Question 4

College Answer

See Lancet 4th Dec 1999; vol 354 and J Cardiothoracic and Vasc Anesth 1999;4:6-11

The pharmacodynamic properties of:

a)   Aprotonin are:

-     non specific serine protease inhibitor

-     inhibitor of trypsin, plasmin, kalikrein, contact phase of coagulation

-     this inhibits fibrinolysis, coagulation and inflammation

-     when given before bypass it may prevent clotting activation, factor consumption and platelet dysfunction leading to reduced blood loss re-operation rate, transfusion

-     adverse effects include fever, anaphylaxis on repeat exposure

b)  DDAVP are: a vasopressin analogue that induces release of the contents of endothelial cell- associated   Weibral-Palade   bodies,   including   von   Willebrand   factor.   In   doses   used   in cardiothoracic surgery (0.3ug/kg) it potentiates primary haemostasis and may lead to water retention and vasoconstriction. It has been shown to have a small effect on transfusion rate but an associated two fold increase in perioperative myocardial infarction

c)   Tranexemic acid are:  a lysine analogue which is a potent, specific inhibitor of fibrinolysis. It has been shown to decrease transfusion rate, reoperation rate but not outcome after cardiothoracic surgery. Adverse effects reported include: myopathy, hypotension and intravascular thrombosis.

Discussion

One could overdiscuss the pharmacological properties of these substances.

A good comparison of their efficacy exists, which is helpful for this particular question. To summarise, tranexamic acid and aprotonin decrease the need for transfusion post cardiac surgery, but DDAVP does not.

That article is not available in full text, but this one is. It is a meta-analysis of drugs used to decrease bleeding during and after cardiac surgery; this is where the college got their statistic about the increased risk of MI with DDAVP.

Given the exotic nature of these substances, and given the author's delighted interest in exotic substances, this topic is afforded a slightly excessive amount of interest in the "Required Reading" section. The table of compared properties from that chapter is reproduced below, in order to simplify revision.

A Comparison of Pharmacological Haemostatic Agents

Properties	DDAVP	Aprotinin	Tranexamic acid
Class	Vasopressin analogue	Non specific serine protease inhibitor	Lysine analogue
Mechanism	Induces release of the contents of endothelial cell- associated Weibral-Palade bodies, including  von Willebrand factor.	Inhibitor of trypsin, plasmin, kalikrein, contact phase of coagulation: this inhibits fibrinolysis, coagulation and inflammation	Potent, specific inhibitor of fibrinolysis (a tissue plasminogen activator inhibitor)
Dose	0.3μg/kg	2 million KIU IV over 20-30min Prime pump with 2 million KIU IV Then, continuous intraoperative infusion of 0.5million KIU/hour	30 mg/kg bolus followed by 16 mg/kg/hr infusion seems to be the favoured dose.
Advantages	May decrease transfusion needs perioperatively May antagonise persistent antiplatelet agent effects	May prevent clotting activation, factor consumption and platelet dysfunction, leading to reduced blood loss.	Reduces transfusion needs Does not increase the risk of MI
Disadvantages	May lead to water retention and vasoconstriction A small effect on transfusion rate but a two fold increase in rate of perioperative MI.	Discontinued! No longer available. Slight increase in the rate of MI	Does not improve outcome
Side effects	Fluid retention Increased afterload Hyponatremia	Sensitization and hypersensitivity reactions, including anaphylaxis	Myopathy Hypotension Intravascular thrombosis.

Laupacis, Andreas, and Dean Fergusson. "Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome." Anesthesia & Analgesia 85.6 (1997): 1258-1267.

 

Levi, Marcel, et al. "Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints." The Lancet 354.9194 (1999): 1940-1947.