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）：高血糖症经常发生在危重儿童中，并与发病率和死亡率增加有关。约25%的心肺衰竭危重患儿（即接受机械通气和/或肌力药物治疗的患儿）在入院24小时内出现高血糖，如果高血糖持续（持续至PICU住院时间的50%），其死亡率将增加6倍。先前的研究表明，胰岛素严格控制血糖，旨在达到正常血糖（TGC- NL），可以改善某些危重症高血糖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。已知高血糖通过激活凝血和损害纤溶导致促血栓状态。这种促血栓形成、抗纤溶状态，可导致血管内纤维蛋白沉积和微血栓形成