Individualized Treatment Effects of Oxygen Targets in Mechanically Ventilated Critically Ill Adults

Importance Among critically ill adults, randomized trials have not found oxygenation targets to affect outcomes overall. Whether the effects of oxygenation targets differ based on an individual’s characteristics is unknown. Objective To determine whether an individual’s characteristics modify the effect of lower vs higher peripheral oxygenation-saturation (Sp o 2 ) targets on mortality. Design, Setting, and Participants A machine learning model to predict the effect of treatment with a lower vs higher Sp o 2 target on mortality for individual patients was derived in the Pragmatic Investigation of Optimal Oxygen Targets (PILOT) trial and externally validated in the Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX) trial. Critically ill adults received invasive mechanical ventilation in an intensive care unit (ICU) in the United States between July 2018 and August 2021 for PILOT (n = 1682) and in 21 ICUs in Australia and New Zealand between September 2015 and May 2018 for ICU-ROX (n = 965). Exposures Randomization to a lower vs higher Sp o 2 target group. Main Outcome and Measure 28-Day mortality. Results In the ICU-ROX validation cohort, the predicted effect of treatment with a lower vs higher Sp o 2 target for individual patients ranged from a 27.2% absolute reduction to a 34.4% absolute increase in 28-day mortality. For example, patients predicted to benefit from a lower Sp o 2 target had a higher prevalence of acute brain injury, whereas patients predicted to benefit from a higher Sp o 2 target had a higher prevalence of sepsis and abnormally elevated vital signs. Patients predicted to benefit from a lower Sp o 2 target experienced lower mortality when randomized to the lower Sp o 2 group, whereas patients predicted to benefit from a higher Sp o 2 target experienced lower mortality when randomized to the higher Sp o 2 group (likelihood ratio test for effect modification P = .02). The use of a Sp o 2 target predicted to be best for each patient, instead of the randomized Sp o 2 target, would have reduced the absolute overall mortality by 6.4% (95% CI, 1.9%-10.9%). Conclusion and relevance Oxygenation targets that are individualized using machine learning analyses of randomized trials may reduce mortality for critically ill adults. A prospective trial evaluating the use of individualized oxygenation targets is needed.