Thiamine as a Metabolic Resuscitator in Septic Shock

硫胺素作为感染性休克的代谢复苏剂

• 批准号: 7786950
• 负责人: Michael William Donnino
• 金额: $ 22.68万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7786950
• 关键词: APACHE II; Acetyl Coenzyme A; Acidosis; Adverse effects; Affect; Allergic Reaction; Animal Model; Antihypertensive Agents; Attenuated; Beriberi; Blood Pressure; Burn Trauma; Cardiovascular system; Cell Respiration; Cessation of life; Citric Acid Cycle; Critical Illness; Double-Blind Method; Enzymes; Exhibits; Failure; Functional disorder; Guidelines; Heart Arrest; Hospitals; Hour; Human; Hypotension; Hypoxia; Inflammatory Response; Injury; Intervention; Intravenous; Investigation; Lactic Acidosis; Lactic acid; Liver; Metabolic; Metabolism; Organ; Participant; Patients; Pharmaceutical Preparations; Placebos; Production; Pyruvate; Pyruvates; Randomized; Randomized Clinical Trials; Resuscitation; Sepsis; Septic Shock; Severity of illness; Shock; Testing; Thiamine; Thiamine Deficiency; Time; Tissues; Translating; Translations; United States; Vasoconstrictor Agents; affection; attenuation; clinical practice; hemodynamics; improved; improved functioning; innovation; intravenous administration; mortality; novel; prospective; public health relevance; 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 may be 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 tricarboxylic acid cycle (i.e., aerobic metabolism). 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 (shock), multi- organ dysfunction, and ultimately death. Whether the provision of thiamine to patients in septic shock would provide a form of metabolic resuscitation through 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 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 deficient states, 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 lactic 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 harbor clinically unrecognized absolute thiamine deficiency. Thus we propose the following prospective, double blind, two-center randomized trial of intravenous thiamine versus placebo in order to test our hypotheses. We believe the proposed study is highly innovative in that providing a form of 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. We will randomize a total of 88 patients who are in septic shock to receive either thiamine or placebo for seven days. 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 improvement of blood pressure and acidosis that would ultimately translate to increased survival; thus, we will perform a randomized clinical trial to evaluate the effect of thiamine (versus placebo) for 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，丙酮酸不能进入三羧酸周期（即有氧代谢）。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（冲击），多器官功能障碍并最终导致死亡。硫胺素在败血性休克中提供给患者是否会通过提高丙酮酸脱氢酶的疗效来提供一种代谢复苏形式。我们假设在败血性休克患者中静脉注射硫胺素将导致乳酸酸中毒的衰减和休克的更快逆转。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）。在硫胺素不足状态的情况下，外源硫胺素会增加丙酮酸脱氢酶的活性4）在没有硫胺素缺乏的情况下，硫胺素缺乏，静脉内硫胺抑制了酸中毒，在败血性休克动物模型5）中，患者的败血性休克动物模型5）与脓毒症的水平较高，硫0蛋白含量较高，硫酸含量较高，硫酸含量较高，硫酸含量较高，硫酸含量较高，硫酸含量较高，而硫酸含量较低，而硫酸含量较高，而硫酸含量较低，而尿素酸性较高，而乳酸酸性较高，则较高6）在患有败血性休克的患者中，少数患者在临床上无法识别的绝对硫胺素缺乏症。因此，我们提出了以下前瞻性，双盲，两中心的随机试验，静脉注射硫胺素与安慰剂，以检验我们的假设。我们认为这项拟议的研究具有很高的创新性，即在化脓性休克中提供一种代谢复苏的形式本质上是一个新颖的概念。此外，这项研究的结果很高，因为目前尚无可用于冲击代谢功能障碍的治疗。我们将随机分组88例感染性休克的患者，以接受硫胺素或安慰剂7天。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），因此该干预措施具有更大的功效潜力，并将其转化为临床实践。 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血压和酸中毒，最终将转化为增加的生存。因此，我们将进行一项随机临床试验，以评估硫胺素（与安慰剂）对败血性休克患者的作用。