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

描述（由申请人提供）：心脏和肺衰竭是儿科重症监护室（PICU）中危重儿童最常见的死亡原因。高血糖是常见的，并且血清葡萄糖的时间、强度、持续时间和变异性与发病率和死亡率相关。严格血糖控制（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手术患者的死亡率和发病率，但最近的大型成人研究显示，在没有充分明确的算法或连续血糖监测的情况下部署TGC时，死亡率和低血糖症在统计学上显著增加。TGC唯一的单中心PICU试验显示，尽管严重低血糖发生率极高，但30天死亡率降低了55%，PICU住院时间（LOS）缩短了10%。低血糖在发育中的儿童大脑中的理论后果比成人更大。因此，在没有缓解这些风险的方案的情况下，不能合理地提出临床实践建议。关键的知识缺口是安全有效的TGC是否能降低心肺衰竭儿童的发病率和死亡率，足以证明低血糖风险低。 为了评估我们的创新和安全的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），称为HALF-PINT：心肺衰竭-儿科胰岛素滴定试验。发生高血糖症的心血管和/或呼吸衰竭患者将被随机分配至正常TGC组（输注胰岛素以将葡萄糖浓度降低至80-110 mg/dL的正常目标范围）或高TGC组（将葡萄糖降低至较高的150-180 mg/dL范围，一些成人数据支持该范围）。两组均将以适合年龄的速率接受相同的标准化静脉葡萄糖，以提供基础热量并预防低血糖。胰岛素输注将采用明确的算法滴定，并结合使用已在>500例重症婴儿和儿童中安全实施的系统进行连续血糖监测。 本研究将检验主要假设，即与HI-TGC组相比，NL-TGC组患者的死亡率更低，PICU LOS更短。该方案还将评估NL-TGC降低器官功能障碍累积率、增加无呼吸机天数、降低院内感染发生率和改善PICU病程后1年神经发育结局的能力。这项随机对照试验将对公共卫生产生重大影响，因为其结果将通过提供关于这一至关重要和有争议的问题的循证指南，为全国范围内儿科重症监护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.