Evaluation of CGP 39393 as the anticoagulant in cardiopulmonary bypass operation in a dog model.

Abstract

Recombinant desulphatohirudin HV1 (CGP 39393), a specific and potent peptidic inhibitor of thrombin, was evaluated as the sole anticoagulant in a dog model of cardiopulmonary bypass. CGP 39393 was administered as a bolus plus infusion for a 1-hour pump period at doses of 1.0 mg/kg + 0.75 mg.kg-1.h-1, 1.0 mg/kg + 1.50 mg.kg-1.h-1, 1.0 mg/kg + 2.25 mg.kg-1.h-1, or 1.0 mg/kg + 3.0 mg.kg-1.h-1 (n = 5 per group). The lowest dose was ineffective, as a high degree of clot formation (314 +/- 160 mg) occurred as determined by quantitation of protein deposits in the pump line filter. The three higher doses inhibited clot formation (35 to 44 mg) but did not reveal a dose-dependent effect (p = 0.308 between groups). All four doses produced the same amount of postoperative blood loss (6.5 to 10 g/kg over 2 hours; p = 0.215 between groups) and no oozing of blood from cut tissues (sternum, muscle, skin) during or after operation. No adverse hemodynamic or hematologic effects were observed. Animals were physiologically stable coming off pump, requiring minimal fluid replacement or other cardiovascular supportive measures. The chromogenic anti-IIa assay could be used to monitor CGP 39393. Some activated partial thromboplastin time and all activated clotting time values were off scale on pump, but they fell immediately after cardiopulmonary bypass, typically reaching near-normal levels within 30 to 60 minutes. No reversal of CGP 39393 was used, as blood levels declined rapidly after cessation of the infusion. This study in a dog model shows that CGP 39393 administered as a bolus plus infusion (minimum dose, 1.0 mg/kg + 1.50 mg.kg-1.h-1) can be used safely and effectively during cardiopulmonary bypass for cardiac operation.