Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial

儿科胰岛素滴定试验中的凝血和纤溶

• 批准号: 8415716
• 负责人: ANIL SAPRU
• 金额: $ 40.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415716
• 关键词: 3 year old; Admission activity; Adult; Algorithms; Ancillary Study; Anticoagulant therapy; Biological Markers; Biological Markers; Blood Glucose; Blood specimen; Cessation of life; Child; Childhood; Clinical; Clinical Trials Design; Coagulants; Coagulation Process; Critical Illness; Critically ill children; DNA; Deposition; Development; Diabetes Mellitus; Diffuse; Enrollment; Environment; Failure; Fibrin; Fibrinolysis; Fibrinolysis Pathway; Fibrinolytic Agents; Funding; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Transcription; Genotype; Glucose; Heart; Heart failure; Hour; Hyperglycemia; IL8 gene; Impairment; Individual; Inflammation; Inflammatory; Informed Consent; Infusion procedures; Insulin; Interleukin-6; Lead; Length of Stay; Link; Lung; Measures; Mechanical ventilation; Mediating; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Observational Study; Organ failure; Outcome; Parents; Pathogenesis; Pathway interactions; Patients; Pediatric Intensive Care Units; Plasma; Plasminogen Activator Inhibitor 1; Proteins; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Regulation; Schedule; Sepsis; Serum; Testing; Thrombosis; Thrombus; Time; Titrations; activated Protein C; adverse outcome; arm; blood glucose regulation; genetic variant; glycemic control; high risk; inhibitor/antagonist; insight; mortality; new therapeutic target; novel therapeutics; research study; therapeutic target

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

描述（由申请人提供）：高血糖经常发生在重症儿童中，并且与发病率和死亡率的增加有关。大约25％的患有心脏和肺部衰竭的重症儿童（即接受机械通气AD/或肌力的人）在入院后24小时内出现高血糖，并且如果维持高血糖症（持续的PICU停留率持续了50％），则会导致6倍的遗产型。先前的研究表明，旨在实现正常血糖（TGC-NL）的胰岛素严格控制的血糖控制可能会导致患有高血糖患病患者选定的患者的死亡率和发病率提高。但是，TGC-NL导致发病率和死亡率提高的确切机制尚不清楚。已知高血糖会通过激活凝血和纤维蛋白溶解损伤而导致促血栓状态。这种促血栓性的抗纤维蛋白水解状态可能导致血管内纤维蛋白沉积和微观 血栓，这可能是导致多器官衰竭发病机理的关键因素。我们建议利用心脏和肺衰竭小儿胰岛素滴定试验（一半品脱） - NHLBI资助的随机，对照对照试验，旨在研究TGC-NL对心脏和肺部失败儿童的临床结果的影响 - 以研究TGC-NL对TGC-NL对纤维蛋白分析和Fibristy的影响，以确定范围范围的范围，以改进该范围，从而在纤维蛋白分析中改进了该范围，从而在该范围内改进了该范围，从而在该范围内改进了该范围，从而在该范围内改进了范围。 TGC-NL有助于改善临床结果。我们建议在半品脱研究中招募800名患有高血糖和心脏和心脏衰竭的重症患者。由于父母试验除了确认血糖以外，父母试验不会收集任何血液样本，因此我们将与参加半品脱试验的儿童的父母或代理人，并获得参与这项辅助研究的知情同意。随机分组后，我们将在第1、3和第5天收集2岁以上的儿童的血液样本（3cc，来自2岁以上的儿童3cc）。我们将测量相应基因中多态性的凝血和纤维蛋白溶解和基因型DNA的选定标记水平。我们将随着时间的时间在生物标志物中随时间的变化与治疗组的分配相关联，以测试通过凝血和纤维蛋白溶解的归一化TGC-NL的有益作用。我们还将测量炎症生物标志物CRP，IL-6和IL-8，以区分TGC对通过炎症的直接影响与间接作用的直接影响。我们还将在相应基因中的TAG SNP进行基因型，并测试血浆和遗传标记与临床结果的关联。这项研究的结果将提供对TGC-NL对临床结果的影响的机理见解，并可能导致使用抗凝血药或纤维蛋白溶解剂作为辅助治疗剂的辅助疗法，这些疗法患有严重疾病的患有高血糖的群体中可能无法进行紧密的葡萄糖控制或对不良临床的影响不足，这可能是不良型临床临床的影响。这项研究的结果可能导致鉴定新的治疗靶标和策略。此外，它可能导致发现蛋白质或遗传标记，这些蛋白质或遗传标志物将发现危害儿童最有可能受益于抗凝疗法，例如活化蛋白C。呢呢 公共卫生相关性：我们建议对心脏和肺衰竭小儿胰岛素滴定试验（一半品脱）进行一项辅助研究，该试验正在研究使用胰岛素输注对血糖降低血糖对高血糖和心脏和心脏和心脏衰竭儿童临床结果的影响的影响。在这项辅助研究中，我们将测量参加半品脱试验的患者的多态性的凝血和纤维蛋白溶解蛋白和基因型DNA水平。这项辅助研究的结果将有助于我们了解归一化血糖提供益处的潜在机制，这可能会导致危重儿童的新治疗策略的发展