GUIDELINES FOR THE USE OF TRANEXAMIC ACID IN CARDIAC SURGERY WITH CARDIOPULMONARY BYPASS

Excessive postoperative bleeding after cardiac operations with the use of cardiopulmonary bypass (CPB) continues to be a source of increased morbidity. Blood conservation has become an area of major concer for the cardiac surgeon and the perfusionist. In our days, excessive bleeding after CPB opearations is a preventable complication.

Several avenues of management have been explored to reduce blood loss and the need for blood transfusion after open heart surgery, namely normovolemic hemodilution, intraoperative autotransfusion, postoperative return of shed medistinal blood, predonation of autologous blood, and pharmacologic manipulation with antifibrinolytic agents.

CAUSES OF EXCESSIVE BLEEDING

Excessive bleeding after cardiac surgery is generally related to a combination of several CPB related alterations in the hemostatic system, such as:

1. hemodilution
2. activation of hemostatic systems by the interaction of blood with the nonendotelial CPB surfaces
3. activation of the extrinsic clotting pathway secondary to surgical trauma and retransfusion of pericardial blood
4. activation of factor X by the contact activation and tissue factor pathways
5. increased thrombin production
6. activation of fibrinolysis by means of several mechanisms.

Many studies have proved that significant alterations in hemostatic mechanisms are induced by the nonbiological surfaces of the CPB circuit. Activation of fibrinolysis during CPB has been well documented and its relevance to postoperative bleeding confirmed by the effectiveness of intraoperative antifibrinolytic therapy with aprotinin, epsilon aminocaproic acid and tranexamic acid in reducing mediastinal drainage, blood products transfusion requirements and the frequency of urgent reoperations to secure hemostasis.

As therapy is considerably more expensive with aprotinin than with the other agents, it is important to review the use of results of prophylactic administration of alternatives to aprotinin, such a tranexamic acid (TA).

TRANEXAMIC ACID

The chemical name of tranexamic acid is: trans-4-(aminomethyl) cyclohexanecarboxylic acid. Its molecular formula is C8H15NO2 and the molecular weight is only 157.21 daltons. The solubility in water is about 1 g/6 mL and it is very little soluble in alcohol and ehter. The lethal dose 50 (LD 50) in mice, rats is 1500 mg/kg.

In some countries the TA is commercialized with the name of Cyklokapron (Kabi Pharmacia). In South America (Brazil) the commercial preparation of TA is on the market as Transamin (Nikkho). The TA infusion can be prepared by dilution in saline or dextrose solutions.

TA is presented in 5 mL ampules containing 250 mg (50 mg/mL).

MECHANISM OF ACTION

Tranexamic acid acts by forming a reversible complex with the plasminogen through the lysine binding sites for fibrin. The saturation of these sites displaces the plasminogen from the fibrin surface, preventing the binding of plasmin to fibrinogen or to fibrin monomers. The net effect of TA is an inhibitory effect on the activation of plasminogen in the fibrinolytic cycle ie. the conversion of plasminogen to plasmin. TA is also a weak noncompetitive inhibitor of plamin, blocking its action on fibrin. The tranexamic acid has been evaluated as an alternative to aprotinin in an attempt to reduce treatment costs. TA is much less expensive and it has been reported as equaly effective in reducing postoperative bleeding and the need for blood products transfusion.

Tranexamic acid has been reported as ten times more potent than epsilon-aminocaproic acid.

DRUG ADMINISTRATION

There are a few dosing protocols for the employment of tranexamic acid in cardiac surgical patients undergoing operations with CPB. Variability of plasma TA concentrations secondary to fluctuations in intravascular volume during CPB remains unknown. It is also unknown whether or not current dosing regimens maintain a therapeutic concentration of TA during CPB.

ADULTS DOSING SCHEMES:

A common and very effective dosing scheme is:

1. 5 gm of TA as a loading dosing at anesthetic induction and before sternal splitting.
2. 5 gm of TA added to the pump prime.
3. 1 gm/hour after closing sternal would for 5 hours.


PEDIATRIC DOSING SCHEMES:

Another dosing scheme adjusted to the body weight is useful for pediatric administration:

1. A loading dose of 10 - 20 mg/kg body weight of TA 2. Follow the loading dose with a continuous infusion of 1-2 mg/kg of TA per hour adjusted for creatinine clearance if necessary to the end of sternal closure. 3. A dose of 500 mg added to the pump prime.

NOTES:
A variety of pediatric dosis of TA have been recommended, from 10-50 mg/kg body weight. Results are not as consistent as in adult patients.
Costs of TA treatment are much lower than cost of aprotinin treatments.