Reappraisal of Ventilator-Free Days in Critical Care Research

Abstract

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.

Adjunct low-dose ketamine infusion vs standard of care in mechanically ventilated critically ill patients at a Tertiary Saudi Hospital (ATTAINMENT Trial): study protocol for a randomized, prospective, pilot, feasibility trial

“…In conclusion, the findings of this pilot trial will contribute to a better understanding of adjunct low-dose ketamine infusion as an analgo-sedative agent and test the feasibility for a larger multicenter, randomized, double-blind, placebo-controlled trial with an adequate power to determine the effect of ketamine infusion as an analgo-sedative agent on clinical outcomes-mirroring other major sedation-related RCTs [18,23,[28][29][30]. Future trials addressing cardiac assessment and hemodynamic metrics in a more protocolized way would be a great addition.…”

“…This outcome was chosen as a patient-centered outcome and based on the mechanistic plausibility data that showed ketamine possibly has a bronchodilatory effect and maintains respiratory drive and airway reflexes [9,12,13]. Because duration of MV is highly influenced by mortality, the median ventilator-free days to day 28 post-randomization will be calculated as a co-primary outcome [23]. See the statistical methods in "Data analysis.…”

Contemporary strategies to improve clinical trial design for critical care research: insights from the First Critical Care Clinical Trialists Workshop

“…Historically, composite outcomes, such as event-free day composite measures (e.g., ventilator-free days, organ failure-free days), have been preferred by the critical care community [84,85]. However, composite outcomes can be difficult to interpret clinically, or in other terms relevant to patients and policy makers [86][87][88]. There are several promising ongoing activities to develop new composite outcome measures (e.g., hierarchical end points [89]) and methods of analysis that improve upon these event-free day metrics [50,77,78,90,91].…”

Helmet Continuous Positive Airway Pressure versus High-Flow Nasal Cannula in COVID-19: A pragmatic randomised clinical trial (COVID HELMET)

“…. We assume the standard deviation (SD) to be 6 in both groups based on a mean estimate of SDs reported from ve trials with VFD as the primary endpoint in the paper by Yehya et al (14). Because we expect a reduction of intubation frequency and days in ventilator to be the driving factor behind a reduction in VFD rather than mortality, we will use Mann-Whitney U-test as the primary statistical method, also based on argumentation by Yeha et al (14).…”