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

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.