Assessment of continuous low-dose and high-dose burst of inhaled nitric oxide in spontaneously breathing COVID-19 patients: A randomized controlled trial

Abstract

Background

Inhaled nitric oxide (iNO) showed to improve oxygenation at low doses by reducing intrapulmonary shunt and to display antiviral properties at high doses. To assess the safety and potential benefits, we designed an exploratory clinical trial comparing low-dose with intermittent high-dose iNO to only intermittent high-dose iNO in hypoxemic COVID-19 patients.

Methods

In this single-center interventional non-inferiority randomized trial (ClinicalTrials.gov, NCT04476992), twenty oxygen-dependent COVID-19 patients were randomly assigned to the high-dose (200 ppm for 30 min) + continuous low-dose (20 ppm) iNO group (iNO_200/20) or the high-dose iNO group (iNO₂₀₀). Methemoglobinemia (MetHb) assessed 48 h after iNO initiation was the primary endpoint. Reverse-transcription polymerase chain reaction for SARS-CoV-2, inflammatory markers during hospitalization, and heart ultrasounds during the iNO₂₀₀ treatments were evaluated.

Results

MetHb difference between iNO groups remained within the non-inferiority limit of 3 %, indicating comparable treatments despite being statistically different (p-value<0.01). Both groups presented similar SpO₂/FiO₂ ratio at 48 h (iNO₂₀₀ vs. iNO_200/20 341[334–356] vs. 359 [331–380], respectively, p-value = 0.436). Both groups showed the same time to SARS-CoV-2 negativization, hospital length of stay, and recovery time. iNO-treated patients showed quicker SARS-CoV-2 negativization compared to a similar group of non-iNO patients (HR 2.57, 95%CI 1.04–6.33). During the 228 treatments, iNO₂₀₀ and iNO_200/20 groups were comparable for safety, hemodynamic stability, and respiratory function improvement.

Conclusions

iNO_200/20 and iNO₂₀₀ are equally safe in non-intubated patients with COVID-19-induced respiratory failure with regards to MetHb and NO₂. Larger studies should investigate whether iNO_200/20 leads to better outcomes compared to non-iNO treated patients.