• Adrien Carla, Bruno Pereira, Hanifa Boukail, Jules Audard, Nathalie Pinol-Domenech, Manuela De Carvalho, Raiko Blondonnet, Ruoyang Zhai, Dominique Morand, Céline Lambert, Vincent Sapin, Lorraine B Ware, Carolyn S Calfee, Julie A Bastarache, John G Laffey, Nicole P Juffermans, Lieuwe D Bos, Antonio Artigas, RoccoPatricia R MPRMLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Michael A Matthay, Daniel F McAuley, Jean-Michel Constantin, Matthieu Jabaudon, and ESICM Translational Biology Group of the Acute Respiratory Failure section.
• Department of Perioperative Medicine, CHU Clermont-Ferrand, Clermont-Ferrand, France.
• Resp Res. 2020 Apr 7; 21 (1): 81.

BackgroundSubphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits.MethodsWe will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects.DiscussionThis study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation.Systematic Review RegistrationPROSPERO (ID: CRD42019157236).

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