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.
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.
|Andersen, Lars W; Kim, Won Young; Chase, Maureen et al. (2016) The prevalence and significance of abnormal vital signs prior to in-hospital cardiac arrest. Resuscitation 98:112-7|
|Andersen, Lars W; Holmberg, Mathias J; Berg, Katherine M et al. (2016) Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial. Crit Care 20:92|
|Andersen, Lars W; Liu, Xiaowen; Peng, Teng J et al. (2015) Pyruvate Dehydrogenase Activity and Quantity Decreases After Coronary Artery Bypass Grafting: a Prospective Observational Study. Shock 43:250-4|
|Peng, Teng J; Andersen, Lars W; Saindon, Brian Z et al. (2015) The administration of dextrose during in-hospital cardiac arrest is associated with increased mortality and neurologic morbidity. Crit Care 19:160|
|Andersen, Lars W; Berg, Katherine M; Saindon, Brian Z et al. (2015) Time to Epinephrine and Survival After Pediatric In-Hospital Cardiac Arrest. JAMA 314:802-10|
|Andersen, Lars W; Holmberg, Mathias J; Doherty, Michelle et al. (2015) Postoperative Lactate Levels and Hospital Length of Stay After Cardiac Surgery. J Cardiothorac Vasc Anesth 29:1454-60|
|Donnino, Michael W; Mortensen, Sharri J; Andersen, Lars W et al. (2015) Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized, double-blind, placebo-controlled, pilot trial. Crit Care 19:275|
|Lokhandwala, Sharukh; Moskowitz, Ari; Lawniczak, Rebecca et al. (2015) Disease heterogeneity and risk stratification in sepsis-related occult hypoperfusion: A retrospective cohort study. J Crit Care 30:531-6|
|Liu, Xiaowen; Pervez, Hira; Andersen, Lars W et al. (2015) Immunocapture and microplate-based activity and quantity measurement of pyruvate dehydrogenase in human peripheral blood mononuclear cells. Bioanalysis 7:583-92|
|Nuzzo, Erin; Berg, Katherine M; Andersen, Lars W et al. (2015) Pyruvate Dehydrogenase Activity Is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis. A Prospective Observational Trial. Ann Am Thorac Soc 12:1662-6|
Showing the most recent 10 out of 26 publications