Effect of Thiamine on Pyruvate Dehydrogenase Activity 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，丙酮酸不能进入克雷布斯循环。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、多器官功能障碍，最终导致死亡。对脓毒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实现代谢复苏尚不清楚。我们假设给脓毒性休克患者静脉注射硫胺素会导致休克

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.