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-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.

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.

Keywords: acute lung injury; fluid therapy; subphenotype.

Figure 1.

Continuous variables by subphenotype used in the latent class analysis of subjects enrolled in the Fluid and Catheter Treatment Trial. Individual continuous variables were placed on a z scale with a mean of zero and SD of one. Standardized variable values for each subphenotype represent their variation from the cohort as a whole (i.e., a standardized variable value of +0.6 in subphenotype 2 reflects that the mean variable value in subphenotype 2 was 0.6 SD above the mean in the overall cohort). Variables are presented from left to right in order of maximum separation between subphenotypes 1 and 2. On the left side of the graph, standardized variables are higher in subphenotype 2; on the right side of the graph, standardized variables are lower in subphenotype 2. BMI = body mass index; BP (systolic) = systolic blood pressure; ICAM-1 = intercellular adhesion molecule-1; Mean Air Press = mean airway pressure; MinVent = total minute ventilation; PAI-1 = plasminogen activator inhibitor-1; PEEP = positive end-expiratory pressure; Plat Press = plateau pressure; RAGE = receptor for advanced glycation end-products; SPD = surfactant protein D; Temp (Celsius) = temperature in degrees Celsius; TNFr1 = tumor necrosis factor receptor-1; vWF = von Willebrand factor; WBC = white blood cell count.

Figure 2.

Categorical variables by subphenotype. There was no significant difference in sex distribution between the two subphenotypes (P = 0.38). Subphenotype 1 had a higher proportion of white patients (P = 0.02). Subphenotype 2 more frequently required vasopressors at study enrollment (P < 0.0001). Chi-squared analyses were performed for all comparisons.

Figure 3.

Within each acute respiratory distress syndrome (ARDS) risk factor, the proportion of subjects assigned to each subphenotype.