Introduction: Despite current standard of care ventilation, acute respiratory distress syndrome (ARDS) mortality remains high. Lung stress is a modifiable determinant of ARDS outcomes for which the optimal ventilator strategy is unknown. This study evaluated whether integrated titration of tidal volume (Vt) and positive end-expiratory pressure (PEEP) to achieve lung stress in the range typical of relaxed breathing in healthy adults is associated with improved survival. Methods: This study was a post-hoc reanalysis that evaluated participants enrolled a previous multicenter randomized trial, EPVent2. The completed trial compared two ventilator titration strategies and did not demonstrate a superior benefit to either one. Adults with early ARDS were included. In this reanalysis, we evaluated a hypothetical idealized range of ventilator support, defined as (1) Vt that achieves an airway driving pressure (∆P) of ≤ 12 cm H2O, and (2) PEEP that resulted in a lung-end-expiratory pressure (LEEP) of 0 ± 2 cm H2O, as measured with esophageal manometry. We evaluated the association of achieving both Vt and LEEP targets with 60-day mortality. Secondary outcomes evaluated plasma biomarkers of systemic inflammation and alveolar epithelial injury. Results: Among 200 participants, only 23% of patients had both Vt and LEEP with the hypothesized ideal range. ∆P ≤ 12 cm H2O (HR 0.35, 95% CI 0.19-0.64; p < 0.01) and LEEP of 0 ± 2 cm H2O (LEEP: 0.54, 95% CI 0.33-0.90; p = 0.02) were each independently associated with improved survival when entered as separate covariates in a multivariable Cox model. Patients with both ∆P and LEEP in the target range had the lowest mortality, followed by patients with only one of the two targets in range; mortality was highest with neither target in range (logrank p< 0.01). Higher ∆P and higher LEEP were associated with higher plasma IL6 and IL8 levels, whereas only LEEP was significantly associated with plasma receptor for advanced glycation end-products (RAGE), an alveolar epithelial injury marker. Conclusions: Tidal volume and PEEP titration that achieved lung stress within the typical range in healthy adults was associated with improved survival, and effects appear additive. These results warrant testing in a prospective randomized trial.
Beitler et al. (Sun,) studied this question.