High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure Due to COVID-19: A Multicenter Phase II Trial
Raffaele Di Fenza, Naman S Shetty, Stefano Gianni, Vibhu Parcha, Valentina Giammatteo, Bijan Safaee Fakhr, Daniel Tornberg, Olof Wall, Piotr Harbut, Peggy S Lai, Jonathan Z Li, Sabrina Paganoni, Stefano Cenci, Ariel L Mueller, Timothy T Houle, Oluwaseun Akeju, Edward A Bittner, Somnath Bose, Louie K Scott, Ryan W Carroll, Fumito Ichinose, Magnus Hedenstierna, Pankaj Arora, M.D Lorenzo Berra, Caio C Araujo Morais, Lauren E Gibson, Takamitsu Ikeda, Eizo Marutani, Yusuke Miyazaki, Anna Fischbach, Lisa Traeger, Martin I Capriles, Eduardo Diaz Delgado, Grant M Larson, Roberta Ribeiro De Santis Santiago, Carolyn La Vita, Binglan Yu, Maurizio F Cereda, Nattaly Greene, Paula Restrepo, James P Flynn, James Regan, Riccardo Pinciroli, Elizabeth I Caskey, Kimberley Hutchinson, N Stuart Harris, Josanna Rodriguez-Lopez, Marvin G Chang, Jacob Wideaus, Matilda Widaeus, Kambiz Shahgaldi, Karl Hagman, Garima Arora, Robert Johnson
American Journal of Respiratory and Critical Care Medicine, doi:10.1164/rccm.202304-0637oc
Rationale: The effects of high-dose inhaled nitric oxide on hypoxemia in coronavirus disease (COVID-19) acute respiratory failure are unknown. Objectives: The primary outcome was the change in arterial oxygenation (Pa O 2 /FI O 2 ) at 48 hours. The secondary outcomes included: time to reach a Pa O 2 /FI O 2 .300mmHg for at least 24 hours, the proportion of participants with a Pa O 2 /FI O 2 .300mmHg at 28 days, and survival at 28 and at 90 days. 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 ppm for 48 hours, compared with the control group receiving usual care (without placebo).
Measurements and Main Results: A total of 193 participants were included in the modified intention-to-treat analysis. The mean change in Pa O 2 /FI O 2 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 O 2 /FI O 2 .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 O 2 /FI O 2 .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. Conclusions: The use of high-dose inhaled nitric oxide resulted in an improvement of Pa O 2 /FI O 2 at 48 hours compared with usual care in adults with acute hypoxemic respiratory failure due to COVID-19.
Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgment: The authors thank the participants, site staff, site investigators, and the entire Nitric Oxide Study Team. This work is dedicated to the recently deceased Prof. Warren M.
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