Breaking the Oxygen Dogma: How High FiO2 May Disrupt Pulmonary Physiology in COVID-19

Background: High concentrations of supplemental oxygen (FiO2 > 0.6) are commonly used to treat acute hypoxemia in critically ill patients. However, the effects of High FiO2 in patients with COVID-19 remain unclear, particularly regarding its impact on hypoxic pulmonary vasoconstriction (HPV) and ventilation–perfusion (V/Q) mismatch. Objective: This study aims to evaluate whether administering lower concentrations of inspired oxygen (FiO2 < 0.6) is associated with improved outcomes—namely reduced need for mechanical ventilation and mortality—in patients with COVID-19 and severe pulmonary involvement. Methods: This retrospective observational cohort included 201 patients with confirmed COVID-19. Patients were grouped by mean FiO2 during the first 24–48 h: High FiO2 (≥0.60) or Low FiO2 (<0.60). The primary outcome was the requirement for mechanical ventilation; the secondary outcome was in-hospital mortality. A composite endpoint (mechanical ventilation and in-hospital death) was also evaluated. Analyses included logistic regression and Kaplan–Meier survival with log-rank testing. Results: High FiO2 (≥0.60) was associated with higher odds of the composite outcome (mechanical ventilation and in-hospital death). In multivariable analysis, Low FiO2 remained associated with lower odds (adjusted OR 0.18; 95% CI 0.08–0.39; p < 0.001). Unadjusted rates were 43.1% vs. 16.1% for mechanical ventilation and 34.3% vs. 8.1% for in-hospital death (High vs. Low FiO2; both p < 0.001). Event-free survival favored the Low FiO2 group (log-rank p < 0.001). The model showed excellent discrimination (AUC 0.96; 95% CI 0.92–0.99). Conclusions: Higher early FiO2 exposure was associated with worse clinical outcomes in severe COVID-19. These findings are consistent with physiological models in which excess oxygen may attenuate hypoxic pulmonary vasoconstriction and increase shunt/dead space. Prospective studies are warranted to assess causality and refine oxygen targets.