Estimating the attributable fraction of mortality from acute respiratory distress syndrome to inform enrichment in future randomised clinical trials

BackgroundEfficiency of randomised clinical trials of acute respiratory distress syndrome (ARDS) depends on the fraction of deaths attributable to ARDS (AF(ARDS)) to which interventions are targeted. Estimates of AF(ARDS) in subpopulations of ARDS could improve design of ARDS trials. MethodsWe performed a matched case-control study using the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE cohort. Primary outcome was intensive care unit mortality. We used nearest neighbour propensity score matching without replacement to match ARDS to non-ARDS populations. We derived two separate AF(ARDS) estimates by matching patients with ARDS to patients with non-acute hypoxaemic respiratory failure (non-AHRF) and to patients with AHRF with unilateral infiltrates only (AHRF-UL). We also estimated AF(ARDS) in subgroups based on severity of hypoxaemia, number of lung quadrants involved and hyperinflammatory versus hypoinflammatory phenotypes. Additionally, we derived AF(AHRF) estimates by matching patients with AHRF to non-AHRF controls, and AF(AHRF-UL) estimates by matching patients with AHRF-UL to non-AHRF controls. ResultsEstimated AF(ARDS) was 20.9% (95% CI 10.5% to 31.4%) when compared with AHRF-UL controls and 38.0% (95% CI 34.4% to 41.6%) compared with non-AHRF controls. Within subgroups, estimates for AF(ARDS) compared with AHRF-UL controls were highest in patients with severe hypoxaemia (41.1% (95% CI 25.2% to 57.1%)), in those with four quadrant involvement on chest radiography (28.9% (95% CI 13.4% to 44.3%)) and in the hyperinflammatory subphenotype (26.8% (95% CI 6.9% to 46.7%)). Estimated AF(AHRF) was 33.8% (95% CI 30.5% to 37.1%) compared with non-AHRF controls. Estimated AF(AHRF-UL) was 21.3% (95% CI 312.8% to 29.7%) compared with non-AHRF controls. ConclusionsOverall AF(ARDS) mean values were between 20.9% and 38.0%, with higher AF(ARDS) seen with severe hypoxaemia, four quadrant involvement on chest radiography and hyperinflammatory ARDS.