Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials

Abstract

Background: Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it.

Methods: A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a Pao₂ to Fio₂ ratio (Pao₂:Fio₂) > 300 on the first study day following enrollment.

Results: The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60-day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. Pao₂:Fio₂ at screening, change in Pao₂:Fio₂ from screening to enrollment, use of vasopressor agents, Fio₂ at enrollment, and serum bilirubin levels were useful predictive variables.

Conclusions: Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials.

Keywords: ICUs; acute lung injury; acute respiratory failure; epidemiology.

Figure 1

Prevalence of rapidly improving ARDS over time. Each circle represents an ARDS Network trial, and circle size is proportional to study sample size. Increase in prevalence of rapidly improving ARDS over time was statistically significant. ALTA = Albuterol for the Treatment of Acute Lung Injury; ALVEOLI = Assessment of Low Tidal Volume and Elevated End-expiratory Volume to Obviate Lung Injury; ARMA = Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Low-Tidal-Volume (VT) Trial; EDEN = Early vs Delayed Enteral Nutrition; FACTT = Fluid and Catheter Treatment Trial; SAILS = Statins for Acutely Injured Lungs from Sepsis.

Figure 2

Kaplan-Meier curves of mortality for rapidly improving ARDS and ARDS > 1 day. Patients discharged home considered alive at 60 days. Shaded area depicts 95% pointwise CIs for each curve.