Epithelial injury and inflammatory phenotypes for personalized ventilation in ARDS: Secondary analysis of the LIVE trial.

BACKGROUND

Guidelines recommend against systematic lung recruitment strategies in acute respiratory distress syndrome (ARDS). sRAGE, an alveolar epithelial injury plasmatic biomarker, and inflammatory phenotypes may guide personalized approaches.

RESEARCH QUESTION: Does baseline sRAGE or inflammatory phenotype identify heterogeneity in the treatment effect of lung recruitment on mortality in ARDS?

STUDY DESIGN AND

METHODS

This analysis included 259 patients with plasma sRAGE measurements from the original LIVE trial that compared lung recruitment with low-PEEP strategies in patients with focal or non-focal ARDS. Baseline sRAGE was dichotomized at 2,440 pg/mL into high and low groups. Inflammatory phenotypes were identified using a validated parsimonious model (IL-8, sTNFr-1, bicarbonate). The primary and secondary outcomes were 90-day mortality and sRAGE trajectory until day 6. Inverse probability weighting and weighted Cox models were used; sRAGE trajectories were assessed using joint models.

RESULTS

High plasma sRAGE (r=0.26, p<0.001), but not the inflammatory phenotype, was moderately correlated with non-focal ARDS. Treatment effect varied by baseline sRAGE (p-for-interaction=0.006), but not by inflammatory phenotype (p-for-interaction=0.56); however, the hyperinflammatory phenotype was associated with 90-day mortality (57% vs 26%, p<0.001). Among high-sRAGE patients, lung recruitment was associated with lower 90-day mortality (HR 0.41, 95%CI 0.18-0.93; p=0.033); among low-sRAGE patients it was associated with higher mortality (HR 3.27, 95%CI, 1.06-10.1; p=0.039). Lung recruitment was associated with different sRAGE slopes compared with low PEEP, with effect modification by baseline sRAGE. Lung recruitment was associated with a steeper decline in sRAGE among patients with high baseline sRAGE (p-for-interaction<0.001), and with a slower decline among patients with low baseline sRAGE (p-for-interaction=0.038). Inflammatory phenotypes did not identify heterogeneity of treatment effect. Sensitivity analyses without inverse probability weighting were directionally consistent.

INTERPRETATION: In ARDS, epithelial injury assessed by plasma sRAGE may identify heterogeneity of treatment effect with lung recruitment, whereas inflammatory phenotypes remained prognostic for mortality.