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Introduction: Distributive shock is associated with a hyperdynamic hypotensive state in response to acute inflammation, and most commonly occurs in patients with sepsis. Nitric oxide is a key mediator in the development of distributive shock. Hypothesis: That the hemoglobin-based nitric oxide scavenger, pyridoxalated hemoglobin polyoxyethylene, would reduce mortality compared to placebo in patients with catecholamine-resistant distributive shock. Methods: In this phase 3, multicenter, randomized, placebo-controlled study, all patients with distributive shock, as assessed by the presence of at least two systemic inflammatory response syndrome (SIRS) criteria, and persistent catecholamine dependence despite adequate fluid resuscitation, who were admitted to one of 61 participating intensive care units were included. Patients were randomized to receive 0.25 mL/kg/h (20 mg/kg/h) pyridoxalated hemoglobin polyoxyethylene or an equal volume of placebo, infused for up to 150 h, in addition to conventional vasopressor therapy. Because treatment could not be blinded, vasopressors and ventilatory support were weaned by protocol. Results: Three-hundred and seventy-seven patients were randomized to pyridoxalated hemoglobin polyoxyethylene (n=183) or placebo (n=194). Age, gender, type of patient (medical or surgical), and APACHE II scores were similar in pyridoxalated hemoglobin polyoxyethylene and placebo patients. Baseline plasma nitrite and nitrate levels were elevated in both groups. Pyridoxalated hemoglobin polyoxyethylene infusion was associated with a rapid increase in systemic blood pressure. Twenty-eight day mortality was 44.3% in the pyridoxalated hemoglobin polyoxyethylene group versus 37.6% in the placebo group, p=0.227. Survivors who had received pyridoxalated hemoglobin polyoxyethylene had a longer vasopressor-free time (21.3 vs 19.7, p=0.035) than did survivors treated with placebo. Conclusions: In this phase III prospective, randomized, controlled trial, the administration of a pyridoxalated hemoglobin solution in patients with septic shock was not beneficial.