit K +
  if GCS<8   <140 mmHg             4-factor PCC (Kcentra)
• ICP       (INTERACT2)           • DOAC: Andexanet alfa
  monitoring • Agents:              (anti-Xa) or
• Neurosurg  - Labetalol IV         Idarucizumab
  consult    - Nicardipine IV       (dabigatran)
             - Clevidipine IV     • Heparin: Protamine sulfate
             - Enalaprilat IV    

Blood Pressure Management in ICH

• INTERACT2 trial: Target SBP <140 mmHg vs <180 mmHg
  • <140 mmHg group: 52% death/major disability at 90 days
  • <180 mmHg group: 55.6% death/major disability (p = 0.06, non-significant, but significant ordinal shift)
• Current recommendation: Acutely lower SBP to <140 mmHg if initial SBP was 150-220 mmHg (considered safe)

Common Causes of ICH by Location

Investigations in ICH

ALL ICH PATIENTS:
• Non-contrast CT (initial - confirms hemorrhage)
• CTA or MRA (if AVM/aneurysm suspected - young patients, lobar location)
• MRI with GRE/SWI (detects microbleeds - amyloid angiopathy)
• CBC, coagulation panel (PT/PTT/INR), platelet count
• BMP, LFT
• Toxicology screen (cocaine, amphetamines - especially young patients)
• 12-lead ECG
• Urinalysis

SELECTIVE:
• Catheter angiography (DSA) - gold standard for AVM/aneurysm
• Lumbar puncture - if subarachnoid extension suspected and imaging equivocal
• Anti-amyloid PET - research setting only

Surgical Intervention in ICH

SURGICAL CONSIDERATIONS:

Indications (STRONGEST):
• Cerebellar hemorrhage >3 cm with neurological deterioration
• Cerebellar hemorrhage compressing brainstem or hydrocephalus
  → External ventricular drain (EVD) + suboccipital craniectomy

Indications (CONDITIONAL):
• Lobar hemorrhage >30 mL within 1 cm of surface
  with neurological deterioration - consider craniotomy
• Progressive hydrocephalus from IVH → EVD

NOT routinely recommended:
• Deep hemorrhages (putamen, thalamus) - surgery not shown to improve outcomes
  (STICH trial: surgical hematoma evacuation = medical management)
• Minimally invasive surgery (MIS) with rt-PA clot lysis (MISTIE III):
  Reduced clot size but no functional benefit

ICP Management if elevated:
• Head of bed 30 degrees
• Hypertonic saline (3% NaCl) or Mannitol 0.25-1 g/kg IV
• Sedation + hyperventilation (temporary: target pCO₂ 30-35 mmHg)
• Decompressive craniectomy (large territory - last resort)

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SECTION C: SECONDARY PREVENTION

C1. RISK FACTOR MODIFICATION

C2. ANTIPLATELET AGENTS FOR NON-CARDIOEMBOLIC STROKE PREVENTION

FIRST-LINE:
Aspirin 81-325 mg/day OR
Aspirin 25 mg + Dipyridamole ER 200 mg BID (ESPS-2, ESPRIT trials) OR
Clopidogrel 75 mg/day

ASPIRIN + CLOPIDOGREL DAPT (SHORT-TERM - 21 days):
• For high-risk TIA (ABCD₂ score ≥4) or minor stroke (NIHSS ≤3)
• CHANCE trial (Chinese): 60% reduction in recurrent stroke vs aspirin alone
• POINT trial (US): Similar benefit; increased minor bleeding, similar major bleeding

LONG-TERM DAPT (>3 months): NOT recommended
• Increases hemorrhagic risk without additional benefit
• MATCH trial and SPS3 trial: No benefit of long-term DAPT

C3. SURGICAL & ENDOVASCULAR SECONDARY PREVENTION

Carotid Stenosis Management

SYMPTOMATIC CAROTID STENOSIS (ipsilateral TIA or stroke):

>70% stenosis: CEA (Carotid Endarterectomy) STRONGLY INDICATED
               • NNT = 6 to prevent 1 stroke over 2 years
               • Best performed within 2 weeks of TIA/stroke

50-69% stenosis: CEA BENEFICIAL (especially in males)
               • NNT = 22

<50% stenosis: MEDICAL MANAGEMENT ONLY (no surgical benefit)

CAS (Carotid Artery Stenting):
• Alternative to CEA in high surgical risk patients
• CREST trial: CAS = CEA for combined outcomes
• Higher periprocedural stroke risk with CAS in older patients

Intracranial Stenosis

INTRACRANIAL STENOSIS (50-99%) - WARFARIN vs ASPIRIN:
• WASID trial: Warfarin = Aspirin (no benefit, more bleeding)
• Current standard: Aspirin + aggressive risk factor management
• Intracranial stenting (SAMMPRIS): Stenting WORSE than aggressive medical therapy
• Aggressive medical management: Aspirin 325 mg + Clopidogrel x 90 days,
  then aspirin alone + intensive statin + BP control

Patent Foramen Ovale (PFO) Closure

PFO CLOSURE vs MEDICAL THERAPY (cryptogenic stroke):
• CLOSURE I, PC Trial: No benefit
• RESPECT, REDUCE, CLOSE trials (2017-2018): 
  PFO closure SUPERIOR to medical therapy in selected patients
  (age <60, large PFO, atrial septal aneurysm, no other cause found)
• Current: PFO closure considered in age <60, cryptogenic stroke, 
  no other identifiable cause, after discussion of risks/benefits

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COMPLETE STROKE MANAGEMENT SUMMARY FLOWCHART

ACUTE STROKE PRESENTATION
          |
          v
    ABCs + Glucose
          |
          v
    Noncontrast CT HEAD (STAT)
          |
    ┌─────┴──────────────────┐
    |                        |
    v                        v
NO BLOOD = ISCHEMIC      BLOOD = HEMORRHAGIC
    |                        |
    v                        |
 WITHIN 4.5h?                |
  ┌───┴──────┐               |
  YES        NO              |
  |          |               |
  v          v               v
 tPA        CTA +     ICH Management:
(0.9 mg/kg  LVO?     • BP <140 mmHg
 IV, max    |        • Reverse anticoag
 90 mg)    YES       • Airway management
  |         |        • Neurosurgery consult
  |         v        • Cerebellar ICH >3cm
  |       EVT           → Surgery
  |     (0-24h)
  |
  └─────────┐
            v
    Antithrombotics at 24h
    (confirm no hemorrhage on repeat CT)
          |
          v
    CARDIOEMBOLIC?  ──YES──> OAC (DOAC preferred)
          |
          NO
          |
          v
    Antiplatelet therapy
    (Aspirin ± Clopidogrel DAPT x21d
     for high-risk TIA/minor stroke)
          |
          v
    Risk factor modification:
    • Statin (atorvastatin 80 mg)
    • BP control (<130/80 mmHg)
    • Smoking cessation
    • Diabetes management
          |
          v
    STROKE UNIT + REHABILITATION
    (PT/OT/Speech - begin 24-48h)

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KEY CLINICAL PEARLS FROM HARRISON'S 22e

1. No reliable clinical signs distinguish ischemic from hemorrhagic stroke - CT is mandatory before any treatment.
2. BP in ischemic stroke: Do NOT routinely lower unless >220/120 mmHg (no tPA) or >185/110 mmHg (pre-tPA) - collateral flow may be BP-dependent.
3. tPA "wake-up stroke" or unknown onset time: MRI DWI/FLAIR mismatch can identify patients who may benefit within extended window.
4. EVT superiority: The five major 2015 trials (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, THRACE) established EVT as standard of care for LVO, with NNT of 2.6 for independent outcome.
5. DAPT timing: Start aspirin within 24-48h of ischemic stroke onset for non-cardioembolic stroke; if tPA given - wait 24h.
6. SPARCL trial: Atorvastatin 80 mg/day reduces recurrent stroke by 16% (absolute risk reduction) in patients with recent stroke/TIA.
7. ICH surgical caveat: STICH trial showed no benefit of early surgical evacuation for most ICH - except cerebellar hemorrhage >3 cm with deterioration.
8. CHA₂DS₂-VASc: Score ≥2 = mandatory anticoagulation; DOACs preferred over warfarin for non-valvular AF (lower intracranial hemorrhage risk).

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