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

Background Efficiency 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. Methods We 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. Results Estimated 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. Conclusions Overall 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.