Efficacy and safety of a 72-h infusion of prostacyclin (1 ng/kg/min) in mechanically ventilated patients with pulmonary infection and endotheliopathy-protocol for the multicenter randomized, placebo-controlled, blinded, investigator-initiated COMBAT-ARF trial.

Abstract

Background: Acute respiratory failure (ARF) is common in critically ill patients, and 50% of patients in intensive care units require mechanical ventilation [3, 4]. The COVID-19 pandemic revealed that COVID-19 infection induced ARF caused by damage to the microvascular pulmonary endothelium. In a randomized clinical trial, mechanically ventilated COVID-19 patients with severe endotheliopathy, as defined by soluble thrombomodulin (sTM) ≥ 4 ng/mL, were randomized to evaluate the effect of a 72-h infusion of low-dose prostacyclin 1 ng/kg/min or placebo. Twenty-eight-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (RR 0.50; CI 0.24 to 0.96 p = .06). The aim of the current trial is to investigate if this beneficial effect and safety of prostacyclin also are present in any patient with suspected pulmonary infection requiring mechanical ventilation and concomitant severe endotheliopathy.

Materials and methods: This is a multi-center, randomized, blinded, clinical investigator-initiated phase 3 trial in mechanically ventilated patients with suspected pulmonary infection and severe endotheliopathy, as defined by sTM ≥4 ng/mL. Patients are randomized 1:1 to a 72-h infusion of low-dose prostacyclin (iloprost) 1 ng/kg/min or placebo (an equal volume of saline). Four-hundred fifty patients will be included. The primary endpoint is 28-day all-cause mortality. Secondary endpoints include 90-day mortality, days alive without vasopressor, mechanical ventilation, and renal replacement therapy in the ICU within 28 and 90 days, and the number of serious adverse reactions or serious adverse events within the first 7 days.

Discussion: This trial will investigate the efficacy and safety of prostacyclin vs. placebo for 72-hours in mechanically ventilated patients with any suspected pulmonary infection and severe endotheliopathy, as defined by sTM ≥4 ng/mL. Trial endpoints focus on the potential effect of prostacyclin to reduce 28-day all-cause mortality.