title: Treatment with beta-hydroxybutyrate and melatonin is associated with improved survival in a porcine model of hemorrhagic shock.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Mulier
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Lexcen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luzcek
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Greenberg
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Beilman
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000401:mortality*; D013552:Swine; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D008550:Melatonin; D020155:3-Hydroxybutyric Acid