Wolf Andrea, Mulier Kristine E, Iyegha Uroghupatei P, Asghar Javariah I, Beilman Gregory J
Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
Shock. 2015 Aug;44 Suppl 1:79-89. doi: 10.1097/SHK.0000000000000315.
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.
D-β-羟基丁酸（BHB）和褪黑素（M）治疗可提高失血性休克动物模型的生存率。在此，我们通过两种给药途径评估了BHB/M在猪失血性休克/多发伤模型中的安全性。此外，我们还评估了在健康猪中静脉内和骨内输注不同剂量的BHB/M后其血清浓度。猪遭受了肺挫伤、肝损伤和出血。受伤动物接受静脉内或骨内推注BHB/M或乳酸林格氏液（LR），随后持续输注相应液体4小时（每组n = 12）。猪先用LR复苏1小时，然后用LR和自体血复苏20小时。在整个实验过程中分析生理数据和血样。在第二项研究中，我们以3种不同剂量对健康猪进行静脉内或骨内输注BHB/M（每组n = 4）。各组在生理测量（心率、平均动脉压和心输出量）、器官功能标志物（丙氨酸转氨酶、天冬氨酸转氨酶、血清尿素氮、总肌酸激酶和乳酸脱氢酶）或组织病理学方面均无差异。接受BHB/M治疗的动物血液中的钠、钾、pH值和乳酸出现了短暂变化。生存率的差异无统计学意义。骨内输注后有生存率降低的趋势，这可能与循环中的BHB和褪黑素水平较低有关。在标准剂量而非双倍剂量下，健康猪静脉内输注BHB/M后的药物血清浓度高于骨内输注。在猪失血性休克/多发伤模型中，先前已证明与生存率提高相关剂量的D-β-羟基丁酸/M是安全的。标准剂量下，静脉输注是首选给药途径。
