Sudden cardiac arrest is a major public health problem, afflicting over 535,000 persons in North America each year with dismal event survival rates near 10%. There is currently no medicinal intervention demonstrated to have a beneficial effect on post-arrest outcome with targeted temperature management arguably being the only intervention known to potentially improve post-cardiac arrest brain injury and survival. Thus, new therapies aimed at reducing the mortality and morbidity in post-cardiac arrest patients are essential. Thiamine is an essential co-factor of pyruvate dehydrogenase (PDH), the enzyme responsible for the conversion of pyruvate into acetyl-CoA and entry into the Krebs Cycle (aerobic metabolism). Previous investigators have found that post-arrest patients exhibit ?venous hyperoxia? or ?luxurious perfusion? ? the systemic and cerebral inhibition of oxygen consumption despite the presence of adequate oxygen delivery. Our preliminary data confirms the finding of depressed cellular oxygen consumption and puts forth the novel data that this depression can be overcome with the administration of in vitro thiamine as demonstrated by improved mortality and neurological morbidity in a mouse model of cardiac arrest. In a murine model of cardiac arrest, we found that intravenous thiamine increased PDH activity, improved cerebral oxygen consumption, mitigated histological injury to various areas of the brain, improved survival, and improved good neurological outcome. While our murine model suggests thiamine may be effective independent of deficiency, we did additionally find that upwards of 44% of post-arrest patients were thiamine deficient similar to rates in septic shock. Based on these data, we hypothesize that the administration of thiamine in post-cardiac arrest patients will mitigate lactic acidosis, improve cellular oxygen consumption, and improve clinical outcome. To test this hypothesis, we will perform a prospective, Phase II randomized pilot study providing thiamine versus placebo for post-cardiac arrest patients. Our primary endpoint will be attenuation of lactic acidosis in the thiamine group as compared to the placebo arm. Lactate serves not only as a surrogate for mortality but also as a parameter that would be directly modified by thiamine. Our secondary endpoints will include determination of whether thiamine will improve cellular oxygen consumption, increase PDH activity, attenuate biomarkers indicative of neurological injury, and improve clinical endpoints of neurological injury and organ-injury. The long-term goal of this line of research is to evaluate thiamine as an adjunctive therapy for post-cardiac arrest patients. Thiamine is safe, inexpensive, and easily administered ? thus, if our hypothesis is proven true and future research proves efficacy, adoption of this adjunctive therapy is feasible and significant.

Public Health Relevance

Cardiac arrest occurs in more than 500,000 patients annually in the United States, and almost 90% of those people will die and many will have brain injury. After cardiac arrest, evidence suggests that our cells' ability to use oxygen is decreased and patients with lower capacity to use oxygen have a higher risk of death. We are proposing a clinical pilot trial of thiamine which may improve the cell's capacity to extract oxygen and result in better outcomes for patients suffering from cardiac arrest.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL136705-01
Application #
9287995
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Sopko, George
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$432,500
Indirect Cost
$182,500
Name
Beth Israel Deaconess Medical Center
Department
Type
Independent Hospitals
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Holmberg, Mathias J; Geri, Guillaume; Wiberg, Sebastian et al. (2018) Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review. Resuscitation 131:91-100
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 :
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