Vitamin C, Sepsis and Coagulopathy: An Ancillary Study of the CITRIS-ALI Trial

维生素 C、败血症和凝血病：CITRIS-ALI 试验的辅助研究

基本信息

批准号：
8956642
负责人：
Donald Fitzpatrick Brophy
金额：
$ 44.3万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-17 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8956642
关键词：
Acute Lung Injury Ancillary Study Animals Anticoagulants Antioxidants Ascorbic Acid Attenuated Basic Science Biological Assay Biological Markers Blood Blood Coagulation Disorders Blood Platelets Blood coagulation Clinic Clinical Clinical Research Coagulants Coagulation Process Collaborations Consumption Cytoplasmic Granules Data Diffuse Disseminated Intravascular Coagulation Doctor of Pharmacy Doctor of Philosophy Dose Double-Blind Method Endothelial Cells Environment Event Exhibits Fibrinolysis Fright Functional disorder Funding Generations Genes Goals Grant Hemostatic Agents Hemostatic function Hour Human Inflammation Mediators Inflammatory Inflammatory Response Infusion procedures Institution Intravenous Lead Measures Mediator of activation protein Mentors Molecular Morbidity - disease rate Multiple Organ Failure Organ Parents Pathway interactions Patients Pattern Pharmacists Pharmacology Pharmacy Schools Pharmacy facility Phase II Clinical Trials Phenotype Placebo Control Placebos Plasma Platelet Activation Platelet aggregation Process Publications Randomized Research Role Scientist Sepsis Sepsis Syndrome Students Surface System Thrombelastography Thrombin Thrombomodulin Thrombophilia Thromboplastin Thrombosis Translational Research United States National Institutes of Health Universities Up-Regulation Virginia Whole Blood Wisconsin attenuation base career cost effective cytokine experience graduate student improved inhibitor/antagonist interest medical schools mortality next generation pre-clinical prevent public health relevance response restoration septic treatment strategy viscoelasticity

项目摘要

DESCRIPTION (provided by applicant): This is an ancillary study associated with a recently funded NIH UM-1 application at our institution [UM1-HL116885-01: Vitamin C: Infusion for the Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI)]. The parent UM-1 is a double-blind, randomized, placebo-controlled, multi-center, Phase II clinical trial examining the efficacy of high dose intravenous vitamin C (VitC, ascorbic acid) infusion for 96 hours in human sepsis-associated acute lung injury. The proposed ancillary study will examine the effects of parenteral VitC on sepsis-associated coagulopathy and platelet dysfunction (which is not being evaluated in the parent UM-1). Sepsis provokes intense systemic pro-inflammatory and pro-coagulant responses that arise from dysregulation of host-derived mediators of inflammation and coagulation. As a result, sepsis-driven coagulation induces consumption of coagulation and fibrinolytic factors that lead to Disseminated Intravascular Coagulation (DIC), one of the most feared complications of sepsis that leads to widespread systemic microvascular thrombosis. DIC is a critical mediator of sepsis-associated multiple organ failure. The long range goal of our research team is to develop optimal strategies to reduce the morbidity and mortality associated with human sepsis, specifically targeting the attenuation of DIC and other thrombotic events that lead to end-organ dysfunction. We have preliminary data suggesting Vitamin C significantly attenuates the inflammatory and pro-coagulant cascades in both animal and human sepsis. The Central Hypothesis is that parenteral VitC reduces sepsis-associated coagulopathy in humans by restoration of hemostatic integrity, and by the normalization of platelet function. We believe the molecular basis by which this occurs is through mechanisms attenuating increases in circulating pro-inflammatory mediators (which are being measured in the parent UM-1 study). The rationale is that if Vitamin C attenuates the inflammatory and coagulation pathways in sepsis, the occurrence of end-organ dysfunction can be reduced thereby improving morbidity and mortality. The specific aims will: (1) Determine the effects of parenteral vitamin C on plasma coagulation biomarkers in patients with severe sepsis; (2) Characterize the effect of parenteral vitamin C on platelet function in patients with severe sepsis; and (3) Determine the relationships between Vit C, persistent hypercoagulability, and DIC score in the CITRIS-ALI study. Finally, consistent with the R-15 mechanism, this study will provide pharmacy- and graduate students hands-on experience in clinical and translational research.

描述（由应用提供）：这是一项与我们机构最近资助的NIH UM-1应用相关的辅助研究[UM1-HL116885-01：维生素C：败血症诱导的急性肺损伤（Citris-Ali）治疗的输液]。母体UM-1是双盲，随机，安慰剂对照，多中心，II期临床试验，检查效率与人类败血症相关的急性肺损伤中，高剂量的静脉内维生素C（VITC，抗坏血酸）输注96小时。拟议的辅助研究将检查亲本VITC对败血症相关的凝血病和血小板功能障碍的影响（在母体UM-1中未评估它们）。败血症会引起强烈的全身性促炎和促凝反应，这些反应是由宿主衍生的炎症和凝结介质失调引起的。结果，败血症驱动的凝血诱导凝血和纤维蛋白水解因子的消耗，导致散布血管内凝血（DIC），这是脓毒症最受欢迎的并发症之一，导致肿大的全身微血管血栓形成。 DIC是败血症相关多器官衰竭的关键介质。我们研究团队的远距离目标是制定最佳策略，以降低与人类败血症相关的发病率和死亡率，特别是针对DIC的衰减和其他导致最终器官功能障碍的衰减。我们有初步的数据表明，维生素C显着减轻了动物和人类败血症的炎症和促凝液的级联反应。中心假设是，父母VITC通过恢复止血完整性和血小板功能的归一化来降低人类败血症相关的凝血病。我们认为，发生这种情况的分子基础是通过衰减循环促炎性介体增加的机制（在父级UM-1研究中正在测量）。理由是，如果维生素C减弱败血症的炎症和凝结途径，则可以减少末端器官功能障碍的发生，从而提高发病率和死亡率。具体目的将：（1）确定父母维生素C对严重败血症患者血浆凝血生物标志物的影响；（2）表征父母维生素C对严重败血症患者血小板功能的影响；（3）确定Citris-Ali研究中VIT C，持续性高凝性和DIC评分之间的关系。最后，与R-15机制一致，这项研究将为临床和翻译研究方面的药房和研究生动手经验。