Epithelial Injury and Inflammatory Phenotypes for Personalized Ventilation in ARDS: Secondary Analysis of the Lung Imaging for Ventilator Setting Trial
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Published on: April 7, 2021
Joris Pensier1, Laurent Renard-Triché2, Camille Theilliere3
1Anesthesiology and Intensive Care, Anesthesia and Critical Care Department B, Saint Eloi Teaching Hospital, University of Montpellier, Montpellier, France; PhyMedExp Laboratory, University of Montpellier, INSERM U1046, CNRS, Montpellier, France; Department of Anesthesia, Critical Care and Pain Medicine, Center for Anesthesia Research Excellence Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Department of Perioperative Medicine, CHU Clermont-Ferrand, Clermont-Ferrand, France; iGReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France.
Background:
Guidelines recommend against systematic lung recruitment strategies in ARDS. Soluble receptor for advanced glycation end products (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 Lung Imaging for Ventilator Setting (LIVE) trial that compared lung recruitment with low positive end-expiratory pressure strategies in patients with focal or non-focal ARDS. Baseline sRAGE levels were dichotomized at 2,440 pg/mL into high and low groups. Inflammatory phenotypes were identified using a validated parsimonious model (IL-8, soluble tumor necrosis factor receptor 1, and 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 < .001), but not the inflammatory phenotype, was moderately correlated with non-focal ARDS. The treatment effect varied by baseline sRAGE (interaction P = .006), but not by inflammatory phenotype (interaction P = .56); however, the hyperinflammatory phenotype was associated with 90-day mortality (57% vs 26%; P < .001). Among patients with high sRAGE levels, lung recruitment was associated with lower 90-day mortality (hazard ratio, 0.41; 95% CI, 0.18-0.93; P = .033); among patients with low sRAGE levels, it was associated with higher mortality (hazard ratio, 3.27; 95% CI, 1.06-10.1; P = .039). Lung recruitment was associated with different sRAGE slopes compared with low positive end-expiratory pressure, with effect modification by baseline sRAGE. Lung recruitment was associated with a steeper decline in sRAGE among patients with high baseline sRAGE levels (interaction P < .001), and with a slower decline among patients with low baseline sRAGE levels (interaction P = .038). Inflammatory phenotypes did not identify heterogeneity of treatment effect. Sensitivity analyses without inverse probability weighting were directionally consistent.
Interpretation:
Our results show that, in ARDS, epithelial injury assessed by plasma sRAGE may identify heterogeneity of treatment effect with lung recruitment, whereas inflammatory phenotypes remain prognostic for mortality.
