Time to ROSC as a Novel Outcome for Pediatric Cardiac Arrest Trials - Project Summary: Pediatric in-hospital cardiac arrest (p-IHCA) is a devastating medical condition associated with high mortality and morbidity. While the American Heart Association provides recommendations to guide resuscitation efforts, most of these are derived from low-quality observational evidence with critical risk for bias. This is because randomized controlled trials (RCT) for intra-arrest interventions are exceedingly difficult to perform. Given the critical need for high-quality RCTs to improve outcomes in this field, new trial design techniques must be developed to help overcome these barriers. One key element of trial design that may be modified to enhance feasibility is the selection of the primary outcome. Traditional endpoints for cardiac arrest studies include return of spontaneous circulation (ROSC), survival to discharge and survival to discharge with favorable neurologic outcome (FNO). However, these outcomes are all problematic for two reasons. First, the binary nature of these endpoints leads to the need for very large sample sizes to detect differences in outcomes. This is especially cumbersome in p-IHCA because not only is it a rare event, but also because the minimal clinically important difference for clinicians treating cardiac arrest is very small, owing to its high lethality. Second, these outcomes are limited in their ability to reflect the success or failure of resuscitation efforts. For example, ROSC reflects a successful circulatory resuscitation, but there is no indication of whether the patient survives to hospital discharge, with or without FNO. Survival and survival with FNO represent more patient-centered outcomes, but they often do not reflect the results of the resuscitation in isolation given the vast number of life-limiting disease states associated with p-IHCA as well as the risk for unrelated complications in the interval between arrest and discharge. Therefore, we propose to explore the use of Time to ROSC as a novel outcome for pediatric cardiac arrest studies. Time to ROSC is a critical element in resuscitation as it represents the period of the “low flow” circulatory state to critical organs including the heart and brain and is strongly associated with survival and survival with FNO. To develop this outcome, we plan to use a large national pediatric cardiac arrest registry to perform simulation-based analyses to determine the optimal statistical strategy for patients who do not achieve ROSC. Following the development phase, we will use data from a recent multicenter trial to evaluate the performance of Time to ROSC under “real world” conditions. As power is likely to increase with this time-to- event analysis, this approach has the potential to significantly decrease the number of patients needed to detect meaningful differences between treatment groups as well as better reflect the direct effects of intra- arrest interventions, making intra-arrest trials more feasible, informative and cost-effective.
