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，在北美每个国家有超过535，000人受到影响。 年，令人沮丧的事件生存率接近10%。目前没有药物干预证明， 有针对性的温度管理可以说是一个有益的影响后逮捕的结果 只有已知的干预可能改善心脏骤停后脑损伤和生存。因此，新的疗法 旨在降低心脏骤停后患者的死亡率和发病率。硫胺素是一种 丙酮酸脱氢酶（PDH）的必需辅因子，PDH是负责丙酮酸转化的酶 转化为乙酰辅酶A并进入克雷布斯循环（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”或“过度灌注”--全身和大脑抑制 尽管存在足够的氧气输送，但氧气消耗量仍然很大。我们的初步数据证实 发现细胞耗氧量降低，并提出了新的数据，这种抑郁症可以 通过改善的死亡率和神经功能， 心脏骤停小鼠模型的发病率。在小鼠心脏骤停模型中，我们发现静脉注射 硫胺素增加PDH活性，改善脑耗氧量，减轻组织损伤， 大脑的各个区域，提高了生存率，改善了良好的神经功能结果。而我们的老鼠 模型表明，硫胺素可能是有效的独立缺乏，我们还发现， 44%的停搏后患者缺乏硫胺素，与感染性休克的发生率相似。根据这些数据，我们 假设在心脏骤停后患者中施用硫胺素将减轻乳酸酸中毒， 改善细胞耗氧量和改善临床结果。为了验证这个假设，我们将执行一个 前瞻性、II期随机试验研究，为心脏骤停后患者提供硫胺素与安慰剂。 我们的主要终点将是与安慰剂相比，硫胺素组乳酸酸中毒的减轻 手臂乳酸盐不仅可以作为死亡率的替代品，而且可以作为一个参数， 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 细胞耗氧量，增加PDH活性，减弱指示神经损伤的生物标志物，和 改善神经损伤和器官损伤临床终点。这项研究的长期目标是 评价硫胺素作为心脏骤停后患者的一种预防性治疗。硫胺素安全，便宜， 并且易于管理-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了有效性， 这种连续疗法是可行的，有意义的。