Rapid Ketone Infusion to Prevent Brain Energy Depletion and Secondary Brain Injury in Severe TBI with Hemorrhagic Shock
Abstract
Recent military operations OEF/OIF (Operation Enduring Freedom/Operation Iraqi Freedom) exposed knowledge gaps in best practices for resuscitation after isolated traumatic brain injury (TBI) and TBI combined with other life-threatening injuries (polytrauma). The combination of TBI with other injuries is especially complex due to synergistic effects between TBI and polytrauma that greatly increase the risk of fatal complications, including blood clotting defects (coagulopathy). Improvements to damage control interventions for TBI, especially TBI with polytrauma, will include strategies to minimize secondary brain damage and maximize recovery potential. Consistently, animal and clinical research identify damaging changes in metabolism in brain tissue after injury including an overall decline in energy production. These data indicate that preventing early metabolic crisis should be a priority in TBI damage control. The goal of these studies is to determine whether providing “brain food” that can circumvent obstacles to glucose metabolism that occur after TBI will prevent metabolic crisis and the spread of damage into undamaged brain tissue adjacent to the injury. We also suspect that providing metabolic support after severe injury will decrease the incidence of coagulopathic complications. The proposed studies will test a hypertonic ketone solution as a resuscitation fluid after isolated TBI and after TBI combined with shock due to blood loss (TBI-HS) in a clinically relevant large animal model to determine whether cerebral metabolic crisis and oxidative damage can be prevented or reduced (Focus Area 3). Hypertonic solutions are shown to reduce brain swelling after TBI and ketones, in this case beta-hydroxybutyrate (BHB), are readily metabolized by the brain even when tissue oxygenation is reduced. In addition, BHB is soluble in saline or water, can be freeze-dried, and blood ketone levels can be non-invasively monitored in breath (Focus Area 1). Additionally, we will measure changes in systemic metabolism, and blood coagulation properties to determine whether BHB treatment has any additional benefit in normalizing platelet function and coagulation after TBI and TBI-HS (Focus Areas 2 and 3). The leading causes of death from potentially survivable injuries in both military and civilian trauma result from TBI and hemorrhage. Optimal resuscitation strategies are critical in the context of brain injury due the need to minimize hemorrhagic complications and prevent death but also to preserve acute brain function, minimize secondary injury, and optimize brain recovery. We believe ketones are a potentially lifesaving strategy that will support brain function and tissue survival after TBI even when blood oxygen-carrying capacity is reduced due to hemorrhage or shock. BHB is currently readily available as a nutritional supplement, has a known safety profile, and could be quickly and cost-effectively developed for clinical application. Positive findings in these studies would support moving forward into early phase clinical trials and could ultimately lead to advances in clinical practice for acute resuscitation of acute TBI and polytrauma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010830
Entities
People
- Jennifer Mcguire
Organizations
- United States Army
- University of Cincinnati