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Thromboxane Mediation of Pulmonary Hemodynamic Responses after Neutralization of Heparin by Protamine in Pigs

Received from the Institute of Surgical Research and Institute of Anesthesiology, Ludwig-Maximilians-University, Munich, Bavaria, West Germany.

Abstract

Protamine neutralization of heparin is often associated with severe hemodynamic side-effects, including pulmonary hypertension and systemic hypotension. Because prostanoids may be involved, the authors studied the role of arachidonic acid metabolites, especially thromboxane A₂, in this process. During anesthesia with enflurane and fentanyl, four groups of pigs were studied: Group 1 (n = 10) received heparin (250 IU/kg), followed by protamine (100 mg) after 15 minutes to neutralize the heparin. The same protocol was used in group 2 (n = 11), except that the thromboxane A₂ receptor antagonist BM 13.177 (10 mg/kg) was infused 5 minutes before the protamine. The protocol for group 1 was also used for group 3 (n = 7) except that these animals were pretreated with indomethacin (10 mg/kg). Animals in group 4 (n = 10) were given protamine only (100 mg). Pulmonary artery pressure and pulmonary vascular resistance increased significantly in group 1 after protamine neutralization of heparin. This was accompanied by significant increases in plasma concentrations of the cyclooxygen-ase products thromboxane B₂, 6-keto-prostaglandin F₁, and prostaglandin F₂. Cyclooxygenase products increased to comparable degrees in group 2, but without hemodynamic effects. Leukocyte counts decreased comparably in both groups. Hemodynamic reactions, as well as changes in plasma prostanoid levels were absent in group 3, and group 4, but leukocyte counts were less affected in animals that received protamine alone. The results indicate that the hemodynamic side-effects of protamine are mediated by prostanoids and that thromboxane A₂ release is the pivotal step, because side effects were effectively prevented by pretreatment with a thromboxane receptor antagonist. Leukocyte or platelet counts were not directly related to the severity of hemodynamic alterations.

Key Words: BLOOD, COAGULATION—protamine, heparin • HORMONES—prostaglandins, thromboxane

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