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Alteplase (rtPA)

Aka. t-PA, rt-PA, Actilyse, Activase, Cathflo

CLASS

  • Thrombolytic

INDICATIONS

  1. Acute STEMI
  2. Acute Ischaemic stroke
    • Last seen well within 4.5 hours
    • In potentially disabling ischaemic stroke who meet perfusion mismatch in addition to clinical criteria can be administered up to 9 hours after last seen well (see Stroke Foundation Guidelines) unless planned for endovascular clot retrieval
  3. Acute massive pulmonary embolism
    • Including Cardiac arrest due to suspected PE
  4. Central venous catheter occlusion

ADMINISTRATION / DOSING

  • Intravenous (IV)
  • Adults:
    • Acute STEMI:
      • 3-hour infusion: 10mg bolus, then 50 mg over 1st hour, then 40 mg over the following 2 hours (if < 65 kg, adjust the dose so total is < 1.5 mg/kg)
      • Accelerated infusion (90mins) total dose not to exceed 100 mg:
        • 15 mg bolus then,
        • 0.75 mg/kg (up to 50mg) over 30 mins then,
        • 0.5 mg/kg (up to 35 mg) over 60 minutes.
    • Acute massive PE
      • IV bolus of 10 mg, then 90 mg infused over 2 hours (if <65 kg, adjust so the total dose is <1.5 mg/kg)
    • Acute Ischaemic stroke
      • 0.9 mg/kg (max. dose 90 mg), give 10% as a bolus, then the rest over 60 mins.
    • Cardiac arrest with suspected PE:
      • 50mg bolus, consider further 50 mg 15 mins after initial bolus. Then you should continue CPR for 50-90 mins.
    • Central venous catheter occlusion:
      • >30 kg: 2 mg in 2 mL into the occluded catheter, consider second dose 120 mins later
      • <30kg: dose equal to 110% of catheter lumen volume, MAX 2 mg in 2mL
  • Children:
    • Refer to paediatric guidelines.
  • Administration-specific things:
    • Precipitates in 5% dextrose, must be drawn up in water for injection or 0.9% sodium chloride (Actilyse (Australian version) comes with diluent in package)
    • It comes in a set-up not-unlike Prothrombinex with a diluent and a transfer device. Don’t shake it up, swirl gently.

MECHANISM OF ACTION

  • It is a tissue plasminogen activator (tPA)
  • It enhances the conversion of plasminogen to plasmin by binding to fibrin initiating fibrinolysis with limited systemic proteolysis.
  • The circulating plasminogen that has been activated will cause a systemic lytic state
  • Alteplase requires fibrin as a cofactor for the activation of plasminogen

PHARMACEUTICS

  • Produced by recombinant DNA technology
  • Excipients:
    • Arginine, phosphoric acid, polysorbate 80 and nitrogen
  • White lyophilised powder for reconstitution
  • When reconstituted it is a colourless to pale yellow transparent solution with a pH of 7.3 and osmolality of 215 mOsm/kg
  • Comes with preservative-free sterile water for injection with a transfer device
  • Once reconstituted, it must be kept between 2 – 30oC and then used within 8 hours

PHARMACOKINETICS

  • Absorption
    • Initial response: ~30 mins
    • Peak plasma: ~60 mins
  • Distribution
    • Distribution half-life: 4.4 – 7 mins
    • Volume of distribution: 8.1 L
  • Metabolism
    • Liver – degraded to constituent amino acids
  • Elimination
    • Total body clearance: 380 – 570 mL/min
    • Parent compound cleared in 26.5 – 46 mins
    • Initial plasma half-life < 5 mins
    • Following 90 min infusion, T1/2  26.5 – 46 mins

PHARMACODYNAMICS

  • CNS
    • Post-lysis cerebral oedema in the infarcted zone
  • CVS
    • Transient drop in blood pressure during administration
    • Arrhythmias with reperfusion after lysis for a myocardial infarction
  • RESP
    • Bronchospasm
  • OTHER
    • Massive haemorrhage

CONTRAINDICATIONS
RELATIVE

  • Everything is a relative contraindication when you’re doing CPR on someone with a massive PE…
  • Age >80 review risk vs benefits given the increased risk of ICH

ABSOLUTE

  • Known hypersensitivity/anaphylaxis reactions to the medication or related excipients (increased risk with ACEi use)
  • Active internal bleeding
  • Current intracranial haemorrhage
  • Intracranial neoplasm, arteriovenous malformation, aneurysm, or other conditions that may increase haemorrhage
  • Bleeding diathesis (e.g. von Willebrand disease, haemophilia, advanced liver disease etc.)
  • Recent (i.e. within 3 months) intracranial or intraspinal surgery, major surgery
  • Recent (i.e. within 3 months) serious head trauma
  • Recent (i.e. within 3 months) stroke, for patients with acute myocardial infarction or pulmonary embolism
  • Severe uncontrolled hypertension
  • Subarachnoid haemorrhage
  • Active peptic ulcer disease
  • Prolonged CPR

IN ACUTE ISCHAEMIC STROKE
In addition to the above:

  • Symptoms began >4.5 hours prior to infusion start, or when time onset is unknown (or >9 hours in specific circumstances, see Stroke Foundation Guidelines)
  • Seizure
  • Platelets <100
  • Already anticoagulated
  • Rapid resolution of symptoms or only minor neurological deficit
  • SBP >185 / SBP >110
  • Blood glucose <2.8 mmol or >22.2 mmol/L
  • Patients < 18 years
  • History of prior stroke and Diabetes Mellitus
  • Severe stroke as assessed by NIHSS >25 or imaging techniques as higher risk of ICH

IN ACUTE MYOCARDIAL INFARCTION
In addition to the above:

  • Ischaemic stroke or TIA in the preceding 6 months, except a current stroke with onset of < 4.5 hours

RISKS

  • Reperfusion arrhythmias (in myocardial infarction) – 10%
  • Severe haemorrhage 1.8%
  • Moderate haemorrhage ~10% (requiring transfusion, but not hemodynamically compromising)
  • Gastrointestinal haemorrhage – ~5%
  • Intracranial haemorrhage – ~0.5-2% (increases to ~4% for >75 y/o patients)
    • With ~25-50% of those ICH being fatal
  • Orolingual angioedema (increased risk with ACEi use): 1-8%
  • Rare:
    • Anaphylaxis
    • Seizure
    • Dysphagia
    • Retroperitoneal haemorrhage
  • Post-stroke modified Rankin Score (mRS) for those treated within 3 hours from the ITT population (NINDS, ECASS-1, ECASS-II, ATLANTIS):
    • mRS 0 – 1 (favourable): 42% vs 29% (alteplase vs placebo)
    • mRS 0 – 2 (independent): 50% vs 40%
    • mRS 5 – 6 (disability or death): 24% vs 25%
    • Death (all causes): 17.6% vs 17.2%ICH: 34% vs 31.6%
    • Symptomatic ICH: 7.9% vs 1.6%

REVERSAL

EVIDENCE


  • Australian Injectable Drugs Handbook, 8th Edition. (2023). Retrieved 28 April 2023, from https://aidh.hcn.com.au/
  • Australian Medicines Handbook. (2023). Retrieved 28 April 2023 from https://amhonline.amh.net.au/       
  • IBM Micromedex. (2023). Retrieved 28 April 2023, from https://www.micromedexsolutions.com
  • MIMS Online. (2023). Retrieved 28 April 2023, from https://www.mimsonline.com.au
  • Stroke Foundation. (2022). Clinical Guidelines for Stroke Management. Living Clinical Guidelines for Stroke Management. https://informme.org.au/guidelines/living-clinical-guidelines-for-stroke-management

FOAMED

LITFL


[cite]


CCC 700 6

Critical Care

Compendium

Dr James Pearlman LITFL Author

ICU Advanced Trainee BMedSci [UoN], BMed [UoN], MMed(CritCare) [USyd] from a broadacre farm who found himself in a quaternary metropolitan ICU. Always trying to make medical education more interesting and appropriately targeted; pre-hospital and retrieval curious; passionate about equitable access to healthcare; looking forward to a future life in regional Australia. Student of LITFL.

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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