Ventilator-free days (VFDs) are a commonly reported composite outcome measure in acute respiratory distress syndrome trials. VFDs combine survival and duration of ventilation in a manner that summarizes the “net effect” of an intervention on these two outcomes. However, this combining of outcome measures makes VFDs difficult to understand and analyze, which contributes to imprecise interpretations. We discuss the strengths and limitations of VFDs and other “failure-free day” composites, and we provide a framework for when and how to use these outcome measures. We also provide a comprehensive discussion of the different analytic methods for analyzing and interpreting VFDs, including Student’s t tests and rank-sum tests, as well as competing risk regressions treating extubation as the primary outcome and death as the competing risk. Using simulations, we illustrate how the statistical test with optimal power depends on the relative contributions of mortality and ventilator duration on the composite effect size. Finally, we recommend a simple analysis and reporting framework using the competing risk approach, which provides clear information on the effect size of an intervention, a statistical test and measure of confidence with the ability to adjust for baseline factors and allow interim monitoring for trials. We emphasize that any approach to analyzing a composite outcome, including other “failure-free day” constructs, should also be accompanied by an examination of the components.

Rationale: The ARDS Network (ARDSNet) used a positive end-expiratory pressure (PEEP)/FiO2 model in many studies. In general, pediatric intensivists use less PEEP and higher FiO2 than this model. Objectives: To evaluate whether children managed with PEEP lower than recommended by the ARDSNet PEEP/FiO2 model had higher mortality. Methods: This was a multicenter, retrospective analysis of patients with pediatric acute respiratory distress syndrome (PARDS) managed without a formal PEEP/FiO2 protocol. Four distinct datasets were combined for analysis. We extracted time-matched PEEP/FiO2 values, calculating the difference between PEEP level and the ARDSNet-recommended PEEP level for a given FiO2. We analyzed the median difference over the first 24 hours of PARDS diagnosis against ICU mortality and adjusted for confounding variables, effect modifiers, or factors that may have affected the propensity to use lower PEEP. Measurements and Main Results: Of the 1,134 patients with PARDS, 26.6% were managed with lower PEEP relative to the amount of FiO2 recommended by the ARDSNet protocol. Patients managed with lower PEEP experienced higher mortality than those who were managed with PEEP levels in line with or higher than recommended by the protocol (P < 0.001). After adjustment for hypoxemia, inotropes, comorbidities, severity of illness, ventilator settings, nitric oxide, and dataset, PEEP lower than recommended by the protocol remained independently associated with higher mortality (odds ratio, 2.05; 95% confidence interval, 1.32–3.17). Findings were similar after propensity-based covariate adjustment (odds ratio, 2.00; 95% confidence interval, 1.24–3.22). Conclusions: Patients with PARDS managed with lower PEEP relative to FiO2 than recommended by the ARDSNet model had higher mortality. Clinical trials targeting PEEP management in PARDS are needed.

Objective: Although all definitions of acute respiratory distress syndrome use some measure of hypoxemia, neither the Berlin definition nor recently proposed pediatric-specific definitions proposed by the Pediatric Acute Lung Injury Consensus Conference utilizing oxygenation index specify which PaO₂/FIO₂ or oxygenation index best categorizes lung injury. We aimed to identify variables associated with mortality and ventilator-free days at 28 days in a large cohort of children with acute respiratory distress syndrome. Design: Prospective, observational, single-center study. Setting: Tertiary care, university-affiliated PICU. Patients: Two-hundred eighty-three invasively ventilated children with the Berlin-defined acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: Between July 1, 2011, and June 30, 2014, 283 children had acute respiratory distress syndrome with 37 deaths (13%) at the Children’s Hospital of Philadelphia. Neither initial PaO₂/FO₂ nor oxygenation index at time of meeting acute respiratory distress syndrome criteria discriminated mortality. However, 24 hours after, both PaO₂/FIO₂ and oxygenation index discriminated mortality (area under receiver operating characteristic curve, 0.68 [0.59–0.77] and 0.66 [0.57–0.75]; p < 0.001). PaO₂/FIO₂ at 24 hours categorized severity of lung injury, with increasing mortality rates of 5% (PaO₂/FIO₂, > 300), 8% (PaO₂/FIO₂, 201–300), 18% (PaO₂/FIO₂, 101–200), and 37% (PaO₂/FIO₂, ≤ 100) across worsening Berlin categories. This trend with 24-hour PaO₂/FIO₂ was seen for ventilator-free days (22, 19, 14, and 0 ventilator-free days across worsening Berlin categories; p < 0.001) and duration of ventilation in survivors (6, 9, 13, and 24 d across categories; p < 0.001). Similar results were obtained with 24-hour oxygenation index. Conclusions: PaO₂/FIO₂ and oxygenation index 24 hours after meeting acute respiratory distress syndrome criteria accurately stratified outcomes in children. Initial values were not helpful for prognostication. Definitions of acute respiratory distress syndrome may benefit from addressing timing of oxygenation metrics to stratify disease severity.

OBJECTIVES: In 2015, the Pediatric Acute Lung Injury Consensus Conference (PALICC) provided the first pediatric-specific definitions for acute respiratory distress syndrome (pediatric acute respiratory distress syndrome [PARDS]). These definitions have since been operationalized in cohort and interventional PARDS studies. As substantial data have accrued since 2015, we have an opportunity to assess the construct validity and utility of the initial PALICC definitions. Therefore, the Second PALICC (PALICC-2) brought together multiple PARDS experts and aimed to identify and summarize relevant evidence related to the definition and epidemiology of PARDS and create modifications to the definition of PARDS. DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). STUDY SELECTION: We included studies of subjects with PARDS, or at risk for PARDS, excluding studies pertaining primarily to adults except as specified for identifying age-specific cutoffs. DATA EXTRACTION: Title/abstract review, full-text review, and data extraction using a standardized data collection form. DATA SYNTHESIS: The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. A total of 97 studies were identified for full-text extraction addressing distinct aspects of the PARDS definition, including age, timing, imaging, oxygenation, modes of respiratory support, and specific coexisting conditions. Data were assessed in a Patient/Intervention/Comparator/Outcome format when possible, and formally summarized for effect size, risk, benefit, feasibility of implementation, and equity. A total of 17 consensus-based definition statements were made that update the definition of PARDS, as well as the related diagnoses of “Possible PARDS” and “At-Risk for PARDS.” These statements are presented alongside a summary of the relevant epidemiology. CONCLUSIONS: We present updated, data-informed consensus statements on the definition for PARDS and the related diagnoses of “Possible PARDS” and “At-Risk for PARDS.”