Clinical paperAssessment of intensive care unit-free and ventilator-free days as alternative outcomes in the pragmatic airway resuscitation trial
Introduction
Sudden cardiac arrest continues to be a major public health problem, impacting over 450,000 persons in the United States each year, with survival of about 10%1. Over the last 30 years, outcomes used in out-of-hospital cardiac arrest (OHCA) clinical trials tended to be binary: return of for example, spontaneous circulation, survival to hospital admission, 72-hour survival, hospital survival and hospital survival with favorable neurologic outcome.2., 3., 4., 5. Binary outcomes, while often used, can require very large sample sizes relative to continuous measures to detect clinically important differences. For example, the Resuscitation Outcomes Consortium Continuous Chest Compressions trial which compared CPR strategies required a sample size of over 23,000 patients.3 Binary outcomes also do not adequately reflect other dimensions of care such as severity of illness, degree of neurologic impairment, or recovery time.6
In other critical condition trials, event-free days such as intensive care unit (ICU)-free days and ventilator-free days have been used as the primary outcome.6., 7., 8., 9., 10., 11., 12., 13. Event-free approaches have several potential advantages including improving the ability to differentiate severity of illness or recovery, requiring smaller sample sizes to detect clinically important differences, and reflecting clinically relevant aspects of care.6 While continuous outcomes may be amenable for application for OHCA trials, an important first step is to understand the properties of these measures in the OHCA population, their correlations with traditional endpoints, the methods for statistical analysis, and their ability to differentiate interventions.
We sought to evaluate the validity and utility of ICU-free days and ventilator-free days as outcome measures in the Pragmatic Airway Resuscitation Trial (PART). Specifically, we evaluated if comparisons of study groups in the PART trial using ICU-free or ventilator-free days using different statistical tests would detect differences that had been observed using binary outcomes, and if support-free days would correlate with ordinal scales of functional recovery.
Section snippets
Study design
We used data from the PART trial.2 This post hoc analysis was approved by the Ohio State University Office of Responsible Research Practices (study number 2021E0418, April 14, 2021) as an “exempt” protocol. The original PART trial was approved by the Institutional Review Boards of participating institutions under federal exception from informed consent rules (21 CFR 50.24) and was registered with clinicaltrials.gov (NCT02419573).
Setting
The PART trial compared different prehospital airway management
Results
Of the 3,004 patients enrolled in the PART trial, 277 (9.3 %) were alive at 30-days. ICU-free days were available for 2,991 (99.6 %) and ventilator-free days were available for 2,947 (98.1 %). Among the 2,989 patients with known ICU days, only 6 exceeded 30 days. Within the first 30 days of the OHCA, 15 patients had a second ICU treatment period, and 1 patient had a third ICU treatment period. ICU-free and ventilator-free days were highly correlated (Pearson’s R = 0.98). The differences between
Discussion
We assessed the use of ICU-free and ventilator-free days as OHCA outcomes in the PART trial. ICU-free and ventilator free days were strongly correlated with the Modified Rankin Scale, suggesting the validity of these measures. ICU and ventilator-free days also demonstrated utility in their ability to differentiate the airway intervention groups of the trial. Our observations support the potential use of these measures in OHCA trial design.
Event-free days have been used as the primary outcome in
Limitations
We conducted this analysis using data from the PART trial; different results may have been observed with a larger dataset and other study interventions. While we illustrated the application of five analytic techniques in the analysis of ICU- and ventilator free days in OHCA, additional approaches and endpoints are possible. The endpoints used in this analysis were based upon documentation in medical records, but we would not expect material differences with independent determination of ICU-free
Conclusion
In this analysis, using data from the PART trial, we demonstrated the potential validity and utility of ICU-free and ventilator-free days as measures of OHCA outcome. ICU-free and ventilator-free days may be useful in the design and analysis of OHCA trials.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Nichol is a consultant to ZOLL Circulation (San Jose, CA), Heartbeam Inc. (Santa Clara, CA), Invero Pharma LLC. (Montvale, NJ) and Orixha Inc. (Saint Cyr Au Mont d’Or, France), He has research funding from ZOLL Medical (Chelmsford, MA) and Vapotherm Inc. (Exeter, NH), Abiomed Inc. (Danvers, MA) and is a member of the
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