Effect of Diazoxide on Hemmorrhagic Shock

Hemorrhagic shock is the most frequent cause of traumatic death in combat, representing almost 50% of the fatalities of military engagement. The loss of blood results in a decrease in oxygen supply to many vital organs of the body and activation of several biochemical processes that lead to cellular apoptosis and necrosis, organ failure, and death of the individual. The goal of this project is to examine the ability of the mitochondrial K+-ATP channel opener, Diazoxide, to preserve vital tissues (brain, liver, kidney) after hemorrhagic shock. Diazoxide has been noted to have an ischemic preconditioning effect. Ischemic preconditioning was originally determined from exposing cardiac tissue to brief episodes of ischemia prior to subsequent, sustained ischemic insult. Results demonstrated a greatly reduced infarction area when compared to tissue not exposed to preconditioning. The preconditioning effect has been demonstrated on other vital organs such as liver, muscle, kidney and intestine, but none of these previous studies have determined the efficacy for utilizing diazoxide for the treatment of hemorrhagic shock, and whether administration during the "golden hour" after shock is therapeutically effective. The long term goal is to develop pharmacological drugs related to Diazoxide that will improve mortality and morbidity from hemorrhagic shock. The specific aims of this research are to determine whether diazoxide treatment can be an effective post-trauma treatment that reduces organ apoptosis and mitochondrial response to shock. We will employ a well-established laboratory rat model of hemorrhagic shock. Animals will receive diazoxide at two time points after hemorrhagic shock, thus simulating combat conditions, where injured personnel receive care subsequent to injury. Neurological assessments, real-time PCR, and immunocytochemistry measures of apoptosis and mitochondrial function will be used to assess the impact of diazoxide treatment on organ protection from hemorrhagic shock. This project is relevant to military nursing research as new therapies and innovative treatments based on these results will dramatically improve the lives of our soldiers. There is a large knowledge deficit pertaining to cellular mechanisms involved with hemorrhagic shock. This information is critical since it will contribute to further development of strategies for emergency care on the battlefield that can increase survival. This project will increase the knowledge base of basic medical science, which is vital for the proper care of our combat and civilian trauma cases under the care of Nurse Corps officers.

Final report is available on NTRL: https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/PB2008106575.xhtml