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: 9287995
• 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/9287995
• 关键词: Acetyl Coenzyme A; Adoption; Anaerobic Bacteria; Animal Model; Area; Attenuated; Biological Markers; Blood Circulation; Brain; Brain Injuries; 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; Organ; 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; mouse model; neuroprotection; novel; novel therapeutics; pilot trial; primary outcome; prospective; pyruvate dehydrogenase; randomized trial

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.

抽象的 突然心脏骤停是一个主要的公共卫生问题，北美遭受了53.5万人 一年，事件惨淡的生存率接近10％。目前尚无医疗干预措施 对暂停后的结果有益，有针对性的温度管理可以说是 只有已知的干预措施可能会改善后心骤停的脑损伤和生存。那是新疗法 旨在降低后心脏骤停患者的死亡率和发病率是必不可少的。硫胺素是一个 丙酮酸脱氢酶（PDH）的必需辅助因子，丙酮酸转化的酶 进入乙酰辅酶A并进入克雷布斯循环（有氧代谢）。以前的调查人员发现 逮捕后患者表现出“静脉高氧”或“豪华灌注” - 系统性和脑抑制 消耗氧气，尽管存在足够的氧气输送。我们的初步数据证实了 发现抑郁的细胞氧消耗，并提出了这种抑郁症的新数据 通过改善死亡率和神经系统证明的体外硫胺素的给药 心脏骤停的小鼠模型中的发病率。在心脏骤停的鼠模型中，我们发现静脉注射 硫胺素增加了PDH活性，改善了脑氧的消耗，减轻组织学损伤 大脑的各个区域，改善了生存，并改善了良好的神经系统结果。而我们的鼠 模型表明硫胺素可能独立于缺乏症有效，我们确实发现 逮捕后患者中有44％的硫胺素缺乏类似于败血性休克率。基于这些数据，我们 假设在后心脏骤停患者中给予硫胺素会减轻乳酸酸中毒， 改善细胞氧的消耗并改善临床结果。为了检验这一假设，我们将执行 前瞻性，II期随机试验研究为后心骤停患者提供硫胺素与安慰剂。 与安慰剂相比 手臂。乳酸不仅用作死亡率的替代物，还可以作为直接的参数 由硫胺素修饰。我们的次要终点将包括确定硫胺素是否会改善 细胞氧的消耗，增加PDH活性，衰减生物标志物，指示神经系统损伤和 改善神经损伤和器官伤害的临床终点。这一研究的长期目标是 评估硫胺素作为后心脏骤停患者的辅助疗法。硫胺素是安全的，便宜的， 并容易管理 - 因此，如果我们的假设被证明是真实的，并且未来的研究证明了效率，则采用 这种辅助疗法是可行的，而且很重要。