Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial

描述（由申请人提供）：高血压经常发生在重症儿童中，并与发病率和死亡率增加有关。大约25%的患有心脏和肺衰竭的重症儿童（即，接受机械通气和/或正性肌力药物的患者）在入院后24小时内出现高血糖症，如果高血糖症持续（持续> PICU停留时间的50%），则导致死亡率增加6倍。先前的研究已经证明，旨在实现正常血糖的胰岛素严格血糖控制（TGC-NL）可以导致选定的高血糖重症患者组的死亡率和发病率的改善。然而，TGC-NL导致发病率和死亡率改善的确切机制尚不清楚。已知高血压通过激活凝血和损害纤维蛋白溶解导致血栓形成前状态。这种促血栓形成、抗纤维蛋白溶解的状态可能导致血管内纤维蛋白沉积和微血栓形成。 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童胰岛素滴定试验（HALF PINT）-一个由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局的影响-研究TGC-NL对纤溶和凝血的影响，并确定TGC对凝血和纤溶紊乱的改善程度-NL有助于改善临床结局。我们计划从HALF PINT研究中招募800例高血糖和心肺衰竭的重症患者。由于母试验将不采集除确认血糖外的任何血样，因此我们将联系入组HALF PINT试验的儿童的父母或代理人，并获得参与本辅助研究的知情同意书。我们将在随机化后第1、3和5天采集血样（2岁及以下儿童3cc，3岁及以上儿童5 ml）。我们将测量选定的凝血和纤溶标志物的血浆水平以及相应基因多态性的基因型DNA。我们将生物标志物随时间的变化与治疗组的分配相关联，以测试TGC-NL的有益作用是否通过凝血和纤溶正常化实现。我们还将测量炎症生物标志物CRP、IL-6和IL-8，以区分TGC对凝血的直接影响和通过炎症产生的间接影响。我们还将对相应基因中的标签SNP进行基因分型，并检测血浆和遗传标记与临床结果的相关性。本研究的结果将为TGC-NL对临床结局的影响提供机制性见解，并可能导致在选定的高血糖重症儿童群体中使用抗凝剂或促纤溶剂作为连续治疗，这些儿童可能不适合严格的血糖控制或处于促血栓形成环境中不良临床结局的风险较高。这项研究的结果可能会导致新的治疗靶点和策略的识别。此外，它可能会导致发现蛋白质或遗传标记，将确定重症儿童最有可能受益于抗凝治疗，如活化蛋白C。! ! ! 公共卫生相关性：我们提出了一项辅助研究的心脏和肺衰竭儿科胰岛素滴定试验（HALF PINT），这是调查正常血糖使用胰岛素输注对高血糖症和心脏和肺衰竭的儿童的临床结果的影响。在这项辅助研究中，我们将在入组HALF PINT试验的患者中测量凝血和纤溶蛋白的血浆水平以及基因型DNA多态性。这项辅助研究的结果将帮助我们了解血糖正常化的潜在机制，这可能会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