Stefaniszyn H J, Novick R J, Salerno T A
J Thorac Cardiovasc Surg. 1984 May;87(5):678-86.
Hemodynamic changes have been documented during protamine infusion into heparinized but not unheparinized pigs and suggest that a protamine-heparin interaction might be responsible. This hypothesis was tested in four groups of pigs by varying the dosage and order of administration of these two drugs: Group I (n = 9) received heparin (3 mg/kg) followed by protamine (3 mg/kg); Group II (n = 9) received protamine (3 mg/kg) followed by heparin (3 mg/kg); Group III (n = 9) received protamine (25 mg/kg) followed by heparin (3 mg/kg); and Group IV (n = 16) received protamine-heparin complex (protamine 3 mg/kg and heparin 3 mg/kg mixed immediately prior to injection). Systemic and pulmonary arterial pressures, systemic and pulmonary vascular resistances, left ventricular end-diastolic pressure, central venous pressure, cardiac output, and heart rate were measured before and at 1.0, 2.5, 5.0, and 15 minutes after protamine, heparin, or protamine-heparin complex infusions. Immediately following protamine infusion, Group I pigs exhibited transiently but significantly increased pulmonary artery pressure, pulmonary vascular resistance, systemic vascular resistance, and central venous pressure and decreased cardiac output with (Group Ib, n = 5) or without (Group Ia, n = 4) systemic hypotension. The fact that no hemodynamic changes occurred in Group II confirms that infusion of clinical doses of protamine produces no hemodynamic changes in unheparinized pigs. Protamine alone in high doses (Group III) produced hemodynamic changes similar to clinical-dose protamine reversal of heparin (Group I). This effect suggests that the presence of heparin in the circulation lowers the threshold for protamine-mediated hemodynamic responses. Infusion of heparin (3 mg/kg) into pigs 15 minutes after treatment with high (25 mg/kg) (Group III) but not clinical (3 mg/kg) (Group II) doses of protamine produced hemodynamic effects similar to clinical-dose protamine reversal of heparin (Group I), suggesting that a protamine-heparin interaction may be responsible. These results also suggest a rapid inactivation in vivo of clinical doses (3 mg/kg) (Group II) of infused protamine. Protamine-heparin complex formed in vitro (Group IV) also produced hemodynamic changes similar to clinical-dose protamine reversal of heparin (Group I), suggesting that formation of this complex in vivo may be the protamine-heparin interaction responsible. Protamine-heparin complex may well be a useful tool in further elucidating the full effects of protamine reversal of heparin.
在向已肝素化而非未肝素化的猪输注鱼精蛋白期间，已记录到血流动力学变化，这表明鱼精蛋白 - 肝素相互作用可能是原因所在。通过改变这两种药物的剂量和给药顺序，在四组猪中对这一假设进行了测试：第一组（n = 9）先接受肝素（3 mg/kg），然后接受鱼精蛋白（3 mg/kg）；第二组（n = 9）先接受鱼精蛋白（3 mg/kg），然后接受肝素（3 mg/kg）；第三组（n = 9）先接受鱼精蛋白（25 mg/kg），然后接受肝素（3 mg/kg）；第四组（n = 16）接受鱼精蛋白 - 肝素复合物（鱼精蛋白3 mg/kg和肝素3 mg/kg在注射前立即混合）。在输注鱼精蛋白、肝素或鱼精蛋白 - 肝素复合物之前以及之后1.0、2.5、5.0和15分钟测量体循环和肺动脉压力、体循环和肺血管阻力、左心室舒张末期压力、中心静脉压、心输出量和心率。在输注鱼精蛋白后，第一组猪立即出现肺动脉压力、肺血管阻力、体循环血管阻力和中心静脉压短暂但显著升高，心输出量降低，伴有（第一b组，n = 5）或不伴有（第一a组，n = 4）体循环低血压。第二组未出现血流动力学变化这一事实证实，在未肝素化的猪中输注临床剂量的鱼精蛋白不会引起血流动力学变化。高剂量（25 mg/kg）的单独鱼精蛋白（第三组）产生的血流动力学变化与临床剂量的鱼精蛋白逆转肝素（第一组）相似。这种效应表明，循环中肝素的存在降低了鱼精蛋白介导的血流动力学反应的阈值。在用高剂量（25 mg/kg）（第三组）而非临床剂量（3 mg/kg）（第二组）的鱼精蛋白治疗15分钟后，向猪输注肝素（3 mg/kg）产生的血流动力学效应与临床剂量的鱼精蛋白逆转肝素（第一组）相似，这表明鱼精蛋白 - 肝素相互作用可能是原因。这些结果还表明，输注的临床剂量（3 mg/kg）（第二组）鱼精蛋白在体内迅速失活。体外形成的鱼精蛋白 - 肝素复合物（第四组）也产生了与临床剂量的鱼精蛋白逆转肝素（第一组）相似的血流动力学变化，这表明体内形成这种复合物可能是鱼精蛋白 - 肝素相互作用的原因。鱼精蛋白 - 肝素复合物很可能是进一步阐明鱼精蛋白逆转肝素全部效应的有用工具。
