Thiamine As A Metabolic Resuscitator In Cardiac Arrest

硫胺素作为心脏骤停中的代谢复苏剂

• 批准号: 9918967
• 负责人: Michael William Donnino
• 金额: $ 43.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918967
• 关键词: Acetyl Coenzyme A; Adoption; Anaerobic Bacteria; Animal Model; Area; Attenuated; Biological Markers; Blood Circulation; Brain; Brain Injuries; Cardiopulmonary Resuscitation; Cell Respiration; Cells; Cerebral cortex; Cerebrum; Cessation of life; Citric Acid Cycle; Clinical; Data; Depressed mood; Emergency medical service; Enzymes; Event; Exhibits; Failure; Future; Goals; Heart Arrest; Hippocampus (Brain); Histologic; Hospitals; Hour; Hyperoxia; In Vitro; Injury; Intervention; Intravenous; Kidney Failure; Lactic Acidosis; Lead; Measures; Mental Depression; Metabolic; Metabolism; Modeling; Mononuclear; Morbidity - disease rate; Nature; Nervous System Trauma; Neurologic; Neurological outcome; North America; Outcome; Oxygen; Oxygen Consumption; Patient-Focused Outcomes; Patients; Pentosephosphates; Perfusion; Persons; Phase; Pilot Projects; Placebos; Public Health; Pyruvate; Randomized; Research; Research Personnel; Resuscitation; Septic Shock; Survival Rate; Temperature; Testing; Thiamine; Thiamine Deficiency; Time; Transketolase; Translating; United States; Venous; alpha ketoglutarate; arm; attenuation; base; brain cell; clinical application; high risk; improved; mortality; mortality risk; mouse model; neuroprotection; novel; novel therapeutics; organ injury; out-of-hospital cardiac arrest; pilot trial; primary endpoint; primary outcome; prospective; pyruvate dehydrogenase; randomized trial; secondary endpoint

Abstract Sudden cardiac arrest is a major public health problem, afflicting over 535,000 persons in North America each year with dismal event survival rates near 10%. There is currently no medicinal intervention demonstrated to have a beneficial effect on post-arrest outcome with targeted temperature management arguably being the only intervention known to potentially improve post-cardiac arrest brain injury and survival. Thus, new therapies aimed at reducing the mortality and morbidity in post-cardiac arrest patients are essential. Thiamine is an essential co-factor of pyruvate dehydrogenase (PDH), the enzyme responsible for the conversion of pyruvate into acetyl-CoA and entry into the Krebs Cycle (aerobic metabolism). Previous investigators have found that post-arrest patients exhibit “venous hyperoxia” or “luxurious perfusion” – the systemic and cerebral inhibition of oxygen consumption despite the presence of adequate oxygen delivery. Our preliminary data confirms the finding of depressed cellular oxygen consumption and puts forth the novel data that this depression can be overcome with the administration of in vitro thiamine as demonstrated by improved mortality and neurological morbidity in a mouse model of cardiac arrest. In a murine model of cardiac arrest, we found that intravenous thiamine increased PDH activity, improved cerebral oxygen consumption, mitigated histological injury to various areas of the brain, improved survival, and improved good neurological outcome. While our murine model suggests thiamine may be effective independent of deficiency, we did additionally find that upwards of 44% of post-arrest patients were thiamine deficient similar to rates in septic shock. Based on these data, we hypothesize that the administration of thiamine in post-cardiac arrest patients will mitigate lactic acidosis, improve cellular oxygen consumption, and improve clinical outcome. To test this hypothesis, we will perform a prospective, Phase II randomized pilot study providing thiamine versus placebo for post-cardiac arrest patients. Our primary endpoint will be attenuation of lactic acidosis in the thiamine group as compared to the placebo arm. Lactate serves not only as a surrogate for mortality but also as a parameter that would be directly modified by thiamine. Our secondary endpoints will include determination of whether thiamine will improve cellular oxygen consumption, increase PDH activity, attenuate biomarkers indicative of neurological injury, and improve clinical endpoints of neurological injury and organ-injury. The long-term goal of this line of research is to evaluate thiamine as an adjunctive therapy for post-cardiac arrest patients. Thiamine is safe, inexpensive, and easily administered – thus, if our hypothesis is proven true and future research proves efficacy, adoption of this adjunctive therapy is feasible and significant.

摘要 心脏骤停是一个主要的公共卫生问题，在北美，每个人都有超过53.5万人受到影响 令人沮丧的事件存活率接近10%。目前还没有药物干预证明 对逮捕后的结果有好处的影响，有针对性的温度管理可以说是 只有已知的干预措施可能改善心脏骤停后的脑损伤和存活率。因此，新的治疗方法 旨在降低心脏骤停后患者的死亡率和发病率至关重要。硫胺素是一种 丙酮酸脱氢酶(PDH)的基本辅助因子，该酶负责丙酮酸的转化 进入乙酰辅酶A和进入克雷布斯循环(有氧代谢)。此前的调查人员发现， 心脏骤停后患者表现出“静脉高氧血症”或“奢侈灌流”--全身和大脑抑制。 尽管存在足够的氧气输送，但仍有氧气消耗。我们的初步数据证实 发现了细胞耗氧量降低的现象，并提出了这种抑郁可能是 通过改善死亡率和神经学表现，克服了体外注射硫胺素的问题 心脏骤停小鼠模型的发病率。在心脏骤停的小鼠模型中，我们发现静脉注射 硫胺素增加PDH活性，改善脑氧耗，减轻组织学损伤 大脑的不同区域，提高存活率，改善良好的神经预后。而我们的小鼠 模型表明硫胺素可能是有效的，不依赖于缺乏，我们还发现 44%的心脏骤停后患者硫胺素缺乏，与感染性休克的发生率相似。根据这些数据，我们 假设在心脏骤停患者中应用硫胺素可以缓解乳酸酸中毒， 改善细胞氧耗，改善临床转归。为了检验这一假设，我们将执行一个 为心脏骤停后患者提供硫胺素和安慰剂的前瞻性第二阶段随机先导研究。 我们的主要终点将是与安慰剂相比，硫胺素组的乳酸酸中毒得到缓解 手臂。乳酸盐不仅可以作为死亡率的替代指标，而且还可以作为一个参数，直接 用硫胺素修饰。我们的次要目标将包括确定硫胺素是否会改善 细胞耗氧量，增加PDH活性，减弱神经损伤的生物标志物，以及 改善神经损伤和器官损伤的临床终点。这一系列研究的长期目标是 目的：评价硫胺素在心脏骤停患者辅助治疗中的作用。硫胺是安全的，便宜的， 而且易于管理--因此，如果我们的假设被证明是正确的，并且未来的研究证明是有效的，那么采用 这种辅助治疗是可行的，也是有意义的。