Mechanism of hypotension following rapid infusion of protamine sulfate in anesthetized dogs

Abstract

Protamine sulfate (PS), used to neutralize the anticoagulant effect of heparin, is often associated with systemic hypotension. Whether this hypotension is secondary to a depression of myocardial function is not clear. The present study tested the hypothesis that systemic hypotension was accompanied by a depression in myocardial function and examined the possible role of histamine in mediating the cardiovascular response to PS. Seven conditioned dogs were chronically instrumented with pressure and ultrasonic dimension transducers. Studies were conducted under halothane anesthesia 7 to 10 days after instrumentation. Cardiac contractility was assessed using the slope, E es, of the linear regression of the left ventricular end-systolic pressure-diameter relationship. Intravenous infusion of PS, 5 mg/kg, when given in periods of less than 30 seconds, decreased systemic arterial pressure by 45% (from 101 ± to 54 +- 5 mm Hg) without change in heart rate. Cardiac output decreased by 22% from control and the slope E es decreased by 37% (from 14.5 ± 1.2 to 8.7 ± 1.4 mm Hg/mm). Systemic vascular resistance decreased by 34% (from 2581 ± 121 to 1712 ± 200 dyne·s·cm −5). The cardiovascular depression caused by PS was transient and could not be reproduced by a repeated dose given within a 60-minute period. Antagonists of histamine (diphenhydramine and cimetidine) could not attenuate the PS-induced cardiovascular depression. This depression was independent of preheparinization and did not occur when PS was infused slowly over a 2-minute period. The data clearly demonstrate negative inotropic and vasodilator effects of PS following rapid administration. These findings suggest that PS should be administered slowly to minimize or to avoid its hypotensive effect, particularly when myocardial function is impaired.