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

 描述（由申请人提供）：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：输注治疗脓毒症诱导的急性肺损伤（CITRIS-ALI）]。母药UM-1是一项双盲、随机、安慰剂对照、多中心、II期临床试验， 大剂量静脉输注维生素C（VitC，抗坏血酸）96小时治疗脓毒症相关急性肺损伤。 拟定的辅助研究将检查肠外VitC对脓毒症相关凝血病和血小板功能障碍的影响（未在母研究UM-1中进行评价）。脓毒症引起强烈的全身性促炎和促凝血反应，这些反应是由宿主来源的炎症和凝血介质的失调引起的。因此，脓毒症驱动的凝血诱导凝血和纤溶因子的消耗，导致弥散性血管内凝血（DIC），这是脓毒症最可怕的并发症之一，导致广泛的全身性微血管血栓形成。DIC是脓毒症相关的多器官衰竭的关键介质。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，特别是针对导致终末器官功能障碍的DIC和其他血栓事件的衰减。我们有初步的数据表明，维生素C显着减弱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VitC通过恢复止血完整性和血小板功能正常化来减少人类脓毒症相关凝血病。我们认为，发生这种情况的分子基础是通过减少循环促炎介质增加的机制（在母研究UM-1中进行了测量）。基本原理是，如果维生素C减弱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，从而改善发病率和死亡率。具体目标是：（1）确定肠外维生素C对严重脓毒症患者血浆凝血生物标志物的影响;（2）描述肠外维生素C对严重脓毒症患者血小板功能的影响;（3）确定CITRIS-ALI研究中维生素C、持续高凝状态和DIC评分之间的关系。最后，与R-15机制一致，本研究将为药学和研究生提供临床和转化研究的实践经验。

 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.