Chomiak P N, Walenga J M, Koza M J, Reilly T M, Turlapathy P, Pifarre R
Department of Surgery, Loyola University Medical Center, Maywood, IL 60153.
Circulation. 1993 Nov;88(5 Pt 2):II407-12.
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.
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 i.v. bolus plus 0.5 mg.kg-1 x h-1 infusion of DuP 714 (n = 10) and the DuP-HI group received 0.5 mg/kg i.v. bolus plus 1.0 mg.kg-1 x 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 i.v. 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.
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.
本研究旨在确定一种新开发的合成肽凝血酶抑制剂（DuP 714；杜邦-默克公司，特拉华州威尔明顿）是否可用于心肺转流（CPB）手术中的抗凝。
将麻醉的杂种犬置于CPB上1小时，然后观察2小时。在进行剂量探索研究后，对最佳剂量组（DuP 714组）和过量剂量组（DuP-HI组）进行了研究。DuP 714组静脉推注0.25 mg/kg DuP 714，随后以0.5 mg·kg⁻¹·h⁻¹的速度输注（n = 10），DuP-HI组静脉推注0.5 mg/kg DuP 714，随后以1.0 mg·kg⁻¹·h⁻¹的速度输注（n = 6）。未使用中和剂。对照组在CPB期间心脏内推注2.0 mg/kg肝素，并根据需要静脉推注0.15 mg/kg，以维持激活凝血时间（ACT）> 300秒（n = 6）。CPB后使用硫酸鱼精蛋白（2.0 mg/kg）来逆转肝素作用。两个DuP 714组的术后失血量均少于肝素组（分别为177 ± 40 g和297 ± 36 g，而肝素组为318 ± 99 g，P = 无显著差异）。与肝素组（4.2 ± 2.4 mg）相比，DuP 714组的泵管过滤器纤维蛋白沉积更高（15.5 ± 3.6 mg，方差分析P < 0.032），而DuP-HI组的沉积量相当（9.3 ± 5.3 mg）。DuP714组在CPB期间及CPB后30分钟记录的ACT水平分别为638 ± 52秒和160 ± 9秒，DuP-HI组分别为> 800秒和436 ± 75秒；然而，仅DuP-HI组在CPB后2小时ACT水平仍升高。CPB后两个DuP 714组的血小板计数均显著更高（P < 0.05）。尿液中几乎完全清除了所有肽。各组的血流动力学（心脏指数和全身血管阻力）未观察到统计学差异。
本研究表明，肽抑制剂DuP 714在犬CPB模型中可有效发挥抗凝作用。减少的失血量和血小板计数未降低证明了其有效性和安全性，即使过量使用也是如此。通过使用ACT水平可实现临床监测。给药后未观察到血流动力学受损的证据。
