Oxalated pyridoxalated hemoglobin polyoxyethylene conjugate normalizes the hyperdynamic circulation in septic sheep.

Abstract

Excessive production of nitric oxide significantly contributes to the hyperdynamic state associated with sepsis. The ability of hemoglobin to scavenge nitric oxide may therefore be beneficial in the treatment of sepsis. In this study, we determined the effects of different doses of the modified human pyridoxalated hemoglobin polyoxyethylene conjugate in an ovine model of hyperdynamic sepsis. Prospective, experimental study. Large animal research laboratory at a university medical center. Sheep (n = 23) were surgically prepared for chronic study. After a 5-day recovery period, all animals received a continuous infusion of live Pseudomonas aeruginosa (2.5 x 10(6) colony-forming units/min) for the next 48 hrs. After 24 hrs of sepsis, the animals were divided into four groups: a) six sheep were used as controls and received a bolus of 200-mL vehicle; b) three sheep received a bolus of 50 mg/kg hemoglobin; c) six sheep received 100 mg/kg of hemoglobin; d) six sheep received 200 mg/kg of hemoglobin. All animals that survived the first 24 hrs of sepsis (n = 21) developed a hyperdynamic circulation. All three doses of hemoglobin reversed this hyperdynamic state by increasing mean arterial pressure and systemic vascular resistance while decreasing cardiac index. Pulmonary arterial pressure increased after hemoglobin infusion. Increased pulmonary arterial pressure did not affect arterial oxygen saturation nor result in the development of pulmonary edema. Infusion of hemoglobin also caused a 30-fold increase in endothelin-1 plasma concentrations and significantly decreased nitrate and nitrite plasma concentrations. The infusion of low doses of pyridoxalated hemoglobin polyoxyethylene conjugate in septic sheep reverses the hyperdynamic circulatory state. An increase in pulmonary arterial pressure was the only observed hemodynamic side effect; changes in the structure or function of other organ systems, or their biochemical correlates were not investigated in this study. In addition to a possible nitric oxide scavenging effect, pyridoxalated hemoglobin polyoxyethylene may affect the nitric oxide synthase and endothelin systems.