Evaluation of a ketogenic formulation for treating patients with acute brain injury

Abstract

Acute brain injury (ABI), including cerebral vascular accidents (CVA) and traumatic brain injury (TBI), are relatively common diseases which may lead to death, significant morbidity and place a heaving burden on health care systems globally, both in suffering and cost.Evidence has emerged from basic science research that ketones (beta-hydroxybutyrate and acetoacetate) which are water-soluble molecules produced by the liver during times of starvation, may have neuroprotective effects. It is therefore theoretically possible that increasing plasma ketone concentrations via intravenous or oral supplementation, may lead to improved outcomes following ABI.This thesis documents a systematic investigation into the possibility that ketone supplementation may lead to benefits in patients with a variety of chronic and acute neurological conditions. While the main emphasis is on ABI, other conditions where ketones may be useful are also reviewed. Beginning with a review of ketones, their potential mechanisms of action and likely neuroprotective roles in disease, this thesis examines the effects of a novel hypertonic intravenous ketone solution on plasma, cerebrospinal fluid (CSF) and brain ketone concentrations in animals, then looks at the hurdles in producing such an intravenous solution as opposed to enteral formulations for humans, before investigating baseline ketone concentrations in patients with ABI and finally culminating in an interventional study where a modified enteral ketone supplement is administered to patients with ABI to determine whether adequate plasma ketone concentrations are attainable.The animal study performed in rats involved the administration of hypertonic saline/ketone solutions of varying concentrations to anaesthetised rats. The results demonstrated that both CSF and beta-hydroxybutyrate (BHB) concentrations increased over time (p<0.0001) and that this was dependent on the BHB concentration in the solution (p<0.0001).