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.

Public Health Relevance

Cardiac arrest occurs in more than 200,000 patients annually in the United States, and 80% of those people die. After cardiac arrest, evidence suggests that our cells' ability to use oxygen breaks down, and when this occurs it is associated with higher rates of death. The ability to metabolize oxygen is partially dependent on thiamine, or vitamin B1. We have found that many post-cardiac arrest patients become deficient in thiamine, and we think that giving thiamine will help restore the cells' normal ability to use oxygen. We are therefore proposing a trial in which patients who get a pulse back after cardiac arrest resuscitation will be treated with either thiamine or placebo for 24 hours. We will measure their oxygen consumption (an indicator of how well their cells are using oxygen) as well as other lab tests that will help us determine how well aerobic metabolism is working, and compare them between groups.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL128814-03
Application #
9546824
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Scott, Jane
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Moskowitz, Ari; Ross, Catherine E; Andersen, Lars W et al. (2018) Trends Over Time in Drug Administration During Adult In-Hospital Cardiac Arrest. Crit Care Med :
Uber, Amy; Grossestreuer, Anne V; Ross, Catherine E et al. (2018) Preliminary observations in systemic oxygen consumption during targeted temperature management after cardiac arrest. Resuscitation 127:89-94
Moskowitz, Ari; Holmberg, Mathias J; Donnino, Michael W et al. (2018) In-hospital cardiac arrest: are we overlooking a key distinction? Curr Opin Crit Care 24:151-157
Moskowitz, Ari; Grossestreuer, Anne V; Berg, Katherine M et al. (2018) The association between tidal volume and neurological outcome following in-hospital cardiac arrest. Resuscitation 124:106-111
Berg, Katherine M (2018) Finding a window: Timing of cardiac ultrasound acquisition during cardiac arrest. Resuscitation 124:A11-A12
Moskowitz, Ari; Andersen, Lars W; Karlsson, Mathias et al. (2017) Predicting in-hospital mortality for initial survivors of acute respiratory compromise (ARC) events: Development and validation of the ARC Score. Resuscitation 115:5-10
Berg, Katherine M; Grossestreuer, Anne V; Uber, Amy et al. (2017) Intubation is not a marker for coma after in-hospital cardiac arrest: A retrospective study. Resuscitation 119:18-20
Myers, Laura; Mikhael, Bassem; Currier, Paul et al. (2017) The association between physician turnover (the ""July Effect"") and survival after in-hospital cardiac arrest. Resuscitation 114:133-140
Moskowitz, Ari; Berg, Katherine M (2017) First do no harm: Echocardiography during cardiac arrest may increase pulse check duration. Resuscitation 119:A2-A3
Moskowitz, Ari; Patel, Parth V; Grossestreuer, Anne V et al. (2017) Quick Sequential Organ Failure Assessment and Systemic Inflammatory Response Syndrome Criteria as Predictors of Critical Care Intervention Among Patients With Suspected Infection. Crit Care Med 45:1813-1819