Persistent severe acute respiratory distress syndrome for the prognostic enrichment of trials

Abstract

Background: Acute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it.

Methods: A secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS.

Results: Of the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); p<0.001] and baseline severity of illness was higher in patients with versus without persistent severe ARDS. Mortality at 60 days [95/232 (41%) versus 233/1299 (18%); p<0.001] was higher, and ventilator-free (p<0.001), intensive care unit-free [0 (0-14) versus 19 (7-23); p<0.001] and non-pulmonary organ failure-free [3 (0-21) versus 20 (1-26); p<0.001] days were fewer in patients with versus without persistent severe ARDS. PaO2:FiO2, FiO2, hepatic failure and positive end-expiratory pressure at enrollment were useful predictive variables.

Conclusions: Patients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials.

Conflict of interest statement

The corresponding author has read the journal’s policy and the authors of this manuscript have the following competing interests: AMC is a co-founder of Proterris and serving as a consultant for an advisory board meeting of Teva Pharmaceutical Industries, July 2018. None declared (ES, DRP, KPC, CO, EJS, IIS). This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Lasagna plot depicting the trajectory of hypoxemia of each individual patient during the first two study days after trial enrollment.

On the second study day, some patients that initially had mild/moderate ARDS (shown as green) progressed to persistent severe ARDS (shown in red). Some patients with an initial presentation of severe ARDS (red) continued to have severe ARDS on the second study day.