Treatment with beta-hydroxybutyrate and melatonin is associated with improved survival in a porcine model of hemorrhagic shock

Abstract

IntroductionThe neuroprotective ketone β-hydroxybutyrate (BHB) and the antioxidant melatonin have been found at elevated levels in hibernating mammals. Previous studies in rat models of hemorrhagic shock have suggested a benefit. We compared infusion of 4M BHB and 43mM melatonin (BHB/M) to 4M sodium chloride and 20% DMSO (control solution) to evaluate for potential benefits in porcine hemorrhagic shock. MethodsHemorrhagic shock was induced to obtain systolic blood pressures <50mmHg for 60min. Pigs were treated with a bolus of either BHB/M (n=9) or control solution (n=8) followed by 4-h infusion of the either BHB/M or control solution. All animals were then resuscitated for 20h after shock. Physiological data were continually recorded, and blood samples were taken at intervals throughout the experiment. Serum samples were analyzed via high resolution NMR for metabolomic response. ResultsBHB/M treatment significantly increased 24-h survival time when compared to treatment with control solution (100% versus 62%; p=0.050), with a trend toward decreased volume of resuscitative fluid administered to animals receiving BHB/M. BHB/M-treated animals had lower base deficit and higher oxygen consumption when compared to animals receiving control solution. Serum metabolite profiles revealed increases in β-hydroxybutyrate (BHB), succinate, 2-oxovalerate and adipate with BHB/M treatment as compared with animals treated with control infusion. ConclusionInfusion of BHB/M conferred a survival benefit over infusion of control solution in hemorrhagic shock. BHB and its products of metabolism are identified in serum of animals subjected to shock and treated with BHB/M. Further preclinical studies are needed to clarify the mechanisms of action of this promising treatment strategy.