BACKGROUND: Inhaled epoprostenol (iEpo) may improve oxygenation in adults with hypoxic respiratory failure, but any effect in children with pediatric acute respiratory distress syndrome (pARDS) is unknown. METHODS: Retrospective observational cohort study 2017-2022 at a single pediatric intensive care unit (PICU) of children who met criteria for pARDS and received iEpo for ≥ 6 h. RESULTS: 18 children were included, with a median age of 2.9 years (IQR 1.4-7.9), severe pARDS in 14/18 (78%), and pulmonary hypertension in 8/18 (44%). Median OSI immediately pre-iEpo initiation was 22.9 (IQR 16.1-27.3), at 6 h was 16.8 (IQR 12.6-27.5, p = 0.57 vs. pre-initiation) and at 12 h was 15.1 (IQR 10.7-27.5, p = 0.48 vs. pre-initiation). Discontinuity regression demonstrated a change in the slope (rate of change) of OSI from increasing slope of +0.60/hr to decreasing slope of -1.38/hour in the 12 h pre- versus post- iEpo initiation (p <
0.001). At 6 h after iEpo initiation, most patients (12/18, 67%) had a decrease in OSI and 5/18 (28%) were responders with a decrease of ≥ 20%. Responders did not differ significantly by presence of pulmonary hypertension, severity of pARDS, or age. The majority of responders (4/5, 80%) had improvement in OSI by 1 h after initiation of iEpo and all (5/5, 100%) had improvement by 4 h after iEpo initiation. CONCLUSION: Rate of change of OSI improved significantly after initiation of iEpo in a cohort children with pARDS, with heterogeneity of response that was not associated with pHTN or other clinical factors evaluated. Improvement in OSI was seen by 4 h in all responders.