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

 描述(申请人提供)：这是一项与我们机构最近资助的NIH UM-1申请相关的辅助研究[UM1-HL116885-01：维生素C：输注治疗败血症所致急性肺损伤(CITRIS-ALI)]。母公司UM-1是一项双盲、随机、安慰剂对照、多中心、II期临床试验，检查疗效 大剂量维生素C静脉滴注96小时治疗人败血症相关性急性肺损伤 这项拟议的辅助研究将检验肠外维生素C对败血症相关凝血障碍和血小板功能障碍的影响(母体UM-1中没有对其进行评估)。脓毒症引起强烈的全身性促炎和促凝血反应，这些反应源于宿主来源的炎症和凝血介质的失调。因此，脓毒症引起的凝血和纤溶因子的消耗导致弥漫性血管内凝血(DIC)，DIC是脓毒症最可怕的并发症之一，导致广泛的全身微血管血栓形成。DIC是脓毒症相关性多器官衰竭的重要介质。我们研究团队的长期目标是开发最佳策略，以降低与人类脓毒症相关的发病率和死亡率，特别是针对DIC和其他导致终末器官功能障碍的血栓事件的减轻。我们有初步数据表明，维生素C显著减轻动物和人类脓毒症的炎症和促凝血级联反应。中心假设是，肠外维生素C通过恢复止血完整性和恢复血小板功能正常化来减少人类脓毒症相关的凝血障碍。我们认为，这种情况发生的分子基础是通过减轻循环促炎介质增加的机制(在母公司UM-1研究中正在测量)。其理论基础是，如果维生素C减弱了脓毒症中的炎症和凝血途径，则可以减少终末器官功能障碍的发生，从而提高发病率和死亡率。具体目标将：(1)确定肠外维生素C对严重脓毒症患者血浆凝血生物标记物的影响；(2)确定肠外维生素C对严重脓毒症患者血小板功能的影响；以及(3)在CITRIS-ALI研究中确定维生素C、持续性高凝状态和DIC评分之间的关系。最后，与R-15机制一致，这项研究将为药学和研究生提供临床和翻译研究的实践经验。

 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.