Heterogeneity of treatment effect: the case for individualising oxygen therapy in critically ill patients

Oxygen therapy is ubiquitous in critical illness but oxygenation targets to guide therapy remain controversial despite several large randomised controlled trials (RCTs). Findings from RCTs evaluating different approaches to oxygen therapy in critical illness present a confused picture for several reasons. Differences in both oxygen target measures (e.g. oxygen saturation or partial pressure) and the numerical thresholds used to define lower and higher targets complicate comparisons between trials. The duration of and adherence to oxygenation targets is also variable with consequent substantial variation in both the dose and the dose separation. Finally, heterogeneity of treatment effects (HTE) may also be a significant factor. HTE is defined as non-random variation in the benefit or harm of a treatment, in which the variation is associated with or attributable to patient characteristics. This narrative review aims to make the case that such heterogeneity is likely in relation to oxygen therapy for critically ill patients and that this has significant implications for the design and interpretation of trials of oxygen therapy in this context. HTE for oxygen therapy amongst critically ill patients may explain the contrasting results from different clinical trials of oxygen therapy. Individualised oxygen therapy may overcome this challenge, and future studies should incorporate ways to evaluate this approach.