Effect of Thiamine on Pyruvate Dehydrogenase Activity in Septic Shock

描述(由申请人提供)：在美国，每年有超过75万名患者发生感染性休克，估计有25万人死亡。感染性休克的特征是低血压、高代谢状态、乳酸酸中毒和潜在的死亡。维生素B1(硫胺素)是丙酮酸脱氢酶的辅助因子，丙酮酸脱氢酶是有氧代谢的关键酶。在没有硫胺素的情况下，丙酮酸向乙酰辅酶A的转化被抑制，丙酮酸不能进入Kreb循环。在厌氧代谢占主导地位的情况下，ATP的产生减少，组织随后缺氧，丙酮酸转化为乳酸酸中毒。这种不能进行有氧代谢的情况，反过来会导致低血压、多器官功能障碍，最终导致死亡。目前尚不清楚为感染性休克患者提供硫胺素是否会通过提高丙酮酸脱氢酶的疗效来提供代谢复苏。我们推测，感染性休克患者静脉注射硫胺素将导致 在乳酸酸中毒的缓解和休克的更快逆转方面。我们进一步假设，其潜在的机制将是通过激活丙酮酸脱氢酶。我们通过以下方式支持这一假说：1)硫胺素是丙酮酸脱氢酶的基本辅助因子，如果没有硫胺素缺乏治疗(即脚气病)，丙酮酸脱氢酶占主导地位，乳酸酸中毒、休克和死亡就会发生。2)静脉注射硫胺素能迅速逆转缺乏硫胺素状态(脚气病)的乳酸酸中毒和血流动力学不稳定。3)在没有硫胺素缺乏的情况下，外源性硫胺素增加丙酮酸脱氢酶的活性4)在没有明显肝脏损伤的败血性休克动物模型中，静脉注射硫胺素可以减轻酸中毒和升高血压。5)在感染性休克的动物模型中，没有明显的肝脏损伤，硫胺素水平与乳酸血症呈负相关，因此硫胺素水平低与乳酸血症水平高有关。 感染性休克患者中，有一小部分患者存在临床上无法识别的绝对硫胺素缺乏症。因此，我们将进行一项前瞻性、双盲、双中心随机试验，比较静脉注射硫胺素和安慰剂，以检验我们的假设。这项拟议的研究具有很高的创新性，因为感染性休克的代谢复苏本质上是一个新的概念，而且，这项研究的结果是高产出的，因为目前还没有治疗休克时代谢功能障碍的方法。由于静脉注射硫胺素基本上没有描述的副作用(除了极其罕见的过敏反应)，干预措施 具有更大的疗效和转化为临床实践的潜力。

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.