Abstract Rationale Driving pressure (ΔP)— the difference between plateau pressure and positive end-expiratory pressure (PEEP)—is a key determinant of survival in ARDS. This cyclic lung strain imposed on alveoli may better capture the interaction between mechanical ventilation and lung injury. The biological link between mechanical stress and alveolar epithelial injury remain incompletely understood. We investigated whether higher driving pressures are associated with elevated circulating biomarkers of epithelial injury (surfactant protein D SP-D and surfactant protein A SP-A) in patients with ARDS. Methods We performed a secondary analysis of the ARMA trial dataset, obtained from the NHLBI BioLINCC repository. Linear regression models with multiple imputations assessed associations between ventilatory parameters (driving pressure, plateau pressure, and PEEP at baseline (Day 0) and follow-up (Day 3)) and biomarkers (log-transformed SP-D/A concentrations, adjusting for baseline SP-D/A). Pooled estimates were calculated using Rubin’s rules, with statistical significance defined as p 0.05. Results Among 667 participants, Day 3 ventilatory parameters showed stronger associations with epithelial injury. For SP-D, higher Day 3 driving pressure (β = 3.09, p = 0.026), plateau pressure (β = 4.58, p = 0.001), and PEEP (β = 8.93, p = 0.016) were significantly associated with increased biomarker concentrations after adjusting for baseline SP-D. Corresponding Day 0 parameters were not significant (p 0.2 for all). For SP-A, none of the ventilatory parameters were significant predictors at either time point. A non-significant trend was observed suggesting that higher Day 3 driving pressure might be associated with lower SP-A levels (β = -0.95, p = 0.065). Conclusions Our secondary analysis shows that epithelial injury, measured by levels of SP-D, is driven by sustained mechanical stress, not just the initial mechanical pressures. These findings support a “pressure-injury axis,” suggesting that persistent exposure to higher driving pressures is strongly linked to lung epithelial damage during the course of ARDS. Our study is limited by its retrospective design, lack of adjustment for unmeasured confounders such as tidal volume, fluid balance, or adjunctive therapies, and the analysis of ventilator parameters as single time-point measurements despite ventilator-induced lung injury being a cumulative process over the time. Future studies integrating longitudinal ventilator profiles with mechanistic biomarkers are needed to elucidate causal pathways between ventilator-induced stress and epithelial damage. This abstract is funded by: None
Zia et al. (2026) studied this question.