High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure due to COVID-19: A Multicenter Phase 2 Trial

Rationale and Objectives: The effects of high-dose inhaled nitric oxide on hypoxemia in COVID-19 acute respiratory failure are unknown. Methods: Mechanically ventilated adults with COVID-19 pneumonia were enrolled in a phase II, multicenter, single-blind, randomized, controlled, parallel-arm trial. Participants in the intervention arm received inhaled nitric oxide at 80 parts-per-million (ppm) for 48h, compared with the control group receiving usual care (without placebo). The primary outcome was the change in arterial oxy-genation (PaO2/FiO2) at 48h. The secondary outcomes included: time to reach a PaO2/FiO2>300 mmHg for at least 24h, the proportion of participants with a PaO2/FiO2>300 mmHg at 28 days, and survival at 28- and 90-days. Measurements and Main Results: 193 participants were included in the modified intention-to-treat analysis. The mean change in PaO2/FiO2 ratio at 48h was 28.3 mmHg in the intervention group and -1.4 mmHg in the control group (mean difference: 39.1 mmHg (95%CrI:18.1-60.3). The mean time to reach a PaO2/FiO2>300 mmHg in the interventional group was 8.7 days com-pared to 8.4 days for the control group (mean difference:0.44(95%CrI:-3.63 to 4.53)). At 28 days, the proportion of participants attaining a PaO2/FiO2>300 mmHg was 27.7% in the inhaled nitric oxide group and 17.2% in the controls (RR:2.03(95%CrI:1.11 to 3.86)). Duration of ventilation and mortality at 28 and 90 days did not differ. No serious adverse events were reported. Conclusions: The use of high-dose inhaled nitric oxide resulted in an improvement of PaO2/FiO2 at 48h compared with usual care in adults with acute hypoxemic respiratory failure due to COVID-19. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical trial registration available at www.clinicaltrials.gov, ID: NCT04306393