17.3 Acute Ischemic Stroke & Intracranial Hemorrhage

Acute Ischemic Stroke: Reperfusion Therapies and Hemodynamics

Acute ischemic stroke (AIS) results from sudden focal vascular occlusion, producing an ischemic core of irreversibly infarcted tissue (cerebral blood flow $[CBF] < 10-12\text{ mL/100g/min}$) surrounded by a dynamic, hypoperfused ischemic penumbra ($CBF\ 12-22\text{ mL/100g/min}$). The penumbra is functionally silent but metabolically viable, preserved temporarily by leptomeningeal collateral circulation. Time is brain: approximately $1.9\text{ million}$ neurons undergo apoptotic and necrotic destruction for every minute an acute proximal large vessel occlusion remains untreated.

1. Intravenous Thrombolysis: Tenecteplase vs. Alteplase

Intravenous thrombolysis remains standard care for eligible patients presenting within $4.5\text{ hours}$ of symptom onset (or last known well):

• Alteplase (rtPA): Dosed at $0.9\text{ mg/kg}$ (maximum $90\text{ mg}$); $10\%$ administered as an initial IV bolus over 1 minute, with the remaining $90\%$ infused over 60 minutes.
• Tenecteplase (TNK): A genetically engineered tissue plasminogen activator with higher fibrin specificity, greater resistance to plasminogen activator inhibitor-1, and a longer half-life that allows single-bolus dosing. Dosed as a single $0.25\text{ mg/kg}$ IV bolus (maximum $25\text{ mg}$) over 5 seconds. Contemporary trials (EXTEND-IA TNK, AcT) demonstrate non-inferiority to alteplase with superior early recanalization rates in large vessel occlusions and substantial operational advantages (eliminates pump setup and simplifies inter-facility transport).
• 2026 AHA/ASA guideline updates: tenecteplase or alteplase is recommended within 4.5 hours for disabling deficits regardless of NIHSS score; for mild non-disabling deficits, dual antiplatelet therapy is preferred to thrombolysis. Thrombolysis can extend to 4.5 to 9 hours or unknown onset when imaging shows a DWI-FLAIR mismatch or salvageable penumbra on perfusion imaging. Adjunctive IV argatroban or eptifibatide is not recommended. Keep glucose at 140 to 180 mg/dL; tighter targets (80 to 130 mg/dL) are not recommended.

Blood Pressure Thresholds for Thrombolysis

Uncontrolled hypertension during thrombolytic administration dramatically amplifies the risk of catastrophic symptomatic intracranial hemorrhage (sICH):

• Pre-Thrombolysis Target: Blood pressure must be reduced to $\text{SBP} < 185\text{ mmHg}$ and $\text{DBP} < 110\text{ mmHg}$ prior to initiating thrombolytic infusion.
• Post-Thrombolysis Maintenance: Maintain $\text{SBP} < 180\text{ mmHg}$ and $\text{DBP} < 105\text{ mmHg}$ continuously for at least $24\text{ hours}$ post-thrombolysis.
• Preferred Antihypertensive Agents: IV Nicardipine infusion ($5\text{ mg/h}$, titrate by $2.5\text{ mg/h}$ every 5-15 minutes to max $15\text{ mg/h}$), IV Clevidipine ($1-2\text{ mg/h}$, titrate by doubling every 90 seconds to max $16-32\text{ mg/h}$), or IV Labetalol ($10-20\text{ mg}$ IV over 1-2 minutes; may repeat or double every 10 minutes to max $300\text{ mg}$).

Absolute Contraindications to IV Thrombolysis

• Acute intracranial hemorrhage on non-contrast head CT.
• Severe head trauma or ischemic stroke within the preceding 3 months.
• Active internal bleeding or acute bleeding diathesis (platelets $<100,000/\mu\text{L}$, $\text{INR} > 1.7$, $\text{aPTT} > 40\text{ seconds}$, or $\text{PT} > 15\text{ seconds}$).
• Use of therapeutic doses of direct oral anticoagulants (DOACs; apixaban, rivaroxaban, dabigatran) within the preceding 48 hours unless specific drug activity assays are normal or reversal agents are administered.
• Intra-axial intracranial neoplasm. (A small unruptured intracranial aneurysm is not a contraindication; benefit and risk are uncertain with an unruptured arteriovenous malformation.)
• Recent intracranial or intraspinal surgery within 3 months.
• Persistent SBP $\ge 185\text{ mmHg}$ or DBP $\ge 110\text{ mmHg}$ refractory to aggressive IV antihypertensive therapy.

2. Endovascular Thrombectomy (EVT): Early and Extended Windows

Endovascular mechanical thrombectomy (EVT) using stent retrievers and direct aspiration catheters is the standard of care for acute Large Vessel Occlusion (LVO) of the anterior circulation (intracranial internal carotid artery [ICA] or middle cerebral artery [MCA] M1 segment):

• Standard Window ($0 - 6\text{ Hours}$): Indicated for patients with pre-stroke modified Rankin Scale (mRS) 0 to 1, causative occlusion of the internal carotid artery or proximal MCA (M1), age $\ge 18$, baseline $\text{NIHSS} \ge 6$, and non-contrast CT Alberta Stroke Program Early CT Score (ASPECTS) $\ge 6$.
• Extended Window ($6 - 24\text{ Hours}$): Two landmark randomized trials established the safety and profound efficacy of EVT in patients presenting between 6 and 24 hours from last known normal, using automated CT perfusion (CTP) or diffusion-weighted MRI (DWI) to identify salvageable penumbra:
  • DAWN Trial ($6 - 24\text{ Hours}$): Enrolled patients with a clinical-imaging mismatch between clinical stroke severity and core infarct volume: $\text{NIHSS} \ge 10$ and infarct core volume $<21\text{ mL}$ (age $\ge 80$), or infarct core volume $<31\text{ mL}$ (age $<80$ with $\text{NIHSS} \ge 10$), or core volume $31-51\text{ mL}$ (age $<80$ with $\text{NIHSS} \ge 20$). EVT demonstrated dramatic functional independence at 90 days ($49\%$ vs. $13\%$; $\text{NNT} = 2.8$).
  • DEFUSE-3 Trial ($6 - 16\text{ Hours}$): Enrolled patients with an acute anterior circulation LVO exhibiting target mismatch criteria: initial ischemic core volume $<70\text{ mL}$, mismatch ratio (penumbra to core) $\ge 1.8$, and absolute mismatch volume $\ge 15\text{ mL}$. EVT improved 90-day functional independence ($45\%$ vs. $17\%$; $\text{NNT} = 3.6$).
• Large-core infarcts: randomized trials (SELECT2, ANGEL-ASPECT, RESCUE-Japan LIMIT, TENSION) showed functional benefit from EVT in selected patients with large ischemic cores (for example ASPECTS 3 to 5), now reflected in the 2026 guideline.
• Basilar artery occlusion: EVT within 24 hours is strongly recommended for patients with NIHSS of 10 or more (ATTENTION, BAOCHE).
• After successful EVT: intensive lowering to SBP below 140 mmHg is not recommended, because trials of intensive targets (ENCHANTED2/MT, OPTIMAL-BP, BP-TARGET) found no benefit or harm. Keep BP at or below 180/105 mmHg.

3. Permissive Hypertension in Non-Reperfused Patients

In AIS patients who do not receive thrombolysis or endovascular thrombectomy, acute blood pressure lowering is strictly avoided. Autoregulation in the ischemic penumbra is completely impaired; blood flow becomes passively dependent on systemic mean arterial pressure. Precipitous blood pressure reduction drops perfusion across leptomeningeal collaterals, rapidly converting the viable penumbra into irreversible infarction.

• Guideline Rule: Blood pressure is not treated unless $\text{SBP} > 220\text{ mmHg}$ or $\text{DBP} > 120\text{ mmHg}$.
• If blood pressure exceeds $220/120\text{ mmHg}$, lower BP cautiously by $15\%$ over the first 24 hours using IV labetalol or nicardipine.
• Exceptions: Concomitant acute myocardial infarction, acute aortic dissection, severe heart failure with pulmonary edema, or hypertensive encephalopathy mandate immediate, controlled blood pressure reduction.

4. Malignant MCA Infarction & Decompressive Hemicraniectomy

Malignant middle cerebral artery infarction occurs in up to $10\%$ of ischemic stroke patients, characterized by massive post-ischemic cytotoxic edema, midline shift, and progressive uncal/subfalcine herniation peaking between post-stroke days 2 and 5. Medical management alone (hyperosmolar therapy with $3\%$ hypertonic saline or mannitol, hyperventilation) carries a catastrophic mortality rate of $70\%$ to $80\%$.

• Landmark Pooled Trials (DECIMAL, DESTINY, HAMLET): A pooled individual-patient meta-analysis of three European randomized controlled trials demonstrated that early decompressive hemicraniectomy (large bone flap diameter $\ge 12\text{ cm}$ with duraplasty) performed within $48\text{ hours}$ of symptom onset in patients aged $\le 60\text{ years}$ with malignant MCA infarction:
  • Reduced 12-month mortality from $71\%$ to $22\%$ (absolute risk reduction about $50\%$; $\text{NNT}$ about 2).
  • Doubled the proportion of patients surviving with moderate disability or better ($\text{mRS} \le 3$: $43\%$ vs. $21\%$).

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Spontaneous Intracerebral Hemorrhage (ICH)

Spontaneous non-traumatic intracerebral hemorrhage (ICH) accounts for $15-20\%$ of all strokes and carries a 30-day mortality approaching $40\%$. Primary etiologies include chronic hypertensive lipohyalinosis of small penetrating arterioles (deep locations: putamen, caudate, thalamus, pons, cerebellum) and cerebral amyloid angiopathy (lobar locations in elderly patients). Hematoma expansion occurs in $30-40\%$ of patients within the first 6 hours and is the most potent predictor of neurological deterioration and death.

1. Acute Blood Pressure Lowering: INTERACT-2 & ATACH-2

Acute hypertension in ICH drives active ongoing bleeding and hematoma expansion. However, excessive blood pressure lowering risks renal hypoperfusion and cerebral ischemia.

• INTERACT-2 Trial (NEJM 2013): Randomized 2,839 patients with spontaneous ICH within 6 hours to intensive SBP lowering ($<140\text{ mmHg}$ within 1 hour) vs. standard guideline care ($<180\text{ mmHg}$). Intensive lowering demonstrated a borderline reduction in functional disability (modified Rankin Scale) and confirmed safety without excess adverse events.
• ATACH-2 Trial (NEJM 2016): Evaluated intensive lowering (target $\text{SBP}\ 110-139\text{ mmHg}$) vs. standard lowering (target $\text{SBP}\ 140-179\text{ mmHg}$) using IV nicardipine. ATACH-2 found no improvement in 90-day mortality or severe disability with aggressive reduction to $<130\text{ mmHg}$, but observed a statistically significant increase in acute renal adverse events within 7 days ($9.0\%$ vs. $4.0\%$).
• Current Guideline Consensus: Rapidly lower blood pressure targeting a systolic BP of $130 - 150\text{ mmHg}$ using continuous, smooth intravenous titrations (IV nicardipine or clevidipine), while strictly avoiding large blood pressure variability and avoiding sustained SBP $<130\text{ mmHg}$.

2. Emergency Coagulopathy Reversal Protocols

Immediate pharmacological reversal of coagulopathy is the highest-priority intervention in acute ICH to arrest hematoma expansion:

3. Surgical Indications in ICH

• Cerebellar Hemorrhage: Cerebellar hemorrhage with neurological deterioration, brainstem compression, or obstructive hydrocephalus, or a volume of at least $15\text{ mL}$ (older series used a diameter above $3\text{ cm}$), warrants urgent suboccipital decompression with hematoma evacuation (2022 AHA/ASA ICH guideline), with or without an external ventricular drain (EVD). An EVD alone, instead of decompression, is not recommended because of the risk of deterioration and upward herniation.
• Supratentorial Lobar / Deep ICH: The STICH I and STICH II trials demonstrated no benefit for routine early open craniotomy in supratentorial deep ganglionic or lobar hemorrhages. However, minimally invasive surgery (MIS) utilizing stereotactic catheter or endoscopic evacuation (the ENRICH trial, 2024: minimally invasive parafascicular evacuation of 30 to 80 mL lobar or anterior basal ganglia hemorrhages within 24 hours) improved 180-day utility-weighted functional outcome, with the benefit driven by lobar hemorrhages.

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Aneurysmal Subarachnoid Hemorrhage (aSAH)

Aneurysmal subarachnoid hemorrhage (aSAH) accounts for $5-10\%$ of all strokes, characteristically presenting as the sudden onset of the "worst headache of life" (thunderclap headache), accompanied by transient loss of consciousness, nausea, vomiting, photophobia, and meningismus.

1. Diagnostic Algorithm and Early Securing

• Non-Contrast Head CT: Exhibits $>99\%$ sensitivity within the first 6 hours of headache onset. Sensitivity progressively declines to $\sim 85\%$ at 48 hours and $\sim 50\%$ at 1 week as blood mixes with cerebrospinal fluid.
• Lumbar Puncture (LP): Mandatory if non-contrast head CT is negative or equivocal but high clinical suspicion persists. Diagnostic hallmark is xanthochromia (pink or yellow supernatant coloration resulting from enzymatic breakdown of hemoglobin to oxyhemoglobin and bilirubin), confirmed by spectrophotometry. Differentiated from a traumatic tap by absence of clearing between tubes 1 and 4 and presence of xanthochromia after centrifugation.
• Early Aneurysm Securing: The ruptured aneurysm must be secured via endovascular coiling or microsurgical clipping as early as feasible, preferably within $24\text{ hours}$ (2023 AHA/ASA, Class 1). Catastrophic rebleeding occurs in up to $15\%$ of patients within the first 24 hours and carries a mortality rate exceeding $70\%$. Before securing, control blood pressure with short-acting titratable IV agents, avoiding hypotension, severe hypertension, and large swings; the 2023 guideline found insufficient evidence for a specific target (SBP below $160\text{ mmHg}$ is a common pragmatic choice). Antifibrinolytic therapy (tranexamic acid) is not useful for improving outcome (ULTRA trial).

2. Delayed Cerebral Ischemia (DCI) and Vasospasm

Delayed Cerebral Ischemia (DCI)—defined as new focal neurological deficits (hemiparesis, aphasia, neglect) or a sustained decrease in GCS score $\ge 2$ points lasting $>1\text{ hour}$ not explained by hydrocephalus, rebleeding, or metabolic derangement—represents the leading cause of late morbidity and mortality following aSAH.

• Temporal Profile: Arterial narrowing (angiographic vasospasm) typically commences on post-bleed day 3 to 4, reaches peak incidence between days 4 and 14, and gradually resolves by day 21.
• Enteral Nimodipine: Every patient with aSAH must receive oral/nasogastric Nimodipine $60\text{ mg}$ enterally every 4 hours for 21 consecutive days. Nimodipine is a dihydropyridine calcium channel blocker that prevents DCI and dramatically improves functional neurological outcomes.

  Caution

  FDA Boxed Warning: Nimodipine must NEVER be administered intravenously. Accidental intravenous administration of enteral nimodipine capsules causes profound systemic vasodilation, refractory shock, cardiovascular collapse, and death.

• Euvolemia over Prophylactic Hypervolemia: The outdated "triple-H therapy" (hypervolemia, hemodilution, hypertension) has been definitively abandoned. Prophylactic hypervolemia does not prevent DCI and precipitates iatrogenic pulmonary edema, myocardial strain, hyponatremia, and cerebral edema. Patients must be maintained in strict euvolemia utilizing isotonic crystalloids ($0.9\%$ normal saline).
• Management of Clinical DCI:
  1. Induced Hypertension: First-line rescue intervention for secured aneurysms. Titrate continuous IV vasopressors (norepinephrine or phenylephrine) to raise blood pressure stepwise while reassessing the neurological examination. The 2023 guideline states that elevating blood pressure in symptomatic vasospasm can reduce progression and severity of DCI; protocols vary and no single target is established. Prophylactic hemodynamic augmentation is not recommended.
  2. Endovascular Rescue Therapy: If clinical DCI fails to improve promptly with induced hypertension, emergent catheter angiography is performed. Endovascular intra-arterial infusion of microvascular vasodilators (nicardipine, verapamil, milrinone) or transluminal balloon angioplasty (for proximal, focal vessel spasm) rapidly restores cerebral perfusion.