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

Critical Care volume 29, Article number: 50 (2025) 

Published: 28 January 2025

Abstract

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.

 

Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia

Intensive Care Medicine (2022) Published: 20 April 2022

Purpose

We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia.

Methods

Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients.

Results

We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93–1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50–80) in the lower oxygenation group versus 67 (50–80) in the higher oxygenation group (p = 0.98). None of the five EQ-5D-5L dimensions differed between groups.

Conclusion

Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa).

 

 

Dangers of hyperoxia

 

by Mervyn Singer, Paul J. Young, John G. Laffey, Pierre Asfar, Fabio Silvio Taccone, Markus B. Skrifvars, Christian S. Meyhoff and Peter Radermacher 

 

Critical Care volume 25, Article number: 440 (2021) Published: 19 December 2021

Oxygen (O2) toxicity remains a concern, particularly to the lung. This is mainly related to excessive production of reactive oxygen species (ROS). Supplemental O2, i.e. inspiratory O2 concentrations (FIO2) > 0.21 may cause hyperoxaemia (i.e. arterial (a) PO2 > 100 mmHg) and, subsequently, hyperoxia (increased tissue O2 concentration), thereby enhancing ROS formation. Here, we review the pathophysiology of O2 toxicity and the potential harms of supplemental O2 in various ICU conditions. The current evidence base suggests that PaO2 > 300 mmHg (40 kPa) should be avoided, but it remains uncertain whether there is an “optimal level” which may vary for given clinical conditions. Since even moderately supra-physiological PaO2 may be associated with deleterious side effects, it seems advisable at present to titrate O2 to maintain PaO2 within the normal range, avoiding both hypoxaemia and excess hyperoxaemia.