title: Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy.
abstract: We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure.
  
  
  
  To identify these subphenotypes in a third ARDS cohort, to test whether subphenotypes respond differently to fluid management strategy, and to develop a practical model for subphenotype identification.
  
  
  
  We used latent class analysis of baseline clinical and plasma biomarker data to identify subphenotypes in FACTT (Fluid and Catheter Treatment Trial; n = 1,000). Logistic regression was used to test for an interaction between subphenotype and treatment for mortality. We used stepwise modeling to generate a model for subphenotype identification in FACTT and validated its accuracy in the two cohorts in which we previously identified ARDS subphenotypes.
  
  
  
  We confirmed that a two-class (two-subphenotype) model best described the study population. Subphenotype 2 was again characterized by higher inflammatory biomarkers and hypotension. Fluid management strategy had significantly different effects on 90-day mortality in the two subphenotypes (P = 0.0039 for interaction); mortality in subphenotype 1 was 26% with fluid-liberal strategy versus 18% with fluid-conservative, whereas mortality in subphenotype 2 was 40% with fluid-liberal strategy versus 50% in fluid-conservative. A three-variable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes.
  
  
  
  This analysis confirms the presence of two ARDS subphenotypes that can be accurately identified with a limited number of variables and that responded differently to randomly assigned fluid management. These findings support the presence of ARDS subtypes that may require different treatment approaches.
authors: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Katie R
authors: 0000-0001-7460-0883
authors: KR
authors: Famous
authors: 2 Department of Psychiatry.
authors: Kevin
authors: K
authors: Delucchi
authors: 3 Department of Medicine, and.|4 Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee; and.
authors: Lorraine B
authors: LB
authors: Ware
authors: 5 Division of Hospital Medicine, Department of Medicine.
authors: Kirsten N
authors: KN
authors: Kangelaris
authors: 6 Division of Nephrology, Department of Medicine, and.|7 Department of Anesthesia, University of California San Francisco, San Francisco, California.
authors: Kathleen D
authors: KD
authors: Liu
authors: 8 Division of Pulmonary and Critical Care, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors: B Taylor
authors: BT
authors: Thompson
authors: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine.|7 Department of Anesthesia, University of California San Francisco, San Francisco, California.
authors: Carolyn S
authors: CS
authors: Calfee
mesh_terms: D015415:Biomarkers / Q000097:blood; D005260:Female; D005440:Fluid Therapy / Q000379:methods*; D006801:Humans; D016015:Logistic Models; D008297:Male; D010043:Outcome and Process Assessment, Health Care / Q000706:statistics & numerical data*; D010641:Phenotype; D011175:Positive-Pressure Respiration; D016032:Randomized Controlled Trials as Topic; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000145:classification / Q000401:mortality / Q000628:therapy*
chemical_list: D015415:Biomarkers
keywords: acute lung injury; fluid therapy; subphenotype