Safety of D-ß-Hydroxybutyrate and Melatonin for the Treatment of Hemorrhagic Shock With Polytrauma.

Abstract

D-ß-hydroxybutyrate (BHB) and melatonin (M) treatment improves survival in animal models of hemorrhagic shock. Here, we evaluated the safety of BHB/M via 2 routes of administration in a porcine hemorrhagic shock/polytrauma model. Furthermore, we assessed BHB/M serum concentrations after intravenous and intraosseous infusion of different BHB/M doses in healthy pigs. Pigs underwent pulmonary contusion, liver injury, and hemorrhage. Injured animals were treated with an intravenous or intraosseous bolus of BHB/M or lactated Ringer's solution (LR), followed by 4 h of continuous infusion of the respective fluid (n = 12 per group). Pigs were resuscitated with LR (1 h) and then LR and shed blood (20 h). Physiological data and blood samples were analyzed throughout the experiment. In a second study, we infused healthy pigs intravenously or intraosseously with BHB/M at 3 different doses (n = 4 per group). There were no differences between groups in physiologic measurements (heart rate, mean arterial pressure, and cardiac output), organ function markers (alanine aminotransferase, aspartate aminotransferase, serum urea nitrogen, total creatinine kinase, and lactate dehydrogenase), or histopathology. The BHB/M-treated animals exhibited transient changes in blood Na, K, pH, and lactate. Differences in survival were not statistically significant. There was a trend toward decreased survival after intraosseous infusion, potentially related to lower circulating BHB and melatonin levels. Healthy pigs had higher drug serum concentrations after intravenous than after intraosseous infusion of BHB/M at the standard, but not the double dose. D-ß-hydroxybutyrate /M in doses previously shown to be associated with improved survival is safe in a porcine hemorrhagic shock/polytrauma model. Intravenous infusion is the preferred route of administration at standard doses.