Multicenter, randomized, placebo-controlled phase III study of pyridoxalated hemoglobin polyoxyethylene in...

To compare the effectiveness and safety of the hemoglobin-based nitric oxide scavenger, pyridoxalated hemoglobin polyoxyethylene, against placebo in patients with vasopressor-dependent distributive shock.

Multicenter, randomized, placebo-controlled, open-label study.

Sixty-one participating ICUs in six European countries (Austria, Belgium, Germany, the Netherlands, Spain, and United Kingdom).

All patients admitted with distributive shock, defined as the presence of at least two systemic inflammatory response syndrome criteria, persisting norepinephrine dependence and evidence of organ dysfunction/hypoperfusion despite adequate fluid resuscitation.

Patients were randomized to receive 0.25 mL/kg/hr pyridoxalated hemoglobin polyoxyethylene (20 mg Hb/kg/hr) or an equal volume of placebo, infused for up to 150 hours, in addition to conventional vasopressor therapy.

The study was stopped after interim analysis showed higher mortality in the pyridoxalated hemoglobin polyoxyethylene group and an increased prevalence of adverse events. At this time, 377 patients had been randomized to pyridoxalated hemoglobin polyoxyethylene (n = 183) or placebo (n = 194). Age, gender, type of patient (medical/surgical), and Acute Physiology and Chronic Health Evaluation II scores were similar between groups. Twenty-eight-day mortality rate was 44.3% in the pyridoxalated hemoglobin polyoxyethylene group versus 37.6% in the placebo group (OR, 1.29; 95% CI, 0.85-1.95; p = 0.227). In patients with higher organ dysfunction scores (Sepsis-related Organ Failure Assessment > 13), mortality rates were significantly higher in the pyridoxalated hemoglobin polyoxyethylene group when compared with those in placebo-treated patients (60.9% vs 39.2%; p = 0.014). Survivors who received pyridoxalated hemoglobin polyoxyethylene had a longer vasopressor-free time (21.3 vs 19.7 d; p = 0.035).

In this randomized, controlled phase III trial in patients with vasopressor-dependent distributive shock, administration of a pyridoxalated hemoglobin solution decreased the need for vasopressors but was associated with a trend to increased mortality.