Thiamine as a Metabolic Resuscitator in Septic Shock

描述（由申请人提供）：在美国，感染性休克每年影响超过750，000例患者，估计有250，000例死亡。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必需酶。在缺乏硫胺素的情况下，丙酮酸向乙酰辅酶A的转化被抑制，丙酮酸不能进入三羧酸循环（即，有氧代谢）。由于无氧代谢占主导地位，ATP产生减少，组织缺氧随之而来，丙酮酸转化为乳酸酸中毒。这种有氧代谢的失败反过来又会导致低血压（休克）、多器官功能障碍，最终导致死亡。对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功效提供一种代谢复苏的形式仍然未知。我们推测，感染性休克患者静脉注射硫胺素可减轻乳酸酸中毒，使休克逆转更快。1）硫胺素是丙酮酸脱氢酶的必需辅因子，没有它，厌氧代谢占主导地位，如果不治疗，会发生乳酸酸中毒、休克和死亡（即，脚气病）2）静脉内硫胺素快速逆转乳酸酸中毒和硫胺素缺乏状态下的血液动力学不稳定性（即，脚气病）3）在没有硫胺素缺乏状态下，外源性硫胺素增加丙酮酸脱氢酶的活性4）在没有硫胺素缺乏的情况下，静脉内硫胺素在脓毒性休克动物模型中减轻酸中毒并增加血压5）在没有显著肝损伤的脓毒性休克患者中，硫胺素水平与乳酸酸中毒负相关，使得较低的硫胺素水平与较高水平的乳酸酸中毒相关6）在脓毒性休克患者中，一小部分患者患有临床上未被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，双中心随机试验静脉注射硫胺素与安慰剂，以检验我们的假设。我们相信这项研究是高度创新的，因为在感染性休克中提供一种代谢复苏形式本质上是一个新概念。此外，该研究的结果是高产率的，因为目前没有可用于治疗休克中的代谢功能障碍的疗法。我们将88名感染性休克患者随机分为两组，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），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：每年感染性休克影响超过750，000名患者，死亡人数超过215，000人。硫胺素（维生素B1）是细胞代谢的重要组成部分，如果没有它，乳酸积累，低血压和死亡最终会发生。我们相信接受硫胺素治疗的重症患者将改善血压和酸中毒，最终转化为生存率的提高;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）对脓毒性休克患者的影响。

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.