Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI)

描述（由申请人提供）：急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是严重脓毒症最常见的后遗症，死亡率超过40%。每年有20万幸运地从急性肺损伤中存活下来的人，会出现持续多年的肺残疾、认知异常和创伤后应激障碍。促炎和促凝过程均随脓毒症的发生而发生。它们损害肺血管和肺泡上皮，导致ALI/ARDS。三十年来，使用靶向单一介质拮抗来减轻脓毒性反应诱导肺损伤的努力未能降低死亡率。只有低潮气量“肺保护”通气和保守的液体管理策略显示死亡率的好处。减少多种失调通路的干预似乎最有可能改善结果。该应用程序提供了新的数据，显示肠外输注高剂量抗坏血酸（维生素C）可破坏导致败血症人类和小鼠肺损伤的多种促炎/促凝级联反应。血浆维生素C水平低于正常水平是脓毒症患者的一贯特征，与多器官衰竭的发生率成反比，并与生存率直接相关。目前尚无多中心试验检验肠外维生素C输注作为减轻脓毒症引起的肺损伤的干预措施。我们建议进行一项随机、双盲、安慰剂对照、多中心的II期概念验证试验，研究大剂量静脉注射维生素C（抗坏血酸）对人类败血症诱导的急性肺损伤的影响。我们的中心假设是：通过静脉输注增强维生素C（抗坏血酸）将减轻严重败血症发作后的肺损伤。我们进一步假设：接受维生素C治疗的患者肺损伤减轻与血浆损伤生物标志物水平降低和肺功能测量改善有关。该提案包含了一项紧密相关的基础科学肺损伤研究，该研究在脓毒性肺损伤的小鼠模型中使用了一种合成维生素C的酶被敲除的小鼠，从而模拟了人类败血症。11期临床试验将由4名具有肺损伤研究历史的经验丰富的医师进行。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the most common sequelae of severe sepsis leading to greater than 40% mortality. In the 200,000 people fortunate enough to survive ALI annually, many years of persisting pulmonary disability, cognitive abnormalities, and post-traumatic stress disorder result. Proinflammatory and procoagulant processes uniformly follow the onset of sepsis. They damage lung vasculature and alveolar epithelium and lead to ALI/ARDS. Three decades of efforts to attenuate septic responses that induce lung injury using targeted single mediator antagonism have failed to reduce mortality. Only low tidal volume "lung-protective" ventilation and conservative fluid management strategies show a mortality benefit. An intervention that attenuates multiple, dysregulated pathways seems most likely to improve outcomes. This application presents new data showing that parenterally infused high dose ascorbic acid (vitamin C) disrupts multiple proinflammatory/procoagulant cascades that lead to lung injury in septic humans and mice. Subnormal plasma vitamin C levels are a consistent feature in septic patients, varying inversely with the incidence of multiple organ failure and directly with survival No multicenter trials have examined parenteral vitamin C infusion as an intervention to attenuate sepsis-induced lung injury. We propose to conduct a randomized, double-blind, placebo-controlled, multi-center phase II proof of concept trial examining high dose intravenous vitamin C (ascorbic acid) infusion in human sepsis induced acute lung injury. Our central hypothesis is that: Parenteral augmentation of vitamin C (ascorbic acid) by intravenous infusion will attenuate lung injury that follows onset of severe sepsis. We further hypothesize that: Attenuated lung injury in patients receiving vitamin C will be associated with reduced plasma levels of injury biomarkers and improved measurements of lung function. The proposal contains a tightly linked basic science lung injury study in a murine model of septic lung injury employing mice in whom enzyme that synthesizes vitamin C has been knocked out, thus simulating human sepsis. The phase 11 trial will be conducted by 4 highly experienced physician- investigators with a history of lung injury research.