Precision Oxygen Therapy in the Intensive Care Unit: Matching Oxygen Exposure to Patient Phenotypes

Oxygen therapy is one of the most widely used interventions in critical care, yet it remains poorly individualized. Recent trials and meta-analysis suggest no mortality difference between conservative and liberal oxygen strategies, reinforcing the perception that dose does not matter within usual ranges. From this perspective, we argue that this apparent neutrality may largely reflect methodological and conceptual limitations, although true clinical equivalence in some patient populations remains plausible and cannot be excluded based on current evidence. Heterogeneous populations, overlapping oxygenation targets, and the absence of exposure metrics (time in hyperoxia, time in hypoxemia, and cumulative partial pressure of arterial oxygen/peripheral oxygen saturation curves) dilute phenotype-specific signals and force distinct physiological responses into a single pooled estimate. We propose a conceptual model in which oxygen behaves as a dose-dependent, time-dependent drug with phenotype-specific therapeutic windows, particularly in chronic hypercapnia, traumatic brain injury, sepsis, and early versus late acute respiratory distress syndrome. Building on this model, we outline a methodological agenda for precision oxygen trials: defining interventions by actual exposure, pre-specifying pathophysiological subgroups, adopting patient-centered core outcome sets, and using adaptive, target-range designs and individual patient data meta-analyses. For contemporary guidelines and research, the key question is no longer whether conservative or liberal oxygen therapy is superior on average, but how to match the right oxygenation range to the right intensive care unit phenotype at the right time. Moving from population-averaged comparisons to exposure-aware, phenotype-oriented strategies is essential if oxygen therapy is to become a truly precision intervention in critical care.