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

维生素 C 输液治疗脓毒症引起的急性肺损伤 (CITRIS-ALI)

基本信息

批准号：
8427795
负责人：
ALPHA Alsbury FOWLER
金额：
$ 76.98万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8427795
关键词：
1-Alkyl-2-acetylglycerophosphocholine Esterase Accounting Acute Acute Lung Injury Address Adrenal Cortex Hormones Adrenergic Agonists Adult Respiratory Distress Syndrome Affect Alveolar Ancillary Study Antioxidants Ascorbic Acid Attenuated Basic Science Biochemical Biological Biological Markers Cause of Death Cessation of life Cognitive Cysteine Data Dose Double-Blind Method Environmental air flow Enzymes Failure Fibrinolysis Human Ibuprofen Immune response Incidence Infusion procedures Injury Interleukin-1 Intervention Intravenous Intravenous infusion procedures Knock-out Lactones Lead Link Liquid substance Lung Measurement Measures Mediator of activation protein Mental Depression Modeling Multicenter Studies Multicenter Trials Multiple Organ Failure Mus Omega-3 Fatty Acids Organ Organ failure Outcome Oxidases Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phenotype Physicians Physiology Placebo Control Placebos Plasma Play Post-Traumatic Stress Disorders Process Randomized Recording of previous events Research Research Personnel Respiratory physiology Role Sepsis Simulate Source TFPI TNF gene Testing Tidal Volume alveolar epithelium base cost effective disability experience improved indexing inhaled nitric oxide lung injury mortality novel strategies pleiotropism randomized trial receptor response septic surfactant synthetic enzyme vascular inflammation

项目摘要

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.

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）是严重败血症的最常见后遗症，导致死亡率大于40％。在200,000人中，足够幸运的是每年都能生存，多年来持续存在肺部残疾，认知异常和创伤后应激障碍。促炎和凝血过程均匀地遵循败血症的发作。它们会损害肺脉管系统和肺泡上皮，并导致ALI/ARDS。三十年的努力减弱使用靶向单个介体拮抗作用诱导肺损伤的化粪池反应的努力未能降低死亡率。只有低潮汐量“肺部保护”通风和保守的流体管理策略显示出死亡率。减弱多种，失调途径的干预措施似乎最有可能改善结果。该应用程序提供了新的数据，表明肠胃外注入的高剂量抗坏血酸（维生素C）破坏了多种促炎/促凝胶级联反应，导致败血性人和小鼠肺损伤。血浆下等离子体维生素C水平在败血症患者中是一致的特征，与多器官衰竭的发生率相反，直接没有多中心试验检查肠胃外维生素C输注，以减轻败血症诱发的肺损伤。我们建议在人类败血症诱导的急性肺损伤中进行随机，双盲，多中心II期概念验证试验。我们的中心假设是：通过静脉输注维生素C（抗坏血酸）的肠胃外增加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的患者的肺损伤将与血浆损伤生物标志物水平降低以及肺功能测量改善有关。该提案包含一项紧密相关的基础科学肺损伤研究，该研究采用小鼠的脓毒肺损伤模型，其中酶合成维生素C的酶被淘汰，从而模拟了人类败血症。第11阶段试验将由4位经验丰富的医师研究人员进行，具有肺部损伤研究史。