Ischemic%20stroke Treatment

• Elevated blood pressure is a major risk factor for both first and subsequent stroke
• Both elevated and low blood pressures are associated with poor outcome in acute ischemic stroke
• Mild and moderately elevated blood pressure should not be routinely lowered in the acute phase of stroke as this may worsen outcome
  
  • Avoid aggressive blood pressure lowering as this is detrimental in acute stroke
• Hypotension and hypovolemia should be corrected in order to maintain systemic perfusion levels that are essential to organ function 
• Elevated blood pressure in stroke may be due to stress of cerebrovascular event, full bladder, nausea, pain, preexisting hypertension, physiological response to increased intracranial pressure or to hypoxia
• Elevated blood pressure usually resolves spontaneously within the first few days after a stroke
• Excessively high blood pressure is lowered to decrease brain edema formation, reduce risk of hemorrhagic transformation of the infarct, prevent further vascular damage and preclude early recurrent stroke

• Benefit of initiating or re-initiating antihypertensive treatment within the first 48-72 hours is not certain in patients with SBP ≥220 mmHg or DBP ≥120 mmHg or mean arterial pressure (MAP) >130, without comorbid conditions requiring urgent antihypertensive therapy and did not receive rt-PA or mechanical thrombectomy
• Starting or restarting antihypertensive medications during hospitalization in neurologically stable patients with blood pressure of >140/90 mmHg is recommended to improve long-term blood pressure control unless otherwise indicated 
• In patients with markedly elevated blood pressure, lower blood pressure by 10-15% during the first 24 hours after onset of stroke

Blood Pressure (mmHg)	Treatment
SBP ≥220 mmHg or DBP 121-140 mmHg	Labetalol: 10-20 mg IV over 1-2 minutes May repeat or double the dose every 10 minutes Max dose: 300 mg in 24 hours or Nicardipine: Initially, 5 mg/hr IV infusion; titrate to desired effect by increasing 2.5 mg/hr every 5 minutes Max dose: 15 mg/hr (Aim for 10-15% decrease in blood pressure) or Captopril: 6.25-12.5 mg PO

• Blood pressure management of patients eligible for thrombolysis is critical before and during the administration of rt-PA and during the ensuing 24 hours because severely elevated blood pressure is associated with parenchymal hemorrhage
• Thrombolysis is not performed in patients with SBP >185 mmHg or DBP >110 mmHg at the time of treatment
• Correct blood pressure using the following:

Blood Pressure (mmHg)

Treatment

SBP >185 mmHg or DBP >110 mmHg

Labetalol: 10-20 mg IV over 1-2 minutes; may repeat once or Nicardipine: 5 mg/hr IV infusion; titrate up to desired effect by 2.5 mg/hr at 5- to 15-minute intervals Max dose: 15 mg/hr When desired blood pressure is attained, adjust to maintain proper blood pressure level or Clevidipine: 1-2 mg/hr IV, titrate by doubling the dose every 2-5 minutes until desired blood pressure is reached Max dose: 21 mg/hr or Other agents (eg Hydralazine, Enalapril)

• If blood pressure is not reduced and remains >185/110 mmHg despite treatment, DO NOT GIVE rt-PA
  
• If medications are given to lower blood pressure, maintain the blood pressure level below 180/105 mmHg for at least the first 24 hours after IV rt-PA

Intravenous Thrombolysis with rt-PA

• rt-PA (Alteplase) is the only thrombolytic proven effective in the treatment of acute ischemic stroke to be administered ideally within 60 minutes of arrival of qualified patients
• Patients eligible for rt-PA should be treated as quickly as possible within the time window as the benefits of rt-PA diminish rapidly over time
• Carefully selected patients may have improved outcomes if treated within extended window of 3 to 4.5 hours of stroke symptom onset
• Administering within 4.5 hours of stroke symptom recognition may be beneficial in patients with acute ischemic stroke who awoke with stroke symptoms or have unclear time of onset >4.5 hours from last known well or at baseline state and who have MRI DW-FLAIR mismatch (DW-MRI lesion smaller than ⅓ of the middle cerebral artery territory and no visible signal change on FLAIR)
  • Studies have shown Tenecteplase may be superior compared to rt-PA when given within 4.5 hours of onset of symptoms in patients with proven large artery occlusion prior to planned thrombectomy
• May be beneficial in patients with acute ischemic stroke who had wake-up stroke, who had CT or MRI core/perfusion mismatch within 9 hours from the midpoint of sleep and whom mechanical thrombectomy is neither indicated nor planned
• Intracranial hemorrhage can occur with use; risk can be reduced by careful selection of patients and presence of competent ancillary care
  
  • Signs and symptoms of intracranial hemorrhage following rt-PA include new headache, acute neurological deterioration, acute hypertension, nausea, or vomiting
  • Should intracranial hemorrhage be suspected, discontinue rt-PA and do CT scan or other tests to detect hemorrhage
• Angioedema is also a potential side effect which may cause partial airway obstruction
• Measure blood pressure and assess neurological status every 15 minutes during and after IV rt-PA infusion for 2 hours, then every 30 minutes for 6 hours, then hourly until 24 hours after IV rt-PA treatment
  • Blood pressure of <180/105 mmHg should be maintained for at least 24 hours after IV rt-PA
• Obtain follow-up CT or MRI at 24 hours after IV rt-PA before starting anticoagulants or antiplatelet agents
• Should be administered with or without multimodal CT, MRI and perfusion imaging
• Should be administered if patient is eligible even if mechanical thrombectomy is being considered
• Should not be administered in patients with acute ischemic stroke while on direct oral anticoagulants except for Dabigatran with normal PT and aPTT results

Endovascular Interventions

• Criteria for endovascular therapy with a stent retriever (all should be present):
  
  • A modified Rankin Scale (mRS) score 0 to 1 prior to stroke
  • Causative occlusion of the internal carotid artery or proximal middle cerebral artery
  • Age ≥18 years
  • NIHSS score of ≥6
  • Alberta Stroke Program Early CT score (ASPECTS) of ≥6
  • Treatment can be initiated (groin puncture) within 6 hours of symptom onset
    • In selected patients with acute ischemic stroke with large vessel obstruction, endovascular therapy is recommended within 24 hours from the onset of symptoms

• Reduced time from symptom onset to reperfusion with endovascular therapies produces better clinical outcomes
  
  • Reperfusion to thrombolysis in cerebral infarction (TICI) grade 2b/3 should be achieved as early as possible and within 6 hours of stroke onset
  • It is not required to observe patients after IV rt-PA to assess for clinical response before pursuing endovascular therapy to achieve beneficial outcomes
• Endovascular therapy with intracranial thrombectomy may be considered in patients with anterior circulation occlusion who have contraindications for IV rt-PA if it can be completed within 6 hours of stroke symptom onset
  • May also be considered in patients <18 years with large vessel occlusion who can tolerate a groin puncture within 6 hours of stroke symptom onset

Other Options

• Mechanical or endovascular thrombectomy 
  • Mechanical thrombectomy is recommended in patients with acute ischemic stroke within 6-16 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria or acute ischemic stroke within 16-24 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN eligibility criteria
  • Mechanical thrombectomy in posterior circulation stroke shows lower risk of symptomatic intracranial hemorrhage and benefits when started beyond 6 hours after symptom onset
  • Endovascular thrombectomy may be considered as treatment in eligible patients with acute basilar artery occlusion despite lack of a published randomized controlled trial to date
  • Effective as an adjunct treatment to IV fibrinolysis or as a treatment in selected patients with proximal large artery occlusions with contraindications to IV fibrinolysis (eg recent surgery and anticoagulant use)
  • Studies have shown that endovascular thrombectomy within an extended time window (up to 24 hours) was beneficial in some selected patients 
  • Blood pressure should be maintained at <180/105 mmHg during and 24 hours after the procedure
• Intra-arterial thrombolysis
  • Beneficial for patients with major ischemic strokes of <6 hours duration due to middle cerebral artery occlusion
• Intravenous fibrinolytics
  • Tenecteplase may be used as an alternative to rt-PA in patients without contraindications to IV fibrinolysis who are eligible to undergo mechanical thrombectomy
  • May be considered as an alternative to rt-PA in patients with minor neurological deficit and no major intracranial occlusion
  • IV defibrinogenating agents or IV fibrinolytic agents other than Alteplase and Tenecteplase is not recommended

• Monitor blood pressure every 15 minutes for 2 hours from the start of rt-PA therapy, then every 30 minutes for 6 hours, then every hour for the next 16 hours

Blood Pressure (mmHg)	Treatment
SBP >180-230 mmHg or DBP >105-120 mmHg	Labetalol: 5-10 mg IV followed by continuous IV infusion at 2-8 mg/min Max dose: 300 mg IV bolus or Nicardipine: 5 mg/hr IV infusion initially, then titrate to desired effect by 2.5 mg/hr every 5-15 minutes Max dose: 15 mg/hr or Clevidipine: 1-2 mg/hr IV then titrate by doubling the dose every 2-5 minutes until desired blood pressure Max dose: 21 mg/hr or Nitroprusside: 0.5 mcg/kg/min IV infusion Max dose: 8 mcg/kg/min
SBP >230 mmHg or DBP 121-140 mmHg	Labetalol: 10-20 mg IV over 2 minutes May repeat every 10-20 minutes Max dose: 300 mg in 24 hours or Labetalol: 10 mg IV followed by continuous IV infusion at 2-8 mg/min Max dose: 300 mg in 24 hours or Nicardipine: 5 mg/hr IV infusion initially, then titrate to desired effect by 2.5 mg/hr every 5-15 minutes Max dose: 15 mg/hr or Clevidipine: 1-2 mg/hr IV then titrate by doubling the dose every 2-5 minutes until desired blood pressure Max dose: 21 mg/hr

• If blood pressure is not controlled or DBP >140 mmHg, consider Sodium nitroprusside infusion at 0.5 mcg/kg/min (max dose: 10 mcg/kg/min)
  
• If medications are given to lower blood pressure, maintain the blood pressure level below 180/105 mmHg for at least the first 24 hours after IV rt-PA treatment

Antiplatelet Agents

Aspirin

• Administered at a dose of 160-325 mg PO to most stroke patients and those who are not candidates for rt-PA within 24-48 hours of stroke onset to prevent early recurrence, mortality and morbidity
  
  • For patients treated with rt-PA, Aspirin should not be given within 24 hours after the start of rt-PA therapy, though might be considered if with concomitant conditions for which such treatment given without rt-PA is known to provide significant benefit or not giving such treatment is known to result in significant risk
  • Contraindicated in patients with Aspirin allergy or suffering from gastrointestinal bleeding

• 21 days of dual antiplatelet therapy with Clopidogrel in minor stroke begun within 24 hours can be beneficial for early secondary stroke prevention for up to 90 days from onset of symptoms 
• Should not be used as a substitute if patient qualifies for other acute interventions (eg rt-PA)

Anticoagulant Agents

Heparins

• Eg unfractionated Heparin (UFH), low-molecular-weight Heparin and heparinoids
• Routine anticoagulation is not recommended
• Should not be used in lieu of rt-PA for treatment of otherwise eligible patients
• Administration within 24 hours of rt-PA is not recommended due to increased risk of bleeding complications
• Subcutaneous UFH and LMWH may be considered for deep venous thrombosis prophylaxis in at-risk patients
  
  • Non-pharmacologic treatments for deep venous thrombosis prevention may also be used
  • Risk versus benefit of pharmacologic agents needs to be considered
• Not shown to decrease mortality and morbidity nor prevent stroke recurrence

• A free radical scavenger which demonstrated neuroprotective effect by inhibition of vascular endothelial cell injury and amelioration of neuronal damage in ischemic brain models
• In Japan, nearly half of ischemic stroke patients receive Edaravone for acute treatment
• Indicated for the improvement of neurological symptoms, disorder of activities of daily living and functional disorder associated with acute ischemic stroke
• Treatment should be initiated within 24 hours after onset of disease and can be continued for up to 14 days

Intracranial Pressure Decompression

• Hyperventilation is an emergency measure which can decrease intracranial pressure by 25-30% when PCO₂ is decreased by 5-10 mmHg
• Mannitol can be administered at a dose of 0.25-0.5 g/kg IV over 20 minutes every 6 hours
• Intra-ventricular catheter CSF drainage is usually done if there is presence of hydrocephalus
• Surgical decompression and hemicraniectomy within 48 hours after onset of symptoms may benefit patients ≥60 years old with very large infarcts to prevent brain herniation
  • May be considered in selected patients >60 years old
• Ventriculostomy and sub-occipital craniectomy may be done for patients with large cerebellar infarcts

Seizure

• The use of prophylactic anti-seizures or long-term anticonvulsant agents is not recommended in patients with 1 self-limiting seizure episode happening at the onset or within 24 hours post-stroke
• New-onset seizures in hospitalized patients with acute stroke are treated with short-acting anti-seizure medications if episodes are not self-limiting
• Monitor patients with immediate post-stroke seizure for recurrent seizure activity and treat per seizure guideline recommendations

Revascularization Procedures

Carotid Endarterectomy (CEA)

• As  primary prevention strategy, it may be considered in asymptomatic patients with a 70-99% carotid stenosis and procedure done by surgeons with morbidity and mortality rate at <3%
• For secondary prevention, it may be done in patients with a 70-99% carotid stenosis with recent ischemic events (<180 days or within 2 weeks) without severe neurological deficit
  • Procedure should be done in centers with <6% perioperative stroke and deaths complication rate
• Antithrombotic therapy should be continued pre- and post-surgical procedure
• It is not recommended for carotid stenosis <50%

Carotid Angioplasty or Stenting (CAS)

• An alternative to CEA for secondary prevention if surgery is inaccessible, undesirable, or technically difficult
• Use of distal protection devices during the procedure and dual antiplatelets for 4 weeks after CAS is recommended
• Risk of cerebral ischemia is increased with a complex anatomy of the aortic arch and internal carotid artery

Intracranial Angioplasty and Stenting (IAS)

• Role in acute ischemic stroke is still unclear and needs additional studies