Iloprost for the Treatment of Severe Septic Shock with Persistent Hypoperfusion: A Double-Blind, Randomized Controlled Trial

Rationale: Preclinical and preliminary clinical data suggest that iloprost may improve tissue perfusion in septic shock. However, its effect on organ failure remains unclear. Objectives: To investigate whether iloprost provides organ protection in septic shock with hypoperfusion. Methods: In this multicenter, double-blind, randomized controlled trial, adults with septic shock and persistent hypoperfusion (i.e., increased capillary refill time and/or skin mottling) were randomized to receive a 48-hour intravenous infusion of iloprost or placebo. The primary outcome was the change in the Sequential Organ Failure Assessment (SOFA) score from randomization to Day 7. Secondary outcomes included mortality at Day 28, organ support-free days by Day 28, and mean daily SOFA score. Measurements and Main Results: A total of 240 patients were randomized, and 236 were included in the analysis. Median (IQR) changes in SOFA score were -4 (-7 to 7) in the iloprost group and -5 (-8 to 5) in the placebo group (median difference, 1; 95% CI, 0-3; P = 0.12). At 28 days, 48 patients (42%) had died in the iloprost group and 47 (39%) had died in the placebo group (relative risk, 1.08; 95% CI, 0.80-1.5). The median average SOFA score was 11.2 (7.4-15.9) in the iloprost group, compared with 10.5 (6.8-16.5) in the placebo group (median difference, 0.25; 95% CI, -1.1 to 1.8). Median (95% confidence interval) between-group differences in 28-day ventilation-, vasopressor-, and renal replacement therapy-free survival days were 0 (0-0), 0 (-1 to 1), and 0 (0-0), respectively. Severe adverse events occurred in 15% of patients in the iloprost group and 7% of patients in the placebo group (P = 0.06). Conclusions: Among patients with septic shock and persistent hypoperfusion, iloprost did not reduce the severity of organ failure. Clinical trial registered with www.clinicaltrials.gov (NCT03788837) and EudraCT (2018-001709-10).