ABSTRACT There are currently no medicinal interventions demonstrated to consistently improve the low survival rate and high incidence of organ injury after out-of-hospital cardiac arrest (OHCA). Among those who initially survive OHCA, death from arrest-related injury to organs remains frustratingly high, and other-organ injuries are common and often debilitating among OHCA arrest patients who survive to discharge.[1] While cerebral injury is the most lethal[2] and most prevalent organ injury, acute kidney injury (AKI) is also common and is associated with mortality and adverse outcomes such as the need for dialysis[3,4]. Our group is currently engaged in a randomized trial to test if thiamine (vitamin B1) protects the brain after cardiac arrest by improving aerobic metabolism reflected in the reduction of lactic acidosis. However, ongoing research conducted by our group and others has raised new and equally important questions. With this K-24 proposal, we plan to address two of these questions by adding new sub-studies to this trial. The first sub-study tests the hypothesis that thiamine protects not just the brain but also the kidney after cardiac arrest, while the second sub-study tests the hypothesis that cardiac arrest patients have abnormally low pools of a-lipoic acid (LA), another critical mediator of aerobic metabolism, which may place a cap on the efficacy of thiamine therapy. The rationale for the first sub-study is based on recent evidence linking decreased aerobic metabolism in the kidney to renal failure in critical illnesses,[5,6] the stimulatory effect of thiamine on aerobic metabolism, and our randomized trial in sepsis showing that thiamine protected kidney function.[7] The second sub-study is based on our preliminary data suggesting that thiamine may not fully restore cellular oxygen consumption after cardiac arrest. Because aerobic glucose metabolism requires both lipoic acid and thiamine as cofactors for two key enzymes, even subacute lipoic acid deficiencies may place a cap on the efficacy of thiamine as a metabolic resuscitator. Experimental provision of LA has been shown to protect against ischaemic brain and kidney injury; these findings contribute to the rationale for examining LA in the context of our existing trial. Together, these studies will advance thiamine as a potential post-arrest intervention for AKI and deepen our understanding of the relationship of other key metabolic components in critical illness, while also providing an excellent platform to mentor future patient-oriented researchers. This award will provide an established and highly productive clinical researcher and mentor with both project and mentoring support and allow continued expansion of his outstanding translational research training program in the Center for Resuscitation Science (CRS) at BIDMC. The breadth of experiments in the scientific portion of the proposal (clinical trial design/execution and patient-based laboratory work) along with the research infrastructure provided by multiple ongoing CRS studies will give mentees the experience and expertise to progress towards independence as the next generation of researchers in the field of resuscitation medicine.

PROJECT NARRATIVE This K-24 application will support sub-studies which will expand the scope of an NIH-funded randomized clinical trial evaluating thiamine (vitamin B1) as a medicinal intervention to improve the exceedingly low survival rate and high incidence of injury to other organs after out-of-hospital sudden cardiac arrest. The proposed sub-studies will specifically establish if thiamine prevents post-arrest kidney injury and provide new insight into the impact of thiamine on other key components of metabolism. The K-24 application will simultaneously provide support for an accomplished investigator/mentor in maintaining a much-needed junior investigator mentoring program in resuscitation science.