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Clinical Trial
. 2023 Dec 15;208(12):1293-1304.
doi: 10.1164/rccm.202304-0637OC.

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

Raffaele Di Fenza  1   2 , Naman S Shetty  3 , Stefano Gianni  1   2 , Vibhu Parcha  3 , Valentina Giammatteo  1   2 , Bijan Safaee Fakhr  1   2 , Daniel Tornberg  4   5 , Olof Wall  4   6 , Piotr Harbut  4   5 , Peggy S Lai  7   2 , Jonathan Z Li  2   8 , Sabrina Paganoni  9   10   2 , Stefano Cenci  1   2 , Ariel L Mueller  1   11   2 , Timothy T Houle  1   11   2 , Oluwaseun Akeju  1   2 , Edward A Bittner  1   2 , Somnath Bose  2   12 , Louie K Scott  13 , Ryan W Carroll  14   2 , Fumito Ichinose  1   15   2 , Magnus Hedenstierna  16 , Pankaj Arora  3 , Lorenzo Berra  1   15   17   2 ; Nitric Oxide Investigators
Collaborators, Affiliations
Clinical Trial

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

Raffaele Di Fenza et al. Am J Respir Crit Care Med. .

Abstract

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 (PaO2/FiO2) at 48 hours. The secondary outcomes included: time to reach a PaO2/FiO2.300mmHg for at least 24 hours, the proportion of participants with a PaO2/FiO2.300mmHg 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 PaO2/FiO2 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 PaO2/FiO2.300mmHg 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 PaO2/FiO2.300mmHg 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 PaO2/FiO2 at 48 hours compared with usual care in adults with acute hypoxemic respiratory failure due to COVID-19.

Keywords: COVID-19; critical illness; nitric oxide; pneumonia; respiration, artificial; viremia.

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Figures

Figure 1.
Figure 1.
Consolidated Standards of Reporting Trials (CONSORT) diagram. COVID-19 = coronavirus disease.
Figure 2.
Figure 2.
Systemic oxygenation at baseline, 24 hours, and 48 hours. This figure depicts the mean change in the PaO2/FiO2 ratio from baseline to 24 and 48 hours from the time of randomization. The treatment group (n = 94) and the control group (n = 99) have been depicted in red and blue, respectively. The data are represented as mean (point) and SEM (error bars).
Figure 3.
Figure 3.
Posterior probability curves for the association of study outcomes with inhaled nitric oxide therapy.
Figure 4.
Figure 4.
Blood and sputum viral count. (A and B) Predicted log10 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load by PCR over time in blood (A) and sputum (B). (A) Treatment group (n = 17 patients; 68 samples) in red, and control group (n = 20 patients; 77 samples) in blue. (B) Treatment group (n = 17 patients; 38 samples) in red, and control group (n = 20 patients; 44 samples) in blue.
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References

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