PURPOSE: The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury. METHODS: We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume. RESULTS: Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01-1.38; P = 0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02-1.07; P = 0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07-3.64; P = 0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher VT. CONCLUSIONS: Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).

Biostatistics Unit Department of Clinical Research and Innovation CHU Clermont Ferrand Clermont Ferrand France

CNRS UMR 6293 INSERM U1103 GReD Université Clermont Auvergne Clermont Ferrand France Department of Medical Biochemistry and Molecular Biology CHU Clermont Ferrand Clermont Ferrand France

Department of Anesthesia and Intensive Care University Hospital of Toulouse University Toulouse 3 Paul Sabatier Toulouse France

Department of Anesthesia Critical Care and Emergency Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico University of Milan Milan Italy

Department of Anesthesiology Heidelberg University Hospital Heidelberg Germany

Department of Anesthesiology University of Pittsburgh School of Medicine Pittsburgh PA USA

Department of Emergency Medicine San Gerardo Hospital Monza Italy

Department of Intensive Care Medicine Academic Medical Center University of Amsterdam Amsterdam The Netherlands Mahidol Oxford Tropical Medicine Research Unit Bangkok Thailand

Department of Intensive Care Medicine OLVG Amsterdam The Netherlands

Department of Perioperative Medicine CHU Clermont Ferrand 1 Place Lucie Aubrac 63003 Clermont Ferrand Cedex 1 France CNRS UMR 6293 INSERM U1103 GReD Université Clermont Auvergne Clermont Ferrand France

Department of Surgical Sciences Molinette Hospital City of Health and Science University of Turin Turin Italy

Division of Pulmonary and Critical Care Medicine Departments of Medicine and Anesthesia Cardiovascular Research Institute University of California San Francisco San Francisco CA USA

Division of Pulmonary and Critical Care Medicine Mayo Clinic Rochester MN USA

Institute of Clinical Biochemistry and Laboratory Diagnostics Faculty of Medicine General University Hospital Charles University Prague Czech Republic

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$a Jabaudon, Matthieu $u Department of Perioperative Medicine, CHU Clermont-Ferrand, 1 Place Lucie Aubrac, 63003, Clermont-Ferrand Cedex 1, France. mjabaudon@chu-clermontferrand.fr. CNRS, UMR 6293, INSERM U1103, GReD, Université Clermont Auvergne, Clermont-Ferrand, France. mjabaudon@chu-clermontferrand.fr.

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$a Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data / $c M. Jabaudon, R. Blondonnet, B. Pereira, R. Cartin-Ceba, C. Lichtenstern, T. Mauri, RM. Determann, T. Drabek, RD. Hubmayr, O. Gajic, F. Uhle, A. Coppadoro, A. Pesenti, MJ. Schultz, MV. Ranieri, H. Brodska, S. Mrozek, V. Sapin, MA. Matthay, JM. Constantin, CS. Calfee,

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$a PURPOSE: The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury. METHODS: We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume. RESULTS: Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01-1.38; P = 0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02-1.07; P = 0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07-3.64; P = 0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher VT. CONCLUSIONS: Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).

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