Effect of Thiamine on Pyruvate Dehydrogenase Activity in Septic Shock

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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. 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 improved function of a key enzyme of metabolism, pyruvate dehydrogenase, and this will ultimately lead to improved acidosis and perfusion leading to increased survival; thus, we will perform a randomized clinical trial to evaluate the effect of thiamine (versus placebo) on pyruvate dehydrogenase activity (and outcome measures) in patients with septic shock.