Methods in the design and implementation of the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial.

Background: Few papers discuss the pragmatics of conducting large, cluster randomized clinical trials. Here we describe the sequential steps taken to develop methods to implement the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) trial that tested the effect of a nurse-implemented, goal-directed, comfort algorithm on clinical outcomes in pediatric patients with acute respiratory failure.

Methods: After development in a single institution, the RESTORE intervention was pilot-tested in two pediatric intensive care units (PICUs) to evaluate safety and feasibility. After the pilot, the RESTORE intervention was simplified to enhance reproducibility across multiple PICUs. The final RESTORE trial was developed as a cluster randomized clinical trial where the unit of randomization was the PICU, stratified by PICU size, and the unit of inference was the patient. Study execution was revised based on our Data and Safety Monitoring Board's recommendation to consult with the Department of Health and Human Services' Office of Human Research Protection (OHRP) on how best to consent eligible subjects. OHRP deemed that the RESTORE intervention posed greater than minimal risk and that all enrolled subjects provide consent reflecting their level of participation.

Results: Thirty-one PICUs of varying size, organization and academic affiliation participated and over 2800 critically ill infants and children supported on mechanical ventilation for acute pulmonary disease were enrolled. The primary outcome for the trial was the duration of mechanical ventilation; secondary outcomes included time awake and comfortable, total sedative exposure and iatrogenic withdrawal symptoms. Throughout the clinical trial the investigative team worked to maintain treatment fidelity, enrollment milestones and co-investigator enthusiasm. We considered the potential impact of competing clinical trials through a decision-making framework.

Conclusions: The RESTORE clinical trial was a large and complex multicenter study that has provided the necessary evidence to guide sedation practices in the field of pediatric critical care. Specific issues that were unique to this trial included level of consent, adding clinical sites to augment enrollment and evaluating the potential impact of competing clinical trials.

Trial Registration: ClinicalTrials.gov , Identifiers: Pilot trial: NCT00142766 ; Retrospectively registerd on 2 September 2005. Cluster randomized trial: NCT00814099 . Registered on 23 December 2008.