Aprotinin
CLASS
- antifibrinolytic
MECHANISM OF ACTION
- single chain polypeptide which occurs naturally in bovine lung and other tissues
- inhibits fibrionlysis via inactivation of free plasmin
- also inhibits trypsin and kallikrein
-> when given prior to bypass: prevents clotting activation, factor consumption, platelet dysfunction -> reduced blood loss and transfusion
PHARMACEUTICS
- clear, colourless solution
- 1.4mg/mL in 0.9% saline = 10,000 kallikrein inactivator units
DOSE
- IV dose = 500,000 -> 1,000,000 KIU -> 200,000 KIU/hr until bleeding stops
INDICATIONS
- life-threatening haemorrhage from hyperplasminaemia
- acute pancreatitis
- reduction of blood loss during bypass surgery, prostatectomy & liver transplantation
- prevention of DVT
ADVERSE EFFECTS
- increased mortality -> moratorium
- renal failure
- can have hypersensitivity on repeat exposure
- can produce thrombophlebitis
PHARMACOKINETICS
- Absorption – IV only
- Distribution – highly protein bound
- Metabolism – lysosomes of kidneys
- Elimination – t1/2 = 1 hr
EVIDENCE
Positive
- shown to decrease bleeding and transfusion requirements with regard to patient with platelet dysfunction post cardiac bypass (inhibition of platelet aggregation -> prevention of microaggregate formation) in multiple previous trials (Cochrane review 2001 & JTCVD 2004)
- used to help with haemostasis and shown to decrease transfusion requirements in multiple studies including in trials recently
- transfusion and bleeding in cardiac surgical patients produces increased morbidity and therapies to decrease this are therefore important
Negative
- recent published meta-analysis and FDA inquiry has revealed a significant increase in morbidity associated with its use (in particular a significant increase in acute renal dysfunction) but not increase in CVA, MI or mortality. (Circulation 2007;115:2801–13)
- NEJM January 2006 – observational study with >4000 patients -> increased risks of CVA, MI, renal failure and CCF
- increased risk of renal dysfunction (decreased GFR) but does not increase risk for renal failure requiring dialysis
- BART trial in (Blood conservation using antifibrinolytics; a randominsed trial) – a trial comparing Aprotinin, Tranexamic and Epsilon-aminocaproic acid in preliminary data found that aprotinin produced a trend towards increased mortality -> moratorium on aprotinin use pending BART data -> significant increase in mortality and morbidity and recommended not using aprotinin in high risk cardiac surgery (May 2008 – NEJM)
There currently needs to be more information gathered to make a final decision on whether or not aprotinin should be disallowed in cardiac surgery.
References and Links
CCC Pharmacology Series
Respiratory: Bosentan, Delivery of B2 Agonists in Intubated Patients, Nitric Oxide, Oxygen, Prostacyclin, Sildenafil
Cardiovascular: Adenosine, Adrenaline (Epinephrine), Amiodarone, Classification of Vasoactive drugs, Clevidipine, Digoxin, Dobutamine, Dopamine, Levosimendan, Levosimendan vs Dobutamine, Milrinone, Noradrenaline, Phenylephrine, Sodium Nitroprusside (SNiP), Sotalol, Vasopressin
Neurological: Dexmedetomidine, Ketamine, Levetiracetam, Lignocaine, Lithium, Midazolam, Physostigmine, Propofol, Sodium Valproate, Sugammadex, Thiopentone
Endocrine: Desmopressin, Glucagon Therapy, Medications and Thyroid Function
Gastrointestinal: Octreotide, Omeprazole, Ranitidine, Sucralfate, Terlipressin
Genitourinary: Furosemide, Mannitol, Spironolactone
Haematological: Activated Protein C, Alteplase, Aprotinin, Aspirin, Clopidogrel, Dipyridamole, DOACs, Factor VIIa, Heparin, LMW Heparin, Protamine, Prothrombinex, Tenecteplase, Tirofiban, Tranexamic Acid (TXA), Warfarin
Antimicrobial: Antimicrobial Dosing and Kill Characteristics, Benzylpenicillin, Ceftriaxone, Ciprofloxacin, Co-trimoxazole / Bactrim, Fluconazole, Gentamicin, Imipenem, Linezolid, Meropenem, Piperacillin-Tazobactam, Rifampicin, Vancomycin
Analgesic: Alfentanil, Celecoxib, COX II Inhibitors, Ketamine, Lignocaine, Morphine, NSAIDs, Opioids, Paracetamol (Acetaminophen), Paracetamol in Critical Illness, Tramadol
Miscellaneous: Activated Charcoal, Adverse Drug Reactions, Alkali Therapies, Drug Absorption in Critical Illness, Drug Infusion Doses, Epidural Complications, Epidural vs Opioids in Rib Fractures, Magnesium, Methylene Blue, Pharmacology and Critical Illness, PK and Obesity, PK and ECMO, Sodium Bicarbonate Use, Statins in Critical Illness, Therapeutic Drug Monitoring, Weights in Pharmacology
Toxicology: Digibind, Flumazenil, Glucagon Therapy, Intralipid, N-Acetylcysteine, Naloxone, Propofol Infusion Syndrome
Critical Care
Compendium
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.
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