Montalescot G, Zapol W M, Carvalho A, Robinson D R, Torres A, Lowenstein E
Department of Anesthesia, Massachusetts General Hospital, Boston 02114.
Circulation. 1990 Nov;82(5):1754-64. doi: 10.1161/01.cir.82.5.1754.
Protamine reversal of heparin anticoagulation in patients is occasionally associated with life-threatening acute pulmonary hypertension. In a sheep model, we evaluated the effect on this adverse cardiopulmonary reaction of modifying the type of heparin (low molecular weight heparin compared with unfractionated heparin) and the type of heparin antagonist (polybrene compared with protamine). Protamine reversal of low molecular weight heparin (LMWH) and polybrene reversal of unfractionated heparin induced more than a 10-fold increase of plasma thromboxane B2 levels, a threefold increase of pulmonary vascular resistance and pulmonary artery pressure, and a 25% decrease of PaO2. A similar adverse reaction followed protamine reversal of conventional unfractionated heparin. However, with polybrene (1 mg/kg) reversal of LMWH (1 mg/kg), we measured neither pulmonary hypertension (pulmonary artery pressure was 22.6 +/- 3.6 mm Hg at 1 minute after polybrene reversal of LMWH compared with 47.9 +/- 4.2 mm Hg after protamine reversal of unfractionated heparin, p less than 0.005 groups differ), hypoxemia (PaO2 was unchanged 2 minutes after polybrene compared with a decrease of 26 mm Hg 2 minutes after protamine, p less than 0.05), nor acute release of thromboxane into arterial plasma (thromboxane B2 was 0.2 +/- 0.1 at 1 minute after polybrene compared with 3.7 +/- 1.7 ng/ml at 1 minute after protamine, p less than 0.005). The hemodynamic effects and mediator release were also benign after neutralization of larger doses of LMWH (3 mg/kg) by polybrene (3 mg/kg). The increases of activated clotting time and activated partial thromboplastin time due to both types of heparin were completely reversed with polybrene. Anti-Xa activity increased to more than 3 IU/ml 4 minutes after LMWH anticoagulation (p less than 0.01) but was only partially neutralized by polybrene. Various polyanion-polycation complexes that are formed when heparin anticoagulation is reversed induce thromboxane release and acute pulmonary vasoconstriction in awake sheep. Reversal of LMWH anticoagulation with polybrene does not elicit this adverse reaction.
鱼精蛋白用于逆转患者肝素抗凝作用时，偶尔会引发危及生命的急性肺动脉高压。在一个绵羊模型中，我们评估了改变肝素类型（低分子量肝素与普通肝素相比）和肝素拮抗剂类型（鱼精蛋白与鱼精蛋白相比）对这种不良心肺反应的影响。低分子量肝素（LMWH）用鱼精蛋白逆转以及普通肝素用鱼精蛋白逆转均导致血浆血栓素B2水平升高超过10倍，肺血管阻力和肺动脉压升高3倍，动脉血氧分压（PaO2）降低25%。普通肝素用鱼精蛋白逆转后也出现了类似的不良反应。然而，低分子量肝素（1mg/kg）用鱼精蛋白（1mg/kg）逆转后，我们未检测到肺动脉高压（低分子量肝素用鱼精蛋白逆转后1分钟肺动脉压为22.6±3.6mmHg，而普通肝素用鱼精蛋白逆转后为47.9±4.2mmHg，两组差异p<0.005）、低氧血症（鱼精蛋白后2分钟PaO2无变化，而鱼精蛋白后2分钟降低26mmHg，p<0.05），也未检测到血栓素急性释放到动脉血浆中（鱼精蛋白后1分钟血栓素B2为0.2±0.1，而鱼精蛋白后1分钟为3.7±1.7ng/ml，p<0.005）。用鱼精蛋白（3mg/kg）中和大剂量低分子量肝素（3mg/kg）后，血流动力学效应和介质释放也无不良影响。两种肝素导致的活化凝血时间和活化部分凝血活酶时间延长均被鱼精蛋白完全逆转。低分子量肝素抗凝后4分钟抗Xa活性增加至超过3IU/ml（p<0.01），但仅被鱼精蛋白部分中和。肝素抗凝作用被逆转时形成的各种聚阴离子 - 聚阳离子复合物会在清醒绵羊中诱导血栓素释放和急性肺血管收缩。用鱼精蛋白逆转低分子量肝素抗凝不会引发这种不良反应。
