Investigation of a Thrombin Inhibitor Peptide as an Alternative to Heparin in Cardiopulmonary Bypass Surgery

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Abstract

Background.

This study was undertaken to determine if a newly developed synthetic peptide thrombin inhibitor (DuP 714; DuPont-Merck, Wilmington, Del) could be used as an anticoagulant in cardiopulmonary bypass (CPB) surgery.

Methods and Results.

Anesthetized mongrel dogs were placed on CPB for 1 hour and then observed for 2 hours. Following a dose-finding study, the optimal dose (DuP 714 group) and an overdose (DuP-HI group) were studied. The DuP 714 group received 0.25 mg/kg IV bolus plus 0.5 mg · kg−1 · h−1 infusion of DuP 714 (n=10) and the DuP-HI group received 0.5 mg/kg IV bolus plus 1.0 mg · kg−1 · h−1 infusion of DuP 714 (n=6). No neutralizing agent was used. The control group received 2.0 mg/kg intracardiac bolus of heparin with 0.15 mg/kg IV bolus injections as needed to maintain the activated clotting time (ACT) at >300 seconds during CPB (n=6). Protamine sulfate (2.0 mg/kg) was used to reverse heparin after CPB. Postoperative blood loss for both DuP 714 groups was less than that for heparin (177±40 and 297±36 versus 318±99 g,P=NS). The DuP 714 group revealed higher pump line filter fibrin deposits (15.5±3.6 mg,P<.032 ANOVA) compared with the heparin group (4.2±2.4 mg), whereas the DuP-HI group showed equivalent deposits (9.3±5.3 mg). The ACT levels recorded during and 30 minutes after CPB were 638±52 and 160±9 seconds in the DuP 714 group and >800 and 436±75 seconds in the DuP-HI group; however, the ACT level only in the DuP-HI group remained elevated 2 hours after CPB. Platelet counts were significantly higher (P<.05) in both DuP 714 groups after CPB. There was nearly complete elimination of all peptide in the urine. No statistical difference was observed in hemodynamics (cardiac index and systemic vascular resistance) in any of the groups.

Conclusions.

This study reveals that the peptide inhibitor DuP 714 can effectively function as an anticoagulant in a canine CPB model. The efficacy and safety, even when overdosed, are demonstrated by reduced blood loss and lack of platelet count reduction. Clinical monitoring can be achieved by the use of ACT levels. No evidence of hemodynamic compromise was noted with the drug administration. (Circulation.1993;88[part 2]:407–412.)

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