Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy

Abstract

Rationale: We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure.Objectives: 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.Methods: 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. Measurements and Main Results: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-conservative strategy versus 18% with fluid-liberal, whereas mortality in subphenotype 2 was 40% with fluid-conservative strategy versus 50% in fluid-liberal. A threevariable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes.Conclusions: 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.

Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome

“…Thus, we hypothesize that the mechanism underlying ARDS in neutropenic subjects may be driven by direct epithelial and/or endothelial injury that is not chlorolipid dependent. In large clinical trials of ARDS, a hyperinflammatory subphenotype characterized by high circulating levels of IL-8, high IL-6, and Ang-2 has been described that associates with higher mortality and a differential response to ventilator and fluid management (57,58). Because 2-ClFA may have additional specificity to identify neutrophil-mediated lung injury, these markers may have utility as potential enrichment factors for trials examining antiinflammatory (59,60) or antipermeability treatments in ARDS (61).…”

Balanced Crystalloids versus Saline in the Intensive Care Unit. The SALT Randomized Trial

“…To definitively evaluate the effect of balanced crystalloids versus saline on patient-centered outcomes, a large, randomized trial that carefully accounts for differences in baseline risk of AKI (8), volume of crystalloid received (7), and underlying pathophysiology (9)(10)(11)(12) among patients in the intensive care unit (ICU) is required. Such a trial faces numerous logistical challenges, including the need to enroll thousands of patients, deliver the assigned crystalloid in a time-sensitive manner, and collect detailed data on the exact amounts of crystalloid administered, the physiological effects (e.g., serum chloride), and outcomes.…”

Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial

“…Differential effects of treatment may depend in part on the combination of biologic and clinical factors in ARDS, as shown in two retrospective studies using ARDSnet trial data. 26,27 Most of the previous pre-clinical studies used KGF as a preventive measure to mitigate the degree of lung injury. 11,13 It is possible that KGF receptors may not be expressed on the target alveolar epithelial cells in patients in whom the epithelium is injured and therefore cannot mediate a therapeutic effect.…”