More questions than answers for the use of inhaled nitric oxide in COVID-19.

Inhaled nitric oxide (iNO) is a potent vasodilator approved for use in term and near-term neonates, but with broad off-label use in settings including acute respiratory distress syndrome (ARDS). As an inhaled therapy, iNO reaches well ventilated portions of the lung and selectively vasodilates the pulmonary vascular bed, with little systemic effect due to its rapid inactivation in the bloodstream. iNO is well documented to improve oxygenation in a variety of pathological conditions, but in ARDS, these transient improvements in oxygenation have not translated into meaningful clinical outcomes. In coronavirus disease 2019 (COVID-19) related ARDS, iNO has been proposed as a potential treatment due to a variety of mechanisms, including its vasodilatory effect, antiviral properties, as well as anti-thrombotic and anti-inflammatory actions. Presently however, no randomized controlled data are available evaluating iNO in COVID-19, and published data are largely derived from retrospective and cohort studies. It is therefore important to interpret these limited findings with caution, as many questions remain around factors such as patient selection, optimal dosing, timing of administration, duration of administration, and delivery method. Each of these factors may influence whether iNO is indeed an efficacious therapy - or not - in this context. As such, until randomized controlled trial data are available, use of iNO in the treatment of patients with COVID-19 related ARDS should be considered on an individual basis with sound clinical judgement from the attending physician.

Real-world use of inhaled nitric oxide therapy in patients with COVID-19 and mild-to-moderate acute respiratory distress syndrome.

Background: Inhaled nitric oxide (iNO) has been studied in patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 when it may be too late to impact disease course. This article aims to describe real-world iNO use and outcomes in patients with COVID-19 with mild-to-moderate ARDS in the United States. Methods: This was a retrospective medical chart review study that included patients who were ≥18 years old, hospitalized for COVID-19, met the Berlin ARDS definition, received iNO for ≥24 hours continuously during hospitalization, and had a partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F ratio) of >100 to ≤300 mmHg at iNO initiation. Outcomes included oxygenation parameters, physician-rated Clinical Global Impression-Improvement (CGI-I) scale scores, and adverse events. Response to iNO was defined as >20% improvement in P/F ratio. Results: Thirty-seven patients at six sites were included. A P/F ratio of ≤100 was the most common reason for exclusion (n=146; 83% of excluded patients). The mean P/F ratio (SD) increased from 136.7 (34.4) at baseline to 140.3 (53.2) at 48 hours and 151.8 (50.0) at 72 hours after iNO initiation. The response rate was 62% (n=23). During hospitalization, no patient experienced adverse events, including methemoglobinaemia, airway injury, or worsening pulmonary oedema associated with iNO. At discharge, 54.0% (n=20) of patients improved or remained stable according to the CGI-I. Conclusion: In patients hospitalized with COVID-19 and mild-to-moderate ARDS, iNO was associated with improvement in the P/F ratio with no reported toxicity. This study provides additional evidence supporting a favourable benefit-risk profile for iNO in the treatment of mild-to-moderate ARDS in patients with COVID-19 infection.