CVA Thrombolysis

Aka: CVA Thrombolysis, Stroke Thrombolysis, Thrombolysis in Cerebrovascular Accident, CVA Fibrinolytic Checklist, CVA Thrombolytic Contraindications

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II. Indications (Inclusion Criteria)

  1. Age over 18 years
  2. Clinical Diagnosis of acute Ischemic Stroke with persistent deficits (typically with NIH Stroke Scale 5 or higher)
  3. CT Head compatible with Ischemic CVA diagnosis
  4. Known time of onset under 4.5 hours before Thrombolytics
    1. Expedite evaluation and discuss with stroke team
    2. Do not use intravenous tPA beyond 4.5 hours of symptom onset unless indicated below (typically with neurology Consultation)
    3. No benefit and increased risk Intracranial Hemorrhage when extended to 6 hours
      1. Arora and Menchine in Herbert (2014) EM: Rap 14(1): 8
    4. Consider TPA in significant focal deficits despite NIH Stroke Scale <5
      1. Demaerschalk (2016) Stroke 47:581-641 [PubMed]
    5. AHA review (ECASS3 trial) in 2012 suggested possible benefit at 3 to 4.5 hours onset
      1. Benefited select group of patients (not FDA approved)
      2. CT Head with perfusion-weighted imaging to define penumbra in late presentations may be considered if no delay
      3. No contraindications listed below
        1. Age <80 years old AND
        2. NIH Stroke Scale between 5 and 25 AND
        3. No oral Anticoagulant use (even if coagulation tests normal) AND
        4. Not a diabetic with prior Ischemic Stroke
      4. However, repeat analysis of ECASS3 suggests risk more than benefit for 3 to 4.5 hour window
        1. Alper (2020) BMJ Evid Based Med 25(5):168-71 +PMID: 32430395 [PubMed]

III. Contraindications (Exclusion Criteria)

  1. Improving or mild neurologic deficit (NIH Stroke Scale <5)
    1. Consult neurology
    2. Deficit (e.g. Abnormal Gait, Hemianopia, Aphasia) may result in significant Disability despite a low level NIH Score
  2. Seizure at onset
  3. Blood Sugar abnormality
    1. Hypoglycemia (<50 mg/dl)
    2. Hyperglycemia (>400 mg/dl)
  4. Serious Head Injury or CVA within last 90 days
  5. Intracranial or intraspinal surgery within last 90 days
  6. Intracranial neoplasm, AV Malformation or aneurysm
  7. History of Intracranial Hemorrhage
  8. Multilobar infarct larger than one third total Cerebral Hemisphere on head imaging (typically CT Head)
  9. Suspected Subarachnoid Hemorrhage (SAH)
    1. Hemorrhage on CT Head
    2. History suggests SAH even despite negative Head CT
  10. Hypertension refractory to Antihypertensives
    1. Systolic Blood Pressure over 185
    2. Diastolic Blood Pressure over 110
  11. Major surgery or serious Trauma in last 14 days
  12. Gastrointestinal Hemorrhage in last 21 days
  13. Genitourinary Hemorrhage in last 21 days
  14. Puncture of inaccessible artery within 7 days
  15. Bleeding Diathesis
    1. Heparin use within 48 hours of stroke onset
    2. Platelet Count <100,000/mm3
  16. Anticoagulant use (relative contraindications - discuss with stroke team for regional guidelines)
    1. Warfarin and INR >1.7
    2. Dabigatran (Pradaxa) within last 2 days or abnormal coagulation tests (PTT, Thrombin Time or Ecarin clotting test)
    3. Rivaroxaban or Apixiban and abnormal PT/INR or Factor Xa activity
      1. Thrombolysis may be considered if no DOAC use in 48 hours
    4. Dual antiplatelet drugs (e.g. Aspirin and Clopidogrel)
    5. Reversal of Anticoagulation prior to tPA is not in guidelines and is not supported by adequate studies to date
      1. Chausson (2018) Stroke 49(10): 2526-28 +PMID:30355096 [PubMed]
    6. References
      1. Jauch (2013) Stroke 44(3):870-947 [PubMed]
  17. Pregnancy is NOT a contraindication
    1. However there is limited data on safety for the mother and fetus
    2. Informed Consent (see below) should have the added caveat that safety is unclear in pregnancy
    3. Theoretically, tPA is too large a molecule to cross the placenta
      1. Selim (2013) Stroke 44(3): 868-9 [PubMed]
    4. One study of Thrombolytics in primarily first trimester CVA showed higher mother and baby complication rates
      1. Del Zotto (2011) Stroke Res Tres +PMID:21331336 [PubMed]
    5. Another study demonstrated similar complication rates to NINDS
      1. Leonhardt (2006) J Thromb Thrombolysis 21(3): 271-6 +PMID:16683220 [PubMed]
    6. References
      1. Lin and Coralic in Herbert (2014) EM:Rap 15(1): 8

IV. Protocol: Informed Consent

  1. Review risks and benefits of CVA Thrombolysis with patient and family
    1. Thrombolysis <3 hours for presumed Ischemic CVA without contraindication is an approved emergency intervention
    2. Consent should be obtained but is not required if it cannot be obtained in a timely matter
  2. Given 18 patients with moderate to severe stroke (NIH Stroke Scale of 5 or more)
  3. No TPA given
    1. Good CVA recovery: 6 patients (33% or one third)
    2. Poor or no CVA recovery: 12 patients (66% or two thirds)
  4. TPA given within 3 hours
    1. Two additional patients (12%) will have a better outcome, one patient (6%) will have devastating Intracranial Bleeding
    2. Major CNS bleeding: 1 patient (6%) with 45% of those patients dying and the others with typically severe Disability
    3. Good CVA recovery: 8 patients (44%) or an additional 2 patients more than if no TPA had been given
    4. Poor or no CVA recovery: 9 patients (50%)
  5. Stroke mimics account for 15% of cases in which TPA is administered
    1. Examples: Seizure with Todd's Paralysis, Complicated Migraine Headache
    2. Risk of serious bleeding in patients with stroke mimic given TPA is 1%
    3. Tsivgoulis (2015) Stroke 46(5): 1281-7 +PMID:25791717 [PubMed]
  6. References
    1. (1995) N Engl J Med 333:1581-1587 [PubMed]

V. Efficacy

  1. See Informed Consent Above
  2. Thrombolytics are most effective for small vessel strokes
    1. Acute large vessel strokes may benefit from endovascular therapy (mechanical clot removal)
  3. Thrombolysis for acute Ischemic Stroke <3 hours
    1. Re-analysis of NINDS study shows no consistent benefit and increased Intracranial Hemorrhage risk
      1. Hoffman (2009) Ann Emerg Med 54(3):329-36 +PMID: 19464756 [PubMed]
  4. Thrombolysis for acute Ischemic Stroke at 3 to 4.5 hours
    1. Re-analysis of ECASS III study shows no benefit and increased Intracranial Hemorrhage risk
      1. Alper (2020) BMJ Evid Based Med 25(5):168-71 +PMID: 32430395 [PubMed]

VI. Protocol: Thrombolysis

  1. Blood Pressure preparation
    1. See CVA Blood Pressure Control
    2. Failure to control Blood Pressure <185/110 mmHg with the following agents contraindicates Thrombolysis
    3. Preparations (if SBP >185 mmHg or DBP >110 mmHg)
      1. Labetalol 10-20 mg IVP for 1-2 doses or
      2. Nitropaste 1-2 inches or
      3. Enalapril 1.25 mg IVP
  2. t-PA (Alteplase)
    1. Dose: 0.9 mg/kg (maximum 90 mg)
    2. Bolus 10% over first minute
    3. Give remainder over 60 minutes
    4. Indications to stop tPa infusion
      1. Signs of Intracerebral Hemorrhage (ICH) as described below
      2. Severe Angioedema reaction
    5. Tenecteplase (TNKase) has been used instead of Alteplase (t-PA) by some centers
      1. Initial studies have shown similar safety and efficacy when compared with t-PA
      2. However, NOR-TEST 2 trial showed increased Intracranial Hemorrhage and lower efficacy with TNKase
        1. Kvistad (2022) Lancet Neurol 21(6): 511-9 +PMID: 35525250 [PubMed]
  3. Neurologic Exam monitoring after t-PA
    1. Repeat every 15 minutes for 2 hours THEN
    2. Repeat every 30 minutes for 6 hours THEN
    3. Repeat every 60 minutes for 24 hours
  4. Manage Blood Pressure aggressively post-Thrombolytic
    1. Keep Systolic Blood Pressure under 180
    2. Keep Diastolic Blood Pressure under 105
  5. Monitor for signs of Intracerebral Hemorrhage (ICH)
    1. Findings
      1. Acute increase in Blood Pressure
      2. Sudden Headache
      3. Nausea or Vomiting
      4. New neurologic findings
    2. Approach
      1. See Intracerebral Hemorrhage (ICH)
      2. Early neurosurgical Consultation
      3. Stop tPa infusion
      4. Emergent Head CT
      5. Elevate head of bed to 30 degrees if suspected Increased Intracranial Pressure
      6. Intubate if needed
  6. Precautions
    1. Observed in Intensive Care Unit for first 24 hours
    2. Keep Blood Sugar <200 mg/dl
    3. No other antithrombotic agents given for 24 hours
    4. Expect minor bleeding (Gingiva, catheter sites, Bruising)
  7. Repeat imaging
    1. CT Head (or MRI) at 72 hours
    2. As needed for signs of Intracerebral Hemorrhage (ICH) or other new neurologic changes

VII. Adverse Effects

  1. Intracranial Hemorrhage
    1. Asymptomatic Intracranial Bleeding
      1. Controls: 2.9%
      2. t-PA: 4.5%
    2. Symptomatic Intracranial Bleeding
      1. Controls: 0.6%
      2. t-PA: 6.4%
    3. All Intracranial Bleeding
      1. Controls: 3.5%
      2. t-PA: 10.9%
  2. Hemorrhagic deaths occurred in critically ill
    1. Very poor prognosis prior to t-PA
  3. References
    1. NIH rTPA Trial

VIII. References

  1. Burgess and Stowens (2014) Crit Dec Emerg Med 28(5): 2-13
  2. Anderson (1997) Lecture, FP Update, Minneapolis, MN
  3. Lyden (2001) CMEA Medicine Lecture, San Diego
  4. Lyden (1998) CMEA Medicine Lecture, San Diego
  5. Zivin (1999) Neurology 53(1):14-9 [PubMed]

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