Hibernation-based blood loss therapy increases survivability of lethal hemorrhagic shock in rats

Cecilia E. Perez de Lara Rodriguez, Lester R Drewes, Matthew T. Andrews

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12 Scopus citations


A small-volume (1 ml/kg) resuscitation fluid based on metabolic adaptations in hibernating mammals was optimized using a rat model of hemorrhagic shock. A previous study of this therapy tested only one concentration of three specific components: 4 M D-stereoisomer of beta-hydroxybutyrate (BHB), 43 mM melatonin, and 20% DMSO. In this study, we considered the range of concentrations of BHB and melatonin seen during the physiological extremes of rapid arousal from hypothermic torpor in natural hibernators and applied these to the non-hibernating Sprague–Dawley rat model. These extremes normally result in ischemia and reperfusion injury in non-hibernating mammals. Dose-ranging studies were conducted for BHB and melatonin in rats with 60% blood loss. BHB was administered at either 4, 2, or 0.4 M concentration in conjunction with 4.3 mM melatonin and 10% DMSO. Subsequently, melatonin was administered at either 4.3, 0.43, 0.0043, 0.000043, or 0 mM in conjunction with 4 M BHB and 2% DMSO. 10-day mean survival showed a dose-dependent trend: rats survived longer with higher concentration of infused BHB (4 M BHB, 7.38 ± 1.75 days; 2 M BHB, 5.25 ± 2.22 days; 0.4 M BHB, 2.07 ± 2.05 days). Administering 4 M BHB without melatonin resulted in low mean survival times (4.38 ± 1.42 days). All treatments containing both 4 M BHB and melatonin, regardless of melatonin concentration, resulted in mean survival times of ~7.5 days. We conclude there is a dose-dependent trend in which higher BHB concentration resulted in improved survival over 10 days.

Original languageEnglish (US)
Pages (from-to)769-778
Number of pages10
JournalJournal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology
Issue number5-6
StatePublished - Jul 1 2017

Bibliographical note

Funding Information:
We would like to thank the U.S. Army Medical Research and Materiel Command (Grant W81XWH-11-1-0409) for financial support. Very special recognition goes to Dr. Ronald Regal of Mathematics and Statistics Department at the University of Minnesota Duluth, for all of his guidance with statistical analyses. We also thank Alison Kingsbury, Krysta Nelson, and Matt Donohue of the Andrews laboratory as well as Ms. Kristine Mulier and Dr. Gregory Beilman of the Department of Surgery at the University of Minnesota.

Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.


  • Beta-hydroxybutyrate
  • Fluid resuscitation
  • Hemorrhage
  • Hibernation
  • Ketone
  • Melatonin


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