HALF-PINT: Heart and Lung Failure - Pediatric INsulin Titration trial - CCC

描述(由申请人提供)：心肺衰竭是儿科重症监护病房(PICU)危重儿童最常见的死亡原因。高血糖是常见的，血糖的时间、强度、持续时间和变异性与发病率和死亡率有关。严格的血糖控制(TGC)，通过静脉注射胰岛素使血糖浓度正常化，显著降低了选定的危重成人外科患者的死亡率和发病率，但最近的大型成人研究表明，如果没有足够明确的算法或持续的血糖监测，使用TGC在统计上显著增加了死亡率和低血糖。TGC的唯一单中心PICU试验显示，尽管严重低血糖的发生率极高，但30天的死亡率降低了55%，PICU住院时间(LOS)减少了10%。理论上，低血糖对发育中的儿童大脑的影响比对成年人的威胁更大。因此，在没有减轻这些风险的方案的情况下，不能合法地提出临床实践建议。知识方面的关键差距是，安全有效的TGC能否充分降低心肺衰竭儿童的发病率和死亡率，从而证明低血糖风险是合理的。为了评估我们创新和安全的TGC方案在降低危重儿童死亡率和PICU LOS方面的有效性，我们将在20个PICU中进行一项随机临床试验(RCT)，名为半品脱：心肺衰竭-儿科胰岛素滴定试验。发生高血糖的心血管和/或呼吸衰竭患者将被随机分成正常TGC组和高TGC组，在正常TGC组中，胰岛素将被注入以将血糖浓度降低到80-110 mg/dL的正常目标范围，或者在高TGC组中，血糖将被降低到较高的150-180 mg/dL范围，这是一些成人数据所倡导的范围。为了提供基础卡路里和预防低血糖，两组都将以适合年龄的速度接受相同的标准化静脉注射葡萄糖。胰岛素输注将使用显式算法和连续血糖监测相结合的方法进行滴定，该系统已在500名危重婴儿和儿童中安全实施。这项研究将检验基本假设，即与HI-TGC组相比，NL-TGC组的患者具有更低的死亡率和更短的PICU LOS。该方案还将评估NL-TGC在PICU疗程结束后1年内减少器官功能障碍累积速度、增加无呼吸机天数、降低医院感染发生率和改善神经发育结果的能力。这项随机对照试验将对公共卫生产生重大影响，因为其结果将通过就这一极其重要和有争议的问题提供循证指导，为全国儿科危重护理的广泛实践提供信息。

DESCRIPTION (provided by applicant): Heart and lung failure are the most common causes of death in critically ill children in Pediatric Intensive Care Units (PICUs). Hyperglycemia is common, and the timing, intensity, duration and variability of serum glucose are associated with morbidity and mortality. Tight glycemic control (TGC) to normalize blood glucose concentrations with intravenous insulin significantly reduced mortality and morbidity in selected critically ill adult surgical patients, but recent large adult studies show statistically significant increases in mortality and hypoglycemia when TGC is deployed without adequately explicit algorithms or continuous glucose monitoring. The only single-center PICU trial of TGC showed a 55% decrease in 30-day mortality and 10% reduction in PICU length of stay (LOS), despite an extremely high rate of severe hypoglycemia. Theoretical consequences of hypoglycemia in the developing pediatric brain are greater threats than for adults. Therefore, recommendations for clinical practice cannot legitimately be made without a protocol that mitigates these risks. The critical gap in knowledge is whether safe and effective TGC can reduce morbidity and mortality in children with heart and lung failure sufficiently to justify a low risk of hypoglycemia. To evaluate the efficacy of our innovative and safe TGC protocol to reduce mortality and PICU LOS in critically ill children, we will conduct a randomized clinical trial (RCT) in 20 PICUs, called HALF-PINT: Heart and Lung Failure - Pediatric INsulin Titration trial. Patients with cardiovascular and/or respiratory failure who develop hyperglycemia will be randomized to either a Normal-TGC group in which insulin will be infused to reduce glucose concentrations into the normal target range of 80-110 mg/dL or to a High-TGC group in which glucose will be reduced into the higher 150-180 mg/dL range, a range advocated by some adult data. Both groups will receive identical standardized intravenous glucose at an age-appropriate rate in order to provide basal calories and prevent hypoglycemia. Insulin infusions will be titrated with an explicit algorithm combined with continuous glucose monitoring using a system that has been safely implemented in >500 critically ill infants and children. This study will test the primary hypothesis that patients assigned to the NL-TGC group will have a combined outcome of lower mortality and shorter PICU LOS compared with HI-TGC. The protocol will also evaluate the ability of NL-TGC to reduce the rate of accumulation of organ dysfunction, increase ventilator-free days, reduce incidence of nosocomial infections and improve neurodevelopmental outcomes at 1 year after their PICU course. This RCT will have a significant impact on public health in that its results will inform the broad practice of pediatric critical care nationally by providing evidence-based guidance regarding this critically important and controversial issue.