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.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AT005119-03
Application #
8256604
Study Section
Special Emphasis Panel (ZAT1-LD (32))
Program Officer
Pontzer, Carol H
Project Start
2010-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$277,768
Indirect Cost
$132,404
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Donnino, Michael W; Salciccioli, Justin D; Howell, Michael D et al. (2014) Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis of large in-hospital data registry. BMJ 348:g3028
Moskowitz, Ari; Graver, Amanda; Giberson, Tyler et al. (2014) The relationship between lactate and thiamine levels in patients with diabetic ketoacidosis. J Crit Care 29:182.e5-8
Donnino, Michael W; Andersen, Lars W; Giberson, Tyler et al. (2014) Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study. Crit Care Med 42:1804-11
Kim, Won Young; Giberson, Tyler A; Uber, Amy et al. (2014) Neurologic outcome in comatose patients resuscitated from out-of-hospital cardiac arrest with prolonged downtime and treated with therapeutic hypothermia. Resuscitation 85:1042-6
Flaherty, Sarah K; Weber, Rachel L; Chase, Maureen et al. (2014) Septic shock and adequacy of early empiric antibiotics in the emergency department. J Emerg Med 47:601-7
Omar, Yasser G; Massey, Michael; Andersen, Lars W et al. (2013) Sublingual microcirculation is impaired in post-cardiac arrest patients. Resuscitation 84:1717-22
Andersen, Lars W; Mackenhauer, Julie; Roberts, Jonathan C et al. (2013) Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc 88:1127-40
Donnino, Michael W; Salciccioli, Justin D; Dejam, Andre et al. (2013) APACHE II scoring to predict outcome in post-cardiac arrest. Resuscitation 84:651-6
Salciccioli, Justin D; Cocchi, Michael N; Rittenberger, Jon C et al. (2013) Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients. Resuscitation 84:1728-33