GUIDELINES FOR THE USE OF APROTININ IN CARDIAC SURGERY WITH CARDIOPULMONARY BYPASS

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk for increased postoperative blood loss. Excessive postoperative bleeding can be associated with a variety of negative outcomes such as increased mortality, renal failure, sepsis, atrial arrhythmias, prolonged ventilatory support and longer intensive care and hospital stay.

Blood conservation has become a major area of concern for the cardiac surgeon and the perfusionist. The increased postoperative bleeding can be a result of preexisting coagulation disorders, and the effects of CPB such as hemodilution, platelet dysfunction, increased fibrinolysis, complement activation, platelet and neutrophil activation.

Several techniques have been explored to reduce the need for blood transfusion: normovolemic hemodilution, intraoperative autotransfusion, postoperative return of shed mediastinal blood, predonation of autologous blood, and pharmacologic manipulation.

Numerous pharmacologic strategies have been proposed as means to attenuate the alterations in the hemostatic system during CPB. The prophylactic use of antifibrinolytics drugs to reduce postoperative blood loss from CPB-induced fibrinolysis has been demonstrated to be effective.

Aprotinin (Trasylol®) is indicated for prophylactic use to reduce perioperative blood loss and the requirements for blood transfusions in patients undergoing cardiac surgery with CPB.

Several controlled, double-blind, randomized, multicenter clinical trials have demonstrated improved outcomes in aprotinin-treated patients. A substancial reduction in blood loss (50% reduction in chest tube drainage), transfusion (50% to 90% reduction in total donor exposures), and reexploration (40% to 60% reduction) was evident in patients who received aprotinin.

APROTININ

Aprotinin (Trasylol R) is a natural serine protease inhibitor with effects on human plasmin, trypsin, plasma and tissue kallikrein. Aprotinin is obtained from bovine lung. It has a molecular weight of 6512 daltons and consists of 58 aminoacid residues that are arranged in a single polypeptide chain, cross-linked by three disulfite bridges.

Aprotinin is supplied as a clear, colorless, sterile isotonic solution for intravenous administration. Each mililiter contains 10,000 KIU (Kallikrein Inhibitor Units) (1.4 mg/mL) and 9 mg sodium chloride in water for injection. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH to 4.5-6.5.

Trasylol is supplied in 100 ml vials containing 1,000,000 KIU and in 200 ml vials containing 2,000,000 KIU.

MECHANISM OF ACTION

The precise mechanism of action of aprotinin is still under discussion. It has been suggested that aprotinin may act by a few avenues:

• Inhibits plasmin and kallikrein, affecting fibrinolysis;
• Inhibits contact phase activation;
• Preserve the adhesive glycoproteins in the platelet membrane, thus increasing the resistance to damage. Aprotinin preserves the glycoprotein receptor (GIb, GIIb/IIIa) in platelets. The GIb receptor is responsible for platelet adhesion to endothelium ;
• Inhibits fibrinolysis and turnover of coagulation factors and decreases bleeding;
• Prevents the expression of pro-inflammatory adhesive glycoproteins (CD11b) in granulocytes;

The pharmacokinetics of aprotinin has been recently well described and its elimination half-life is approximately 5 hours.

USE IN CARDIOPULMONARY BYPASS

There are basically two well stablished dose regimens for the administration of aprotinin during cardiac surgery with CPB.

FULL DOSE REGIMEN:

The stablished effective administration regimen of aprotinin is known as the "full Hammersmith dose" or high dose. The full Hammersmith dose consists of:

1. Administering a 2,000,000 KIU aprotinin loading dose, intravenously, during a period of about 20-30 minutes, immediately after anesthetic induction;
2. Adding another 2,000,000 KIU aprotinin dose to the CPB circuit prime;
3. Mantain an infusion of 500,000 KIU aprotinin during the surgical procedure until the chest incision is closed.

Some authors prefer to stablish the dose regimen relative to the substance mass instead of biological activity. They recommend to:

1. Administer 280 mg of aprotinin for 20-30 minutes after anesthetic induction and before surgical incision;
2. Add 280 mg of aprotinin to the CPB circuit prime;
3. Administer an infusion of 70 mg/h until the end of operation.


HALF DOSE REGIMEN:

Several authors have adopted a "low dose" regimen which usually corresponds to half of the Hammersmith dose. The low dose regimen consists of:

1. Administer 1,000,000 KIU aprotinin loading dose, intravenously, during a period of about 20-30 miutes, immediately after anesthetic induction;
2. Adding another 1,000,000 KIU aprotinin dose to the CPB circuit prime;
3. Mantain an infusion of 250,000 KIU aprotinin during the surgical procedure until the chest incision is closed.

PEDIATRIC DOSE REGIMEN:

This dose protocol was used in a total of 645 cardiac operations with CPB in children with ages starting at 1 day. About 13.46% of patients underwent circulatory arrest.

The dose regimen consists of:

1. Administering a loading dose of 240 mg/m2 intravenously after anesthetic induction in a period of 20-30 minutes;
2. Adding an identical dose of 240 mg/m2 to the CPB circuit prime:
3. Mantaining an infusion of 56 mg/m2 during surgery and tipically terminating upon the patient leaving the operating room.


Cyanotic children aged 3 months to 12.5 years were given aprotinin in the following regimen:

1. Loading dose of 10,000 KIU/kg
2. Pump prime dose of 10,000 KIU/kg
3. Continuous infusion of 10,000/h up to 3 hours after weaning from CPB.

APROTININ AND MONITORING OF ANTICOAGULATION

Aprotinin is known to prolong activated clotting time (ACT) when celite is used as the activator. Aprotinin in the presence of heparin has been found to prolong the ACT as measured by the Hemochron method or similar surface activation methods. For this reason keeping the ACT above 400-500 seconds may lead to inadequate anticoagulation. If celite is the activator in use, the ACT should be mantained above 700-750 seconds.

Prefereably the alternative activator kaolin (HemoTec, Inc, Englewood, CO) should be used to monitor the heparin effect. Kaolin ACT is not affected by aprotinin, and the usual 400-600 seconds range is adequate for CPB.

Heparin titration can be another useful monitoring alternative, although it is less commonly used than the ACT measurement.

APROTININ AND SYSTEMIC INFLAMMATORY REACTION

It has been suggested that the inhibitory properties of aprotinin could reduce the production of inflammatory mediators responsible for the systemic inflammatory reaction to CPB.

There is still much controversy as to the beneficial effect of the drug on inflammatory reaction to CPB. A few placebo-controlled, randomized, double-blinded trials indicate that aprotinin at doses used clinically has no significant effect on the release of several inflammatory markers in human subjects during CPB. A few other reports claim a reduction on organ disfunction secondary to the inflammatory reaction when aprotinin is administered.

ADVERSE REACTIONS

The use of aprotinin may be followed by a few unwanted reactions of variable intensity. In some cases the adverse reaction may be lethal.

ANAPHYLAXIS AND ALLERGIC REACTIONS

Aprotinin is a bovine protein. As such it may cause anaphylactic reactions in about 0.5% of patients receiving the drug. In order to detect individuals at risk to develop allergic or anaphylatic reactions it is recommended to perform a test in all candidates to aprotinin treatment. All patients should receive a 1 ml (10,000 KIU) test dose intravenously at least 10 minutes prior to the loading dose. In pediatric patients an intradermal skin test at a dilution of 1:100 has been used.

Particular caution is necessary when administering aprotinin (even test doses) to patients who received the drug in the past because of the risk of anaphylaxis. In re-exposure cases, intravenous administration of an H1-histamine antagonist (antihistamine) is recommended shortly before the loading dose infusion.

Patients who experience any allergic reaction to the test dose of aprotinin should not receive further administration of the drug. Even after the uneventful administration of the 1 mL test dose, or without previous exposure to aprotinin, the full therapeutic dose may cause anaphylaxis. If this happens, the infusion should be stopped immediately and emergency treatment for anaphylaxis should be applied.

Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing an allergic reaction.

OTHER REACTIONS

It has been postulated that aprotinin may cause an increased incidence of renal insufficiency and graft thrombosis. However several studies failed to demonstrate a statistically significant difference between treated and control patients in order to corroborate that relashionship.

FOOTNOTES:

1. Administer the loading dose over a 20-30 minutes period. Rapid administration of aprotinin can cause a transient arterial hypotension.
2. The maximum amount of aprotinin that can be safely administered in single or multiple doses has not been determined. Doses up to 17.5 million KIU have been administered within a 24 hour period without any apparent toxicity or side effects.
3. Aprotinin should be administered through a central vein. No other drug should be administer into the same line.
4. In a pediatric population allergic reactions ocurred in 0.8% of first exposure cases and in 3.0% of second exposure cases. Third time exposures presented 7.7% of reactions.
5. Allergic reactions consists mostly of generalized erythema caused by histamine release, arterial hypotension or bronchospasm during infusion of the loading dose.
6. Over 25 clinical trials have supported the efficacy of aprotinin to reduce postoperative bleeding and the need for blood products transfusion.
7. Aprotinin administered in the early postoperative period is usually ineffective in reducing postoperative bleeding and the requirements of blood products.
8. Greater benefits are obtained in the higher risk group of patients: reoperations, patients with impaired hemostasis, pretreated with aspirin, and patients with coagulopathy. Patients for whom transfusion is either unavailable or unacceptable also benefit from the aprotinin use.
9. The low-dose aprotinin is sometimes used in preference to high-dose aprotinin because of the considerable economic savings with little loss in efficiency.
10. The main disadvantage of aprotinin is the high cost per treatment. It has been estimate to cost about US$ 1,800.00 per procedure (US$ 300.00 per 200 ml vial).

Aprotinin (Trasylol) - Four years of clinical use in 10 countries. Miles - Pharmaceutical Division, September 1994.

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