Effect of Thiamine on Pyruvate Dehydrogenase Activity in Septic Shock

硫胺素对感染性休克中丙酮酸脱氢酶活性的影响

• 批准号: 8300600
• 负责人: Michael William Donnino
• 金额: $ 10.29万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300600
• 关键词: Acetyl Coenzyme A; Acidosis; Adverse effects; Affect; Allergic Reaction; Animal Model; Antibodies; Attenuated; Beriberi; Biological Assay; Blood Pressure; Cell Count; Cell Respiration; Cessation of life; Citrate (si)-Synthase; Citric Acid Cycle; Critical Illness; Cytolysis; Double-Blind Method; Enrollment; Enzymes; Failure; Freezing; Functional disorder; Hour; Human; Hypotension; Hypoxia; Inflammatory Response; Injury; Intervention; Intravenous; Investigation; Lactic Acidosis; Lactic acid; Lead; Liver; Measurement; Measures; Metabolic; Metabolism; Mitochondria; NADH; Organ; Outcome Measure; Participant; Patients; Perfusion; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Placebos; Procedures; Production; Proteins; Pyruvate; Pyruvate Metabolism Pathway; Randomized; Randomized Clinical Trials; Reaction; Resuscitation; Sampling; Septic Shock; Shock; Testing; Thiamine; Thiamine Deficiency; Time; Tissues; Translations; United States; Vasoconstrictor Agents; affection; attenuation; base; clinical practice; hemodynamics; improved; improved functioning; innovation; intravenous administration; novel; prospective; pyruvate dehydrogenase; randomized trial

DESCRIPTION (provided by applicant): Septic shock affections over 750,000 patients each year in the United States with an estimated 250,000 deaths. Septic shock is characterized by hypotension, high metabolic state, lactic acidosis and potentially death. Vitamin B1 (thiamine) is a co-factor for pyruvate dehydrogenase, an essential enzyme for aerobic metabolism. In the absence of thiamine, the conversion of pyruvate to acetyl-CoA is inhibited and pyruvate cannot enter the Kreb's cycle. With anaerobic metabolism predominating, ATP production is reduced, tissue hypoxia ensues, and pyruvate is converted to lactic acidosis. This failure to undergo aerobic metabolism, in turn, leads to hypotension, multi- organ dysfunction, and ultimately death. Whether the provision of thiamine to patients in septic shock would provide metabolic resuscitation by improving the efficacy of pyruvate dehydrogenase remains unknown. We hypothesize that the administration of intravenous thiamine to patients in septic shock will result in attenuation of lactic acidosis and a more rapid reversal of shock. We further hypothesize that the underlying mechanism for this will be through the activation of pyruvate dehydrogenase. We support this hypothesis through the following: 1) Thiamine is an essential co-factor for pyruvate dehydrogenase without which anaerobic metabolism predominates and lactic acidosis, shock, and death occurs if untreated (i.e., beriberi) 2) Intravenous thiamine rapidly reverses lactic acidosis and hemodynamic instability in thiamine deficient states (i.e., beriberi) 3) In the absence of thiamine deficiency, exogenous thiamine increases the activity of pyruvate dehydrogenase 4) In the absence of thiamine deficiency, intravenous thiamine attenuates acidosis and increases blood pressure in an animal model of septic shock 5) In patients with septic shock without significant liver injury, thiamine levels are negatively associated with lacti acidosis such that lower thiamine levels are associated with higher levels of lactic acidosis 6) In patients with septic shock, a small percentage of patients have clinically unrecognized absolute thiamine deficiency. Thus we will perform a prospective, double blind, two-center randomized trial of intravenous thiamine versus placebo in order to test our hypotheses. The proposed study is highly innovative in that metabolic resuscitation in septic shock is essentially a novel concept Moreover, the results of this investigation are high yield in that there is currently no therapy available for treatment of metabolic dysfunction in shock. Since intravenous thiamine has essentially no described side effects (save the extremely rare allergic reaction), the intervention has an even greater potential for efficacy and translation into clinical practice. PUBLIC HEALTH RELEVANCE: Septic shock affects over 750,000 patients each year with over 215,000 deaths. Thiamine (vitamin B1) is an essential component of cellular metabolism without which lactic acid build-up, low blood pressure, and death will ultimately occur. We believe that critically ill patients who receive thiamine will have improved function of a key enzyme of metabolism, pyruvate dehydrogenase, and this will ultimately lead to improved acidosis and perfusion leading to increased survival; thus, we will perform a randomized clinical trial to evaluate the effect of thiamine (versus placebo) on pyruvate dehydrogenase activity (and outcome measures) in patients with septic shock.

描述（由申请人提供）：美国每年有750,000名患者的败血性休克感受，估计有25万人死亡。败血性休克的特征是低血压，高代谢状态，乳酸性酸中毒和潜在的死亡。维生素B1（硫胺素）是丙酮酸脱氢酶的共同因素，这是有氧代谢的必不可少的酶。在没有硫胺素的情况下，丙酮酸转化为乙酰辅酶A，丙酮酸不能进入KREB的周期。随着厌氧代谢为主，ATP产生减少，组织缺氧随之而来，丙酮酸转化为乳酸酸中毒。这种未能经历有氧代谢的情况又导致低血压，多器官功能障碍并最终导致死亡。硫胺素向患者提供败血性休克是否会通过提高丙酮酸脱氢酶的疗效来提供代谢复苏。我们假设将静脉硫胺素施用给败血性休克患者将导致 乳酸性酸中毒的衰减和冲击的迅速逆转。我们进一步假设，这种基本机制将是通过丙酮酸脱氢酶的激活。我们通过以下以下方式支持这一假设：1）硫胺素是丙酮酸脱氢酶的必要共同因素，没有此化合物的厌氧代谢占主导地位和乳酸性酸中毒，休克，如果没有治疗（即beriberi）（即Beriberii）2）静脉曲张迅速扭转了乳酸酸性和血小化酸性的含量（beriberi）。在没有硫胺素不足的情况下，外源硫胺素会增加丙酮酸脱氢酶的活性4）在缺乏硫胺素缺乏的情况下，静脉硫胺素会减轻酸中毒的酸中毒，并增加败血性休克动物模型5）在患者中，患者没有明显的肝酸性水平，硫酸含量较高，硫胺素水平较高，硫酸含量较高，硫酸含量较高，而硫酸含量较高，硫酸含量较低，而硫酸含量较低，而硫酸含量较低，硫酸含量较低，而硫酸含量较高，而硫酸含量较高，而硫酸含量较高，而硫酸含量较低，而硫酸含量较低。 在 败血性休克患者，少数患者在临床上无法识别绝对硫胺素缺乏症。因此，我们将进行静脉注射硫胺素与安慰剂的前瞻性，双盲，两中心随机试验，以检验我们的假设。拟议的研究具有很高的创新性，因为化脓性休克中的代谢复苏本质上是一个新颖的概念，因此该研究的结果很高，因为目前尚无治疗可休克中代谢功能障碍的治疗。由于静脉注射硫胺素基本上没有描述的副作用（节省极罕见的过敏反应），因此 具有更大的功效和转化为临床实践的潜力。 公共卫生相关性：败血性冲击每年影响超过750,000名患者，死亡超过215,000例。硫胺素（维生素B1）是细胞代谢的重要组成部分，乳酸累积，低血压和死亡最终将发生。我们认为，接受硫胺素的重症患者将改善代谢，丙酮酸脱氢酶的关键酶的功能，这最终将改善酸中毒和灌注，从而提高生存率；因此，我们将进行一项随机临床试验，以评估硫酸酯（与安慰剂）对脓毒症性休克患者丙酮酸脱氢酶活性（和结果测量）的影响。