Dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats

Purpose. Our previous study demonstrated that dexmedetomidine drastically reduced mortality and inhibited the inflammatory response during endotoxemia in rats. The aim of this study was to clarify the dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxemia in rats. Methods. Male Wistar rats (n = 96) were anesthetized intraperitoneally with pentobarbital sodium and assigned to one of two protocols: one representing the dose- related effects of dexmedetomidine, and the other, the time-related effects of dexmedetomidine. To evaluate the dose- related effects, the animals were randomly assigned to one of four groups (n = 15 each): endotoxemic group (group E), receiving intravenous Escherichia coli endotoxin (15 mg.kg(-1) over 2 min); small-dose group (group S), treated with a small dose of dexmedetomidine (2.5 mu g.kg(-1).h(-1), IV); medium-dose group (group M), treated with a medium dose (5 mu g.kg(-1).h(-1), IV); and large-dose group (group L), treated with a large dose (10 mu g.kg(-1).h(-1), IV). To evaluate the time-related effects, the animals were randomly assigned to one of three groups (n = 12 per group): endotoxemic group; early posttreatment group, treated with 10 mu g.kg(-1).h(-1) dexmedetomidine at 1 h after endotoxin injection; and late posttreatment group, treated with 10 mu g.kg(-1).h(-1) at 2 h after endotoxin injection. Hemodynamics and arterial blood gases were recorded and plasma cytokine concentrations were measured throughout the observation period. The mortality rate was assessed up to 8 h after endotoxin injection. Results. In the dose-related study, the mortality rates at 8 h after endotoxin injection were 81%, 26%, 32%, and 20% for groups E, S, M, and L, respectively. Plasma tumor necrosis factor-alpha (TNF) concentrations were lower in groups M and L than in group E at 2 h after endotoxin injection. Plasma interleukin-6 (IL-6) concentrations were lower in groups M and L than in group E at 4 and 5 h after endotoxin injection. In the time-related study, the mortality rates at 8 h after the endotoxin injection were 83%, 33%, and 58% for the endotoxemic, early posttreatment, and late posttreatment groups, respectively. The TNF concentration was lower in the early posttreatment group than in the endotoxemic group at 2 h after endotoxin injection, and the IL-6 concentration was lower in the early posttreatment group than in the endotoxemic group at 5 h after endotoxin injection. Conclusion. Dexmedetomidine dose-dependently attenuated extremely high mortality rates and increases in plasma cytokine concentrations after endotoxin injection. Moreover, the early administration of dexmedetomidine drastically reduced the high mortality rate and inhibited cytokine responses in endotoxin-exposed rats. These findings suggest that dexmedetomidine administration may be effective during sepsis.