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To assess the safety and efficacy of the hemoglobin-based nitric oxide scavenger, pyridoxalated hemoglobin polyoxyethylene (PHP), in patients with distributive shock.Phase II multicenter, randomized (1:1), placebo-controlled study.Fifteen intensive care units in North America.Sixty-two patients with distributive shock, ≥2 systemic inflammatory response syndrome criteria, and persistent catecholamine dependence despite adequate fluid resuscitation (pulmonary capillary wedge pressure ≥12).Patients were randomized to PHP at 0.25 mL/kg/hr (20 mg/kg/hr), or an equal volume of placebo, infused for up to 100 hrs, in addition to conventional vasopressor therapy. Because treatment could not be blinded, vasopressors and ventilatory support were weaned by protocol.Sixty-two patients were randomized to PHP (n = 33) or placebo (n = 29). Age, sex, etiology of shock (sepsis in 94%), and Acute Physiology and Chronic Health Evaluation II scores (33.1 ± 8.3 vs. 30 ± 7) were similar in PHP and placebo patients, respectively. Baseline plasma nitrite and nitrate levels were markedly elevated in both groups. PHP infusion increased systemic blood pressure within minutes. Overall 28-day mortality was similar (58% PHP vs. 59% placebo), but PHP survivors were weaned off vasopressors faster (13.7 ± 8.2 vs. 26.3 ± 21.4 hrs; p = .07) and spent less time on mechanical ventilation (10.4 ± 10.2 vs. 17.4 ± 9.9 days; p = .21). The risk ratio (PHP/placebo) for mortality was .79 (95% confidence interval, .39–1.59) when adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II score, and etiology of sepsis. No excess medical interventions were noted with PHP use. PHP survivors left the intensive care unit earlier (13.6 ± 8.6 vs. 17.9 ± 8.2 days; p = .21) and more were discharged by day 28 (57.1 vs. 41.7%).PHP is a hemodynamically active nitric oxide scavenger. The role of PHP in distributive shock remains to be determined.