Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial

描述(由申请人提供)：高血糖经常发生在危重儿童中，并与发病率和死亡率的增加有关。大约25%的患有心肺衰竭的危重儿童(即那些接受机械通气和/或正压治疗的儿童)在入院后24小时内出现高血糖，如果高血糖持续(持续&gt；50%的PICU住院时间)，导致死亡几率增加6倍。先前的研究已经证明，以达到正常血糖为目标的胰岛素严格控制血糖(TGC-NL)可以改善部分高血糖危重患者的死亡率和发病率。然而，TGC-NL导致发病率和死亡率改善的确切机制尚不清楚。已知高血糖可通过激活凝血系统和抑制纤溶系统而导致血栓前状态。这种促血栓、抗纤溶状态可能导致血管内纤维蛋白沉积和微量 血栓，这可能是多器官衰竭发病机制的关键因素。我们建议利用心肺衰竭儿科胰岛素滴定试验(半品脱)，这是一项由NHLBI资助的随机对照试验，旨在研究TGC-NL对心肺衰竭儿童临床结果的影响，以调查TGC-NL对纤溶和凝血的影响，并确定TGC-NL改善紊乱的凝血和纤溶作用对改善临床结果的程度。我们建议从半品脱研究中招募800名患有高血糖和心肺衰竭的危重患者。由于家长试验除了确认血糖外不会采集任何血液样本，我们将与参加半品脱试验的儿童的父母或代孕母亲联系，并获得参与这项辅助研究的知情同意。我们将在随机抽样后的第1、3和5天采集血样(2岁及以下儿童血样3毫升，3岁及以上儿童血样5毫升)。我们将测量选定的凝血和纤溶标志物的血浆水平，并检测相应基因的多态性。我们将把生物标记物随时间的变化与分配给治疗臂的情况相关联，以测试TGC-NL的益处是否通过凝血和纤溶的正常化实现。我们还将检测炎症生物标志物CRP、IL-6和IL-8，以区分TGC对凝血的直接作用和通过炎症的间接作用。我们还将对相应基因中的标签SNPs进行分型，并测试血浆和遗传标记物与临床结果的相关性。这项研究的结果将为TGC-NL对临床结果的影响提供机械性的见解，并可能导致在选定的高血糖危重儿童群体中使用抗凝剂或纤溶剂作为辅助治疗，这些儿童可能无法严格控制血糖或在血栓前环境中面临较高的不良临床结果风险。这项研究的结果可能会导致确定新的治疗靶点和策略。此外，它可能会导致蛋白质或遗传标记的发现，这些标记将识别最有可能从激活蛋白C等抗凝治疗中受益的危重儿童。 公共卫生相关性：我们建议对心肺衰竭儿科胰岛素滴定试验(半品脱)进行一项辅助研究，该试验正在调查使用胰岛素输注使血糖正常化对患有高血糖和心肺衰竭的儿童的临床结局的影响。在这项辅助研究中，我们将测量参加半品脱试验的患者的血浆凝血和纤溶蛋白水平以及多态的基因DNA。这项辅助研究的结果将帮助我们理解血糖正常化带来益处的潜在机制，这可能导致危重儿童新的治疗策略的发展。

DESCRIPTION (provided by applicant): Hyperglycemia occurs frequently among critically ill children and is associated with increased morbidity and mortality. Approximately 25% of critically ill children with heart and lung failure (i.e., those receiving mechanical ventilation ad/or inotropes) develop hyperglycemia within 24 hours of admission, and if the hyperglycemia is sustained (lasting for > 50% of PICU stay), it results in a 6-fold increase in the odds of mortalit. Previous studies have demonstrated that tight glycemic control with insulin, aimed at achieving normoglycemia (TGC- NL) can result in improvement in mortality and morbidity in selected groups of critically ill patients with hyperglycemia. However, the precise mechanism by which TGC-NL leads to improvement in morbidity and mortality is not known. Hyperglycemia is known to result in a pro-thrombotic state via activation of coagulation and impairment of fibrinolysis. This pro-thrombotic, anti-fibrinolytic state, may lead to intravascular fibrin deposition and micro thrombi, which can be a key contributor to the pathogenesis of multi-organ failure. We propose to take advantage of The Heart and Lung Failure Pediatric Insulin Titration trial (HALF PINT) - an NHLBI-funded randomized, controlled trial designed to study the impact of TGC-NL on clinical outcomes among children with heart and lung failure - to investigate the effect of TGC-NL on fibrinolysis and coagulation and to determine the extent to which improvement in deranged coagulation and fibrinolysis by TGC-NL contributes to improvement in clinical outcomes. We propose to enroll 800 critically ill patients with hyperglycemia and heart and lung failure from the HALF PINT study. Since the parent trial will not collect any blood samples other than for confirmation of blood glucose, we will approach parents or surrogates of children enrolled in the HALF PINT trial and obtain informed consent for participation in this ancillary study. We will collect blood samples (3cc from children 2 years and younger, and 5ml from children 3 years and older) at Days 1, 3, and 5 after randomization. We will measure plasma levels of selected markers of coagulation and fibrinolysis and genotype DNA for polymorphisms in the corresponding genes. We will correlate changes over time in the biomarkers with allocation to treatment arm to test whether the beneficial effects of TGC-NL are achieved via normalization of coagulation and fibrinolysis. We will also measure inflammatory biomarkers CRP, IL-6 and IL-8 to differentiate direct effects of TGC on coagulation from indirect effects via inflammation. We will also genotype for tag SNPs in the corresponding genes and test for association of the plasma and genetic markers with clinical outcomes. The results from this study will provide mechanistic insights into the effect of TGC-NL on clinical outcome and could lead to the use of anti-coagulant or pro fibrinolytic agents as adjunctive therapies among select groups of critically ill children with hyperglycemia who may not be amenable to tight glucose control or are at higher risk of adverse clinical outcomes from a pro thrombotic environment. Results from this study may lead to identification of novel therapeutic targets and strategies. In addition, it may lead to discovery of protein or genetic markers that will identify critically ill children most likely to benefit from anticoagulant therapies such as activated protein C. ! ! ! PUBLIC HEALTH RELEVANCE: We propose an ancillary study to The Heart and Lung Failure Pediatric Insulin Titration trial (HALF PINT), which is investigating the impact of normalizing blood glucose using insulin infusions on clinical outcomes among children with hyperglycemia and heart and lung failure. In this ancillary study, we will measure plasma levels of coagulation and fibrinolysis proteins and genotype DNA for polymorphisms among patients enrolled in the HALF PINT trial. The results from this ancillary study will help us to understand potential mechanisms through which normalizing blood glucose provides benefit, which may lead to development of new therapeutic strategies in critically ill children