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(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，导致超过40%的死亡率。在每年幸存于ALI的20万人中，多年来持续存在的肺部残疾、认知异常和创伤后应激障碍导致了ALI。促炎症和促凝血的过程在脓毒症发生后一致发生。它们损伤肺血管和肺泡上皮，导致ALI/ARDS。三十年来，使用有针对性的单一介质拮抗剂来减轻引起肺损伤的败血症反应的努力未能降低死亡率。只有低潮气量的“肺保护”呼吸机和保守的液体管理策略才能显示出死亡率的好处。减少多条失调通路的干预似乎最有可能改善结果。这项应用提供了新的数据显示，静脉注射大剂量抗坏血酸(维生素C)可以破坏导致败血症人类和小鼠肺损伤的多种促炎/促凝血剂级联反应。在脓毒症患者中，血浆维生素C水平低于正常水平是一个一贯的特征，与多器官衰竭的发生率成反比，与存活率成正比没有多中心试验研究过静脉输注维生素C作为减轻脓毒症所致肺损伤的干预措施。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)治疗人类败血症所致急性肺损伤。我们的中心假设是：静脉输注维生素C(抗坏血酸)可以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治疗的患者的肺损伤减轻将与血浆损伤生物标志物水平的降低和肺功能测量的改善有关。该提案包含了一项紧密联系的基础科学肺损伤研究，该研究是在一种败血症肺损伤的小鼠模型中进行的，该模型使用的是合成维生素C的酶已经被敲除的小鼠，从而模拟人类败血症。11期试验将由4名有肺损伤研究历史的经验丰富的内科研究员进行。

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