Lower versus higher oxygenation targets in critically ill patients with severe hypoxaemia: secondary Bayesian analysis to explore heterogeneous treatment effects in the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial

Abstract

Background: In the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial, a lower (8 kPa) vs a higher (12 kPa) PaO2 target did not affect mortality amongst critically ill adult patients. We used Bayesian statistics to evaluate any heterogeneity in the effect of oxygenation targets on mortality between different patient groups within the HOT-ICU trial.

Methods: We analysed 90-day all-cause mortality using adjusted Bayesian logistic regression models, and assessed heterogeneous treatment effects according to four selected baseline variables using both hierarchical models of subgroups and models with interactions on the continuous scales. Results are presented as mortality probability (%) and relative risk (RR) with 95% credibility intervals (CrI).

Results: All 2888 patients in the intention-to-treat cohort of the HOT-ICU trial were included. The adjusted 90-day mortality rates were 43.0% (CrI: 38.3-47.8%) and 42.3% (CrI: 37.7-47.1%) in the lower and higher oxygenation groups, respectively (RR 1.02 [CrI: 0.93-1.11]), with 36.5% probability of an RR <1.00. Analyses of heterogeneous treatment effects suggested a dose-response relationship between baseline norepinephrine dose and increased mortality with the lower oxygenation target, with 95% probability of increased mortality associated with the lower oxygenation target as norepinephrine doses increased.

Conclusions: A lower oxygenation target was unlikely to affect overall mortality amongst critically ill adult patients with acute hypoxaemic respiratory failure. However, our results suggest an increasing mortality risk for patients with a lower oxygen target as the baseline norepinephrine dose increases. These findings warrant additional investigation.

Clinical trial registration: NCT03174002.

Keywords: Bayesian analysis; heterogeneity of treatment effects; intensive care unit; oxygen therapy; respiratory insufficiency.

Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig 1

Posterior probability distribution for the adjusted relative risk (RR) for 90-day all-cause mortality in the primary analysis using weakly informative priors. Upper part: cumulative posterior probability distribution for the adjusted RR. P(RR ≤ X) is the probability that the RR is smaller or equal to any given value specified on the X-axis, being ‘X’; P(RR > X) is the probability that the RR is larger than any given value specified on the X-axis, being ‘X’. An RR <1 indicates benefit from the lower oxygenation target; an RR >1 indicates benefit of the higher oxygenation target. Lower part: full posterior probability distribution; full vertical line=median value; coloured area=95% credibility interval.

Fig 2

Posterior probability distributions of the adjusted relative risks (RRs) of the treatment effect on 90-day all-cause mortality according to the four pre-specified baseline variables in the primary analysis using weakly informative priors. The posterior probability distributions of RRs in each subgroup from the subgroup-based models are displayed together with the posterior distribution from the corresponding analysis of all patients not considering subgroups. An RR 1 indicates benefit of the higher oxygenation target. PaO2:FiO2FiO2, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; SOFA, Sequential Organ Failure Assessment.

Fig 3

Conditional effects plots for 90-day all-cause mortality, using weakly informative priors. These plots illustrate the estimated interactions between treatment allocation and 90-day all-cause mortality on the continuous scale. The levels of the individual variables of interest are plotted on the X-axes; the probabilities of mortality are plotted on the Y-axes. Within each subplot, the odds ratio (OR) with 95% credibility interval for the interaction effect between the lower oxygenation target and the baseline variable assessed is presented. The posterior probabilities that the interaction OR is 1.00 (positive interaction) are also presented. PaO2:Fio2, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; SOFA, Sequential Organ Failure Assessment. In total, 95% of patients had a PaO2:FiO2 ratio <35.5 kPa.