OBJECTIVE: To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostaglandin E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome (ARDS). DESIGN: Randomized, prospective, multicenter, double-blind, placebo-controlled, phase III clinical trial. SETTING: Forty-seven community and university-affiliated hospitals in the United States. PATIENTS: A total of 350 patients with ARDS were enrolled in this clinical trial. INTERVENTION: Patients were prospectively randomized in a 1:1 ratio to receive either liposomal prostaglandin E1 or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 microg/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 microg/kg/hr) was attained or intolerance to further increases developed. Patients received standard aggressive medical/surgical care during the infusion period. OUTCOME MEASURES: The primary outcome measure was the time it took to wean the patient from the ventilator. Secondary end points included time to improvement of the PaO2/FIO2 ratio (defined as first PaO2/FIO2 > 300 mm Hg), day 28 mortality, ventilator dependence at day 8, changes in PaO2/FIO2, incidence of and time to development/resolution of organ failure other than ARDS. RESULTS: A total of 348 patients could be evaluated for efficacy. The distribution of variables at baseline describing gender, lung injury scores, Acute Physiology and Chronic Health Evaluation II scores, PaO2/FIO2, pulmonary compliance, and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostaglandin E1 (n = 177) and the placebo (n = 171) treatment arms. There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostaglandin E1 group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E1 and 19.6 in those administered placebo; p = .94). Similarly, mortality at day 28 was not significantly different in the two groups (day 28 mortality, 57 of 176 (32%) in the liposomal prostaglandin E1 group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E1 was associated with a significantly shorter time to reach a PaO2/FIO2 ratio of >300 mm Hg (median number of days to reaching a PaO2/FIO2 ratio >300 mm Hg: 9.8 days in the liposomal prostaglandin E1 group and 13.7 days in patients receiving the placebo; p = .02). Among the subgroups examined, time to off mechanical ventilation was significantly reduced in patients who received at least 85% of a full dose (i.e., > 45.9 microg/kg) of liposomal prostaglandin E1 (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E1 group and 16.3 days in patients receiving placebo; p = .05). The overall incidence of serious adverse events was not significantly different in the liposomal prostaglandin E1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E1 compared with 33% of the placebo group, with hypotension and hypoxia (occurring in 52% and 24% of the liposomal prostaglandin E1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, respectively) being noted most frequently. CONCLUSIONS: In the intent-to-treat population of patients with ARDS, treatment with liposomal prostaglandin E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival.

Hydrogen peroxide (H2O2) levels are increased in the exhaled breath of patients with the acute respiratory distress syndrome (ARDS). Because liposome-encapsulated prostaglandin E1 (PGE1) downregulates the CD11/CD18 receptor of the neutrophil, thereby limiting endothelial adhesion, the use of this drug should decrease the excretion of H2O2 in the expiratory condensate of patients with ARDS. Patients > 11 yr of age with ARDS (diffuse, patchy infiltrates by chest radiograph; Pao2/fraction of inspired oxygen [P/F] ratio < or = 200 mm Hg; pulmonary capillary wedge pressure < or = 18 mm Hg; and the requirement for mechanical ventilation) were randomized to receive placebo (n = 14) or escalating doses (0.15-3.6 micrograms/kg) of liposomal PGE1 (n = 14) every 6 h for up to 7 days. Condensate was collected every morning from the expiratory tubing that was submerged in an ice saltwater bath (-5 degrees C). H2O2 levels were measured by using a horseradish peroxidase assay. Other data collected included white blood cell count and P/F ratios. There was no significant difference in the concentration of H2O2 in the expiratory condensate between the liposomal PGE1 group and the control group either before (0.99 +/- 0.52 vs 0.93 +/- 0.48 mumol/L) or during treatment (1.04 +/- 0.45 vs 0.76 +/- 0.25 mumol/L). Liposomal PGE1 treatment improved the P/F ratio and decreased the white blood cell count over time. Despite its ability to downregulate the CD11/CD18 neutrophil receptor, liposomal PGE1 did not reduce exhaled H2O2 excretion. Implications: White blood cells (WBC) are thought to be part of the cause of the acute respiratory distress syndrome, a lung disease. WBC in the lung produce hydrogen peroxide, which is exhaled. Liposomal PGE1 inhibits WBC function but was found to have no effect in decreasing exhaled hydrogen peroxide in patients with the acute respiratory distress syndrome.