Thiamine v placebo to improve oxygen consumption after in-hospital cardiac arrest

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 DESCRIPTION (provided by applicant): Over 200,000 people suffer an in-hospital cardiac arrest (IHCA) each year in the United States, and over 80% of those will die. In spite of this extremely high mortality, relatively few trials have been done to investigate treatments to improve outcomes after IHCA. In patients who achieve return of spontaneous circulation (ROSC), the most common cause of death is shock and multi- organ failure. The post-arrest syndrome has been likened to sepsis/septic shock, and both conditions appear to be characterized by impaired oxygen extraction in many patients. This may contribute to increased lactate, failure to clear lactate, and decreased oxygen consumption (VO2), all of which are associated with higher mortality in both sepsis and post-cardiac arrest. We have also found that pyruvate dehydrogenase (PDH), an enzyme required for the Krebs Cycle, is low in sepsis and after cardiac arrest, and that lower levels are associated with higher mortality in sepsis. All of these indicators suggest a dysfunction in aerobic metabolism, and an intervention that could rectify this defect could lead to lower lactate values, increased VO2 and potentially better outcomes. Thiamine, a co-factor of PDH, is also required for aerobic metabolism. We have found that thiamine deficiency is common in septic shock and after cardiac arrest, and that thiamine levels are inversely associated with lactate levels in septic shock and other forms of critical illness. We have also found that thiamine administration lowers lactate and improves survival in thiamine deficient septic shock patients, is associated with a rise in VO2 in criticall ill patients with preserved cardiac index (regardless of thiamine level), and appears to increase PDH activity after major cardiac surgery. We therefore hypothesize that thiamine will increase VO2, increase PDH activity and decrease lactate after IHCA. We propose a phase II randomized, blinded, placebo-controlled trial in 60 patients who obtain sustained ROSC after in-hospital cardiac arrest and have preserved cardiac index to test this hypothesis. All enrolled patients will be randomized to either thiamine 200mg or placebo every 12 hours for 24 hours. We will record VO2 and cardiac index data continuously for 24 hours, and will check PDH quantity and activity and lactate at 0, 12 and 24 hours. The primary outcome will be the change in VO2, and the secondary outcomes will be change in PDH activity and lactate. We anticipate that VO2 and PDH activity will rise while lactate will decrease in patients who receive thiamine as compared to placebo. Prior research on VO2 after cardiac arrest is extremely limited, and as such we believe our data will be a significant contribution to the literature on cardiac arrest and the post-arrest syndrome, even if our study results are not positive.