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

Abstract

<b>Rationale:</b> The effects of high-dose inhaled nitric oxide on hypoxemia in coronavirus disease (COVID-19) acute respiratory failure are unknown. <b>Objectives:</b> The primary outcome was the change in arterial oxygenation (Pa_O₂/Fi_O₂) at 48 hours. The secondary outcomes included: time to reach a Pa_O₂/Fi_O₂.300mmHg for at least 24 hours, the proportion of participants with a Pa_O₂/Fi_O₂.300mmHg at 28 days, and survival at 28 and at 90 days. <b>Methods:</b> 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 ppm for 48 hours, compared with the control group receiving usual care (without placebo). <b>Measurements and Main Results:</b> A total of 193 participants were included in the modified intention-to-treat analysis. The mean change in Pa_O₂/Fi_O₂ ratio at 48 hours was 28.3mmHg in the intervention group and 21.4mmHg in the control group (mean difference, 39.1mmHg; 95% credible interval [CrI], 18.1 to 60.3). The mean time to reach a Pa_O₂/Fi_O₂.300mmHg in the interventional group was 8.7 days, compared with 8.4 days for the control group (mean difference, 0.44; 95% CrI, 23.63 to 4.53). At 28 days, the proportion of participants attaining a Pa_O₂/Fi_O₂.300mmHg was 27.7% in the inhaled nitric oxide group and 17.2% in the control subjects (risk ratio, 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. <b>Conclusions:</b> The use of high-dose inhaled nitric oxide resulted in an improvement of Pa_O₂/Fi_O₂ at 48 hours compared with usual care in adults with acute hypoxemic respiratory failure due to COVID-19.