Predictors of methemoglobin formation in high-dose inhaled nitric oxide therapy: A retrospective cohort study

High-dose inhaled nitric oxide (iNO), defined as doses exceeding 20 parts per million (ppm) and reaching up to 300 ppm, has demonstrated promising antimicrobial properties. However, elevated concentrations of nitric oxide (NO) can increase the formation of methemoglobin (MetHb), which can impair oxygen transport. Understanding factors influencing MetHb formation is essential to guide safe clinical use of iNO therapy.

We conducted a retrospective analysis of 660 high-dose iNO treatments administered to 71 individuals between April 2020 and January 2022 under three prospective protocols at a large academic medical center. The study protocols included healthy volunteers, non-pregnant patients with COVID-19 pneumonia, and pregnant patients with COVID-19 pneumonia. MetHb levels were recorded at baseline and post-treatment using CO-oximeter. Mixed-effects modeling was used to identify predictors of MetHb formation with repeated measures.

iNO concentration was positively associated with MetHb formation, while COVID-19 pneumonia, older age, higher baseline MetHb, and increased respiratory rate were inversely associated. No significant associations were found for sex, race, or hemoglobin concentration. Nitrogen dioxide levels remained within normal ranges, and no systemic hypotension or toxicity were observed. In tachypneic patients with COVID-19 pneumonia, high-dose iNO reduced respiratory rate.

High-dose iNO up to 300 ppm was well tolerated across diverse patient populations. MetHb formation was influenced not only by iNO doses but also by individual physiological factors. These findings support the safety of high-dose iNO and provide a basis for individualized delivery strategies.