Effect of a thromboxane synthetase inhibitor on protamine-induced circulatory changes in sheep

Rapid intravenous administration of protamine after procedures requiring cardiopulmonary bypass is occasionally associated with severe pulmonary hypertension, systemic hypotension, cardiac dysfunction, and lung edema. We hypothesized that the mechanism for these hemodynamic changes after protamine administration is the release of thromboxane. We therefore examined the effect of a thromboxane synthetase inhibitor (OKY-046) on these hemodynamic changes in a sheep model.

Ten female sheep were prepared with lung lymph fistulas and balloon-tipped pulmonary artery, left atrial, arterial, and venous catheters. After a 5-day recovery period, 2 mg/kg protamine was infused 10 minutes after 200 units/kg heparin, with (n = 5; OKY-046 group) and without (n = 5; heparin/protamine group) OKY-046 (10 mg/kg).

In the heparin/protamine group, pulmonary arterial pressure and lung lymphatic flow were significantly increased soon after administration of protamine, from 19 +/- 1 to 51 +/- 2 mm Hg and 5 +/- 1 to 8 +/- 1 ml/hr, respectively. The circulating leukocyte count was significantly reduced, from 3304 +/- 318 to 903 +/- 898 mm3. Cardiac output was also reduced, from 5.8 +/- 0.3 to 3.4 +/- 0.7 L/min/m2. These changes were completely blocked in the OKY-046 group, except for the neutrophil depletion and the increase in lung lymphatic flow.

We conclude that thromboxane plays a significant role in protamine-induced hemodynamic deterioration and pulmonary permeability changes.