Beneficial Effect of Cyclooxygenase Inhibition on Adverse Hemodynamic Responses after Protamine

Abstract

The hypothesis that adverse effects observed when heparin is antagonized by protamine are mediated by metabolites of the arachidonic acid cascade was tested during general anesthesia (enflurane, fentanyl) in 16 pigs classified into two groups. In the first group (n = 9), effects of intravenously administered protamine on systemic hemodynamics, blood/gas tensions, and arterial and mixed-venous prostanoid levels were studied. The second group (n = 7) was pretreated with indomethacin 10 mg/kg, and the same measurements were made. All pigs received heparin 150 units/kg. When protamine 1.1 +/- 0.1 mg/kg was administered over 3 minutes, marked hemodynamic alterations were observed in group 1: pulmonary artery pressure and pulmonary vascular resistance increased, and left ventricular end-diastolic and systemic arterial pressures decreased. Arterial and mixed-venous PO2 values deteriorated in all pigs in group 1 at the end of protamine infusion. These alterations were accompanied by significantly elevated prostanoid levels in arterial and mixed-venous plasma samples: Thromboxane A2, prostaglandin F2 alpha, KH2-PGF2 alpha (a metabolite of prostaglandin F2 alpha), and prostacyclin were maximally elevated at completion of protamine and remained significantly above control values at 5 minutes but were not significantly different from control after 10 minutes. Blocking the cyclooxygenase cascade by pretreatment of the pigs with indomethacin (group 2) prevented hemodynamic and blood gas alterations. It is concluded that in pigs the detrimental side effects associated with the use of protamine to reverse heparin are mediated by metabolites of the cyclooxygenase cascade.(ABSTRACT TRUNCATED AT 250 WORDS)