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

Abstract Introduction 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 4 M BHB and 43 mM melatonin (BHB/M)...

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Published in:	Resuscitation Vol. 83; no. 2; pp. 253 - 258
Main Authors:	Mulier, Kristine E, Lexcen, Daniel R, Luzcek, Elizabeth, Greenberg, Joseph J, Beilman, Gregory J
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier Ireland Ltd 01-02-2012
Subjects:	3-Hydroxybutyric Acid - therapeutic use Animals Antioxidants - therapeutic use Beta-hydroxybutyrate Disease Models, Animal Drug Therapy, Combination Emergency Male Melatonin Melatonin - therapeutic use Metabolomics Resuscitation Resuscitation - methods Shock Shock, Hemorrhagic - drug therapy Shock, Hemorrhagic - mortality Swine Treatment Outcome Shock Metabolomics Melatonin Beta-hydroxybutyrate Resuscitation
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Summary:	Abstract Introduction 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 4 M BHB and 43 mM melatonin (BHB/M) to 4 M 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. Conclusion 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0300-9572 1873-1570
DOI:	10.1016/j.resuscitation.2011.08.003