This study provides novel insights into the use of inhaled nitric oxide in severe ARDS COVID-19 patients. Specifically, we demonstrate that the iNO effect of oxygenation improvement is delayed with a prolonged feature that lasts up to 96h.

Furthermore, we identify a gender-based variation in therapeutic response, with women responding slower than men. We suggest that a lack of immediate improvement within minutes to a few hours after iNO initiation should not be seen as treatment failure and iNO initiation should be considered to continue, as benefits may emerge over several hours or days.

Considering the growing evidence supporting iNO as a rescue therapy for patients with severe ARDS in general and COVID-19 in particular, it may be worthwhile to re-examine the current ARDS and Surviving Sepsis Campaign COVID-19 guidelines that currently recommend against its use.

In addition, we call for future investigations to explore the underlying mechanisms of these delayed and gender-specific responses, with the goal of developing a more tailored therapeutic approach.

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