• Matthew T Siuba, Lucas Bulgarelli, Abhijit Duggal, Alexandre B Cavalcanti, Fernando G Zampieri, Diego Ariel Rey, Wellington Dos Reis Lucena, Israel S Maia, Denise M Paisani, Ligia N Laranjeira, NetoAry SerpaASDepartment of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil; Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Aust, and Rodrigo Octávio Deliberato.
• Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH. Electronic address: siubam@ccf.org.
• Chest. 2024 Oct 1; 166 (4): 754764754-764.

BackgroundARDS is a heterogeneous condition with two subphenotypes identified by different methodologies. Our group similarly identified two ARDS subphenotypes using nine routinely available clinical variables. However, whether these are associated with differential response to treatment has yet to be explored.Research QuestionAre there differential responses to positive end-expiratory pressure (PEEP) strategies on 28-day mortality according to subphenotypes in adult patients with ARDS?Study Design And MethodsWe evaluated data from two prior ARDS trials (Higher vs Lower Positive End-Expiratory Pressures in Patients With the ARDS [ALVEOLI] and the Alveolar Recruitment in ARDS Trial [ART]) that compared different PEEP strategies. We classified patients into one of two subphenotypes as described previously. We assessed the differential effect of PEEP with a Bayesian hierarchical logistic model for the primary outcome of 28-day mortality.ResultsWe analyzed data from 1,559 patients with ARDS. Compared with lower PEEP, a higher PEEP strategy resulted in higher 28-day mortality in patients with subphenotype A disease in the ALVEOLI study (OR, 1.61; 95% credible interval [CrI], 0.90-2.94) and ART (OR, 1.73; 95% CrI, 1.01-2.98), with a probability of harm resulting from higher PEEP in this subphenotype of 94.3% and 97.7% in the ALVEOLI and ART studies, respectively. Higher PEEP was not associated with mortality in patients with subphenotype B disease in each trial (OR, 0.95 [95% CrI, 0.51-1.73] and 1.00 [95% CrI, 0.63-1.55], respectively), with probability of benefit of 56.4% and 50.7% in the ALVEOLI and ART studies, respectively. These effects were not modified by Pao2 to Fio2 ratio, driving pressure, or the severity of illness for the cohorts.InterpretationWe found evidence of differential response to PEEP strategies across two ARDS subphenotypes, suggesting possible harm with a higher PEEP strategy in one subphenotype. These observations may assist with predictive enrichment in future clinical trials.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

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