Thiamine as a Metabolic Resuscitator in Septic Shock

描述（由申请人提供）：美国每年有超过75万患者感染感染性休克，估计有25万人死亡。感染性休克的特点可能是低血压、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的转化受到抑制，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，丙酮酸转化为乳酸性酸中毒。这种不能进行有氧代谢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。是否向脓毒性休克患者提供硫胺素会通过提高丙酮酸脱氢酶的疗效提供一种形式的代谢复苏尚不清楚。我们假设，对脓毒性休克患者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。我们通过以下方式来支持这一假设：1)硫胺素是丙酮酸脱氢酶的重要辅助因子，如果不进行治疗，厌氧代谢占主导地位，乳酸酸中毒、休克和死亡就会发生（如脚气病）2)静脉注射硫胺素可迅速逆转硫胺素缺乏状态（如脚气病）下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下，外源性硫胺素可增加丙酮酸脱氢酶的活性4)在没有硫胺素缺乏的情况下，在脓毒性休克动物模型中，静脉注射硫胺素减轻酸中毒并升高血压5)在没有明显肝损伤的脓毒性休克患者中，硫胺素水平与乳酸酸中毒呈负相关，即较低的硫胺素水平与较高的乳酸酸中毒水平相关6)在脓毒性休克患者中，一小部分患者存在临床未发现的绝对硫胺素缺乏症。因此，我们提出以下前瞻性，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。我们认为这项研究具有高度的创新性，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产的，因为目前还没有治疗休克代谢功能障碍的方法。我们将随机抽取88例脓毒性休克患者，让他们在7天内服用硫胺素或安慰剂。由于静脉注射硫胺素基本上没有已知的副作用（除了极其罕见的过敏反应），这种干预措施具有更大的功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 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.