Thaimine as an adjunct metabolic resuscitator in cardiac arrest

泰国胺作为心脏骤停的辅助代谢复苏剂

• 批准号: 9976798
• 负责人: Michael William Donnino
• 金额: $ 12.12万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-09 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9976798
• 关键词: Acetyl Coenzyme A; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Aerobic; Animal Model; Animals; Award; Biological Markers; Blood; Brain; Brain Injuries; Cause of Death; Cell Respiration; Cerebrum; Cessation of life; Citric Acid Cycle; Clinical; Clinical Trials Design; Creatinine; Critical Illness; Data; Dependence; Depressed mood; Dialysis procedure; Enzymes; Funding; Future; Glutathione S-Transferase P; Glycolysis; Goals; Heart; Heart Arrest; Hospitals; Human; Impairment; In Vitro; Incidence; Injury; Injury to Kidney; Intervention; Intravenous; K-Series Research Career Programs; Kidney; Kidney Diseases; Kidney Failure; LCN2 gene; Laboratories; Lactic Acidosis; Link; Measurement; Measures; Mediator of activation protein; Medicine; Mentors; Metabolic; Metabolism; Mitochondria; Morbidity - disease rate; Nervous System Trauma; Neuroprotective Agents; Organ; Outcome; Oxygen Consumption; Parents; Patients; Pattern; Peripheral Blood Mononuclear Cell; Placebos; Prevalence; Production; Property; Publications; Pyruvate; Randomized Clinical Trials; Reaction; Renal function; Research; Research Infrastructure; Research Personnel; Resuscitation; Sampling; Science; Scientist; Sepsis; Septic Shock; Survival Rate; System; Testing; Thiamine; Thiamine Deficiency; Thioctic Acid; Time; Training Programs; Translational Research; United States; United States National Institutes of Health; Work; adverse outcome; alpha ketoglutarate; base; career; cofactor; experience; experimental study; glucose metabolism; improved; insight; ketoglutarate dehydrogenase; mortality; next generation; organ injury; out-of-hospital cardiac arrest; patient oriented; placebo group; post gamma-globulins; prevent; primary outcome; programs; protective effect; pyruvate dehydrogenase; randomized trial; rat KIM-1 protein; treatment group

ABSTRACT There are currently no medicinal interventions demonstrated to consistently improve the low survival rate and high incidence of organ injury after out-of-hospital cardiac arrest (OHCA). Among those who initially survive OHCA, death from arrest-related injury to organs remains frustratingly high, and other-organ injuries are common and often debilitating among OHCA arrest patients who survive to discharge.[1] While cerebral injury is the most lethal[2] and most prevalent organ injury, acute kidney injury (AKI) is also common and is associated with mortality and adverse outcomes such as the need for dialysis[3,4]. Our group is currently engaged in a randomized trial to test if thiamine (vitamin B1) protects the brain after cardiac arrest by improving aerobic metabolism reflected in the reduction of lactic acidosis. However, ongoing research conducted by our group and others has raised new and equally important questions. With this K-24 proposal, we plan to address two of these questions by adding new sub-studies to this trial. The first sub-study tests the hypothesis that thiamine protects not just the brain but also the kidney after cardiac arrest, while the second sub-study tests the hypothesis that cardiac arrest patients have abnormally low pools of a-lipoic acid (LA), another critical mediator of aerobic metabolism, which may place a cap on the efficacy of thiamine therapy. The rationale for the first sub-study is based on recent evidence linking decreased aerobic metabolism in the kidney to renal failure in critical illnesses,[5,6] the stimulatory effect of thiamine on aerobic metabolism, and our randomized trial in sepsis showing that thiamine protected kidney function.[7] The second sub-study is based on our preliminary data suggesting that thiamine may not fully restore cellular oxygen consumption after cardiac arrest. Because aerobic glucose metabolism requires both lipoic acid and thiamine as cofactors for two key enzymes, even subacute lipoic acid deficiencies may place a cap on the efficacy of thiamine as a metabolic resuscitator. Experimental provision of LA has been shown to protect against ischaemic brain and kidney injury; these findings contribute to the rationale for examining LA in the context of our existing trial. Together, these studies will advance thiamine as a potential post-arrest intervention for AKI and deepen our understanding of the relationship of other key metabolic components in critical illness, while also providing an excellent platform to mentor future patient-oriented researchers. This award will provide an established and highly productive clinical researcher and mentor with both project and mentoring support and allow continued expansion of his outstanding translational research training program in the Center for Resuscitation Science (CRS) at BIDMC. The breadth of experiments in the scientific portion of the proposal (clinical trial design/execution and patient-based laboratory work) along with the research infrastructure provided by multiple ongoing CRS studies will give mentees the experience and expertise to progress towards independence as the next generation of researchers in the field of resuscitation medicine.

抽象的 目前尚无药用干预措施始终提高低生存率 院外心脏骤停（OHCA）后的器官损伤发病率很高。在那些最初 生存OHCA，与逮捕相关的器官造成的死亡仍然令人沮丧，其他器官受伤 很常见，并且在生存为出院的OHCA逮捕患者中经常使人衰弱。[1]而脑 受伤是最致命的[2]，最普遍的器官损伤，急性肾脏损伤（AKI）也很常见，很常见 与死亡率和不良后果有关，例如对透析的需求[3,4]。我们的小组目前是 进行了一项随机试验，以测试硫胺素（维生素B1）是否通过 改善乳酸酸中毒还原反射的有氧代谢。但是，正在进行的研究 由我们的小组和其他人进行的，提出了新的和同样重要的问题。有了这个K-24提案， 我们计划通过在此试验中添加新的子研究来解决其中两个问题。第一个子研究测试 硫胺素不仅保护大脑，而且保护心脏骤停后的肾脏的假设，而 第二个子研究检验了心脏骤停患者异常低的库的假设 A-硫酸（LA），另一种关键的有氧代谢介质，可能在 硫胺素治疗的功效。第一个子研究的理由是基于最新的证据 肾脏中有氧代谢减少了肾衰竭的肾衰竭，[5,6] 有氧代谢的硫胺素和败血症的随机试验表明硫胺素受保护的肾脏 功能。[7]第二个子研究基于我们的初步数据，表明硫胺素可能无法完全 恢复心脏骤停后的细胞氧消耗。因为有氧葡萄糖代谢都需要 氟酸和硫胺素作为两个关键酶的辅助因子，甚至是亚急性lipoic酸缺乏症 硫胺素作为代谢复苏者的功效的帽子。已显示LA的实验规定 防止缺血性脑和肾脏损伤；这些发现有助于检查的基本原理 在我们现有审判的背景下。这些研究将共同​​提高硫胺素作为潜在的逮捕后 干预AKI，并加深我们对其他关键代谢组成部分关系的理解 重症疾病，同时还为指导未来的以患者为导向的研究人员提供了出色的平台。这 奖项将为项目和高产的临床研究人员和指导提供项目和指导 指导支持并允许继续扩大其出色的翻译研究培训计划 BIDMC的复苏科学中心（CRS）。科学部分实验的广度 该提案（临床试验设计/执行和基于患者的实验室工作）以及研究 多个正在进行的CRS研究提供的基础设施将为受训者提供经验和专业知识 作为复苏医学领域的下一代研究人员，朝着独立发展。