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: 8690137
• 负责人: ANIL SAPRU
• 金额: $ 39.25万
• 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/8690137
• 关键词: 3 year old; Admission activity; Adult; Algorithms; Ancillary Study; Anticoagulant therapy; 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; public health relevance; 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）：高血糖在危重儿童中经常发生，并且与发病率和死亡率增加相关。大约 25% 的心肺衰竭危重儿童（即接受机械通气和/或正性肌力药物的儿童）在入院 24 小时内出现高血糖，如果高血糖持续存在（持续超过 PICU 住院时间的 50%），则会导致死亡几率增加 6 倍。先前的研究表明，使用胰岛素严格控制血糖以达到正常血糖（TGC-NL）可以改善选定的高血糖危重患者群体的死亡率和发病率。然而，TGC-NL 改善发病率和死亡率的确切机制尚不清楚。已知高血糖会通过凝血激活和纤维蛋白溶解受损导致促血栓形成状态。这种促血栓形成、抗纤溶状态可能导致血管内纤维蛋白沉积和微纤维蛋白沉积。 血栓，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——研究 TGC-NL 对纤溶和凝血的影响，并确定通过以下方法改善凝血和纤溶紊乱的程度： TGC-NL 有助于改善临床结果。我们建议从 HALF PINT 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收集任何血液样本，因此我们将联系参加 HALF PINT 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。我们将在随机化后的第 1、3 和 5 天采集血液样本（2 岁及以下儿童 3cc，3 岁及以上儿童 5ml）。我们将测量选定的凝血和纤维蛋白溶解标志物的血浆水平，以及相应基因多态性的基因型 DNA。我们将把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 的有益效果是否是通过凝血和纤溶正常化来实现的。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。这项研究的结果将为 TGC-NL 对临床结果的影响提供机制见解，并可能导致在特定的高血糖危重儿童群体中使用抗凝剂或促纤溶剂作为辅助治疗，这些儿童可能不适合严格的血糖控制，或者在促血栓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新的治疗靶点和策略的确定。此外，它还可能导致蛋白质或遗传标记的发现，从而识别出最有可能受益于抗凝治疗（如活化蛋白 C）的危重儿童。 ！ ！ 公共健康相关性：我们建议对心肺衰竭儿童胰岛素滴定试验 (HALF PINT) 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高血糖和心肺衰竭儿童临床结果的影响。在这项辅助研究中，我们将测量参加 HALF PINT 试验的患者的血浆凝血和纤溶蛋白水平以及基因型 DNA 的多态性。这项辅助研究的结果将帮助我们了解血糖正常化带来益处的潜在机制，这可能会导致针对危重儿童制定新的治疗策略