Curley Martha A Q, Gedeit Rainer G, Dodson Brenda L, Amling June K, Soetenga Deborah J, Corriveau Christiane O, Asario Lisa A, Wypij David
School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Trials. 2018 Dec 17;19(1):687. doi: 10.1186/s13063-018-3075-8.
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.
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.
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.
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.
ClinicalTrials.gov , Identifiers: Pilot trial: NCT00142766 ; Retrospectively registerd on 2 September 2005. Cluster randomized trial: NCT00814099 . Registered on 23 December 2008.
很少有论文讨论开展大型整群随机临床试验的实用方法。在此，我们描述了为实施呼吸衰竭镇静滴定随机评估（RESTORE）试验而采取的一系列步骤，该试验旨在测试由护士实施的目标导向性舒适算法对急性呼吸衰竭儿科患者临床结局的影响。
在单一机构研发后，RESTORE干预措施在两个儿科重症监护病房（PICU）进行了预试验，以评估安全性和可行性。预试验后，对RESTORE干预措施进行了简化，以提高在多个PICU中的可重复性。最终的RESTORE试验设计为一项整群随机临床试验，随机分组单位为PICU，按PICU规模分层，推断单位为患者。根据数据与安全监测委员会的建议，对研究实施进行了修订，即就如何最好地征得符合条件的受试者同意，咨询美国卫生与公众服务部人类研究保护办公室（OHRP）。OHRP认为RESTORE干预措施带来的风险大于最小风险，所有入组受试者都应提供反映其参与程度的同意书。
31个规模、组织形式和学术背景各异的PICU参与了研究，超过2800例因急性肺部疾病接受机械通气支持的危重症婴幼儿和儿童被纳入研究。该试验的主要结局是机械通气时间；次要结局包括清醒且舒适的时间、镇静剂总暴露量和医源性戒断症状。在整个临床试验过程中，研究团队努力维持治疗的保真度、入组里程碑以及共同研究者的积极性。我们通过一个决策框架考虑了竞争性临床试验的潜在影响。
RESTORE临床试验是一项大型复杂的多中心研究，为指导儿科重症监护领域的镇静实践提供了必要证据。该试验特有的具体问题包括同意的程度、增加临床地点以扩大入组人数以及评估竞争性临床试验的潜在影响。
ClinicalTrials.gov，标识符：预试验：NCT00142766；于2005年9月2日追溯注册。整群随机试验：NCT00814099。于2008年12月23日注册。
