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

Abstract

The 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 43 mM melatonin (BHB/M) to 4M sodium chloride and 20% DMSO (control solution) to evaluate for potential benefits in porcine hemorrhagic shock. Hemorrhagic shock was induced to obtain systolic blood pressures <50 mmHg for 60 min. 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 20 h 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. BHB/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. Infusion 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.