Thiamine as a Metabolic Resuscitator 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。感染性休克的特征可能是低血压、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的转化受到抑制，丙酮酸不能进入三羧酸循环(即有氧代谢)。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(休克)、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效率来提供一种代谢复苏的形式。我们推测，感染性休克患者静脉注射硫胺素将导致乳酸酸中毒的减轻和休克的更快逆转。我们从以下几个方面支持这一假说：1)硫胺素是丙酮酸脱氢酶的重要辅助因子，没有硫胺素的情况下，无氧代谢占主导地位，乳酸血症、休克和死亡如果不经治疗(如脚气病)就会发生。2)静脉注射硫胺素能迅速逆转缺乏硫胺素状态(如脚气病)的乳酸酸中毒和血流动力学不稳定。3)在没有硫胺素缺乏状态的情况下，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感染性休克动物模型中，静脉注射硫胺素可减轻酸中毒并升高血压。硫胺素水平与乳酸酸中毒呈负相关，即低硫胺素水平与高乳酸酸中毒水平相关。6)在感染性休克患者中，有一小部分患者存在临床上未发现的绝对硫胺素缺乏症。因此，我们建议进行以下前瞻性、双盲、双中心的静脉注射硫胺素与安慰剂的随机试验，以验证我们的假设。我们相信这项拟议的研究具有很高的创新性，因为在感染性休克中提供一种形式的代谢复苏本质上是一个新的概念。此外，这项研究的结果是高收益的，因为目前还没有治疗休克时代谢功能障碍的方法。我们将随机选择88名感染性休克患者，分别接受硫胺素或安慰剂治疗7天。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)，这种干预措施具有更大的疗效和转化为临床实践的潜力。 公共卫生相关性：感染性休克每年影响超过75万名患者，超过21.5万人死亡。硫胺素(维生素B1)是细胞代谢的重要组成部分，如果没有它，乳酸堆积、低血压和死亡最终都会发生。我们相信，接受硫胺素治疗的危重患者将改善血压和酸中毒，最终将转化为增加存活率；因此，我们将进行一项随机临床试验，以评估硫胺素(与安慰剂相比)对感染性休克患者的疗效。

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.