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)

• 批准号: 8913252
• 负责人: ALPHA Alsbury FOWLER
• 金额: $ 85.37万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913252
• 关键词: Accounting; 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; 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; Multicenter Studies; Multicenter Trials; Multiple Organ Failure; Mus; Omega-3 Fatty Acids; Organ; Organ failure; Oxidases; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; 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; Source; TFPI; TNF gene; Testing; Tidal Volume; alveolar epithelium; base; cognitive disability; cost effective; disability; experience; improved; improved outcome; indexing; inhaled nitric oxide; lung injury; mortality; mouse model; novel strategies; phase I trial; phase II trial; pleiotropism; randomized trial; receptor; response; septic; surfactant; synthetic enzyme; vascular inflammation

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（由申请方提供）：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，导致超过40%的死亡率。每年有20万人幸运地从急性肺损伤中幸存下来，这些人多年来一直患有肺功能障碍、认知异常和创伤后应激障碍。促炎和促凝血过程一致遵循败血症的发作。它们损伤肺血管和肺泡上皮，导致ALI/ARDS。三十年来，使用靶向单介质拮抗剂来减弱诱导肺损伤的脓毒症反应的努力未能降低死亡率。只有低潮气量“肺保护”通气和保守液体管理策略显示出死亡率获益。削弱多种失调途径的干预似乎最有可能改善结果。本申请提供了新的数据，表明胃肠外输注高剂量抗坏血酸（维生素C）破坏了导致脓毒症人类和小鼠肺损伤的多种促炎/促凝血级联反应。血浆维生素C水平低于正常是脓毒症患者的一个一致特征，与多器官衰竭的发生率呈负相关，与生存率直接相关。没有多中心试验研究静脉输注维生素C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，研究大剂量静脉输注维生素C（抗坏血酸）治疗人脓毒症引起的急性肺损伤。我们的中心假设是：静脉输注维生素C（抗坏血酸）可减轻严重脓毒症发作后的肺损伤。我们进一步假设：接受维生素C治疗的患者肺损伤减轻将与损伤生物标志物的血浆水平降低和肺功能测量改善相关。该提案包含一项密切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合成维生素C的酶被敲除的小鼠，从而模拟了人类脓毒症。11期试验将由4名具有肺损伤研究史的经验丰富的医生-研究者进行。

项目成果

Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock?

• DOI: 10.1186/s13054-015-1131-2
• 发表时间: 2015-11-27
• 期刊: Critical care (London, England)
• 作者: Carr AC;Shaw GM;Fowler AA;Natarajan R
• 通讯作者: Natarajan R

Biological Effects of Intravenous Vitamin C on Neutrophil Extracellular Traps and the Endothelial Glycocalyx in Patients with Sepsis-Induced ARDS.

静脉内维生素C对嗜中性粒细胞外陷阱和内皮糖脂的生物学作用对脓毒症诱导的ARDS患者的生物学作用。

• DOI: 10.3390/nu14204415
• 发表时间: 2022-10-21
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Qiao X;Kashiouris MG;L'Heureux M;Fisher BJ;Leichtle SW;Truwit JD;Nanchal R;Hite RD;Morris PE;Martin GS;Sevransky J;Fowler AA
• 通讯作者: Fowler AA

Intravenous Vitamin C Administered as Adjunctive Therapy for Recurrent Acute Respiratory Distress Syndrome.

• DOI: 10.1155/2016/8560871
• 发表时间: 2016
• 期刊: Case reports in critical care
• 作者: Bharara A;Grossman C;Grinnan D;Syed A;Fisher B;DeWilde C;Natarajan R;Fowler AA
• 通讯作者: Fowler AA