Résumé
Background - Inflammatory phenotypes of acute respiratory distress syndrome (ARDS) predict outcomes and can respond differently to treatment strategies. We aimed to establish whether these phenotypes differ in respiratory mechanics and in response to lung-protective ventilation strategies.Methods - In this retrospective cohort study, data from two cohorts were harmonised. Patients with moderate-to-severe ARDS with oesophageal manometry data from the EPVent-2 trial (14 hospitals across the USA and Canada) and a retrospective cohort at Beth Israel Deaconess Medical Center (Boston, MA, USA) were merged and lung mechanics were compared. Patients had to be aged 18 years or older, have moderate to severe ARDS, and be monitored with oesophageal manometry. To analyse the primary outcome of 60-day mortality after ARDS onset, we used multivariable Cox models for each inflammatory phenotype to study the associations between measures of lung-protective ventilation (driving pressure, transpulmonary driving pressure, and end-expiratory transpulmonary pressure) and 60-day mortality in all patients who had complete data for all variables.Findings - Between Jan 1, 2008, and Jan 31, 2024, 5778 patients were assessed for eligibility (200 in the EPVent-2 cohort and 5578 in the BIDMC cohort). Of these patients, 890 were included in this study cohort (200 from the EPVent-2 trial and 690 from the retrospective cohort), of whom 424 (48%) had the hyperinflammatory phenotype and 466 (52%) had the hypoinflammatory phenotype. 232 (55%) patients in the hyperinflammatory group and 136 (29%) patients in the hypoinflammatory group died within 60 days (p<0·0001). The effects on 60-day mortality were more pronounced among patients with the hypoinflammatory phenotype than the hyperinflammatory phenotype for high respiratory system driving pressure (≥15 cm H2O; adjusted hazard ratio 2·01 [95% CI 1·39–2·91] vs 1·46 [1·11–1·94]; pinteraction=0·033) and high transpulmonary driving pressure (≥12 cm H2O; 2·36 [1·64–3·39] vs 1·18 [0·84–1·60]; pinteraction=0·0010). In addition, having an end-expiratory transpulmonary pressure within plus or minus 2 cm H2O was protective among the hypoinflammatory (0·66 [0·46–0·93]) but not the hyperinflammatory phenotype (0·97 [0·73–1·27]). Excess mortality among the hyperinflammatory phenotype was mediated by extrapulmonary organ failure (proportion mediated 46% [+17 to +79]) but not respiratory failure (0% [–3 to +4]).Interpretation - Our findings suggested that in ARDS, the association between lung-protective mechanical ventilation and 60-day mortality is greater in patients with the hypoinflammatory phenotype than the hyperinflammatory phenotype, therefore patients with hypoinflammatory ARDS could be an important target population for enrichment of future clinical trials. However, our findings do not support different ventilation strategies based on phenotype. Although both phenotypes present with similar lung mechanics, extrapulmonary organ failure is the key driver of excess mortality among patients with the hyperinflammatory phenotype.