Statistical www.selleckchem.com/products/lapatinib.html analysis was performed by analysis of variance followed by post-hoc Newman Keuls testing using the instat program. Twenty-four hour mortality was analyzed by Chi squared test. A P < 0.05 was set as significant.ResultsAnimal illness and mortalityThe CLIP model employed induced severe sepsis with lethargy and sickness behavior observable in the saline-infused animals. Nine of the 10 animals died within 24 hours (90%) indicating that very severe sepsis was provoked (Figure (Figure1).1). Sedation with either drug significantly decreased mortality at 24 hours after CLIP compared with saline (P < 0.01; midazolam 30% and dexmedetomidine 20% mortality, respectively). However, no difference was noted between dexmedetomidine and midazolam (P = 0.6).

Figure 1Kaplan-Meier survival curves for saline, midazolam or dexmedetomidine treated severely septic rats. Dex = dexmedetomidine.Cytokine signalling: TNF-��Both midazolam and dexmedetomidine reduced TNF-�� levels compared with saline-treated controls. At two hours the saline group had a significantly higher level (166 �� 37 pg/ml) than either midazolam (51 �� 12 pg/ml) or dexmedetomidine (50 �� 11 pg/ml); this pattern was also present at four hours (saline 130 �� 54 pg/ml; midazolam 55 �� 8 pg/ml; dexmedetomidine 62 �� 39 pg/ml) and five hours (saline 141 �� 30 pg/ml; midazolam 62 �� 20 pg/ml; dexmedetomidine 73 �� 40 pg/ml). Integrated over time revealed an area under the curve of 626 �� 137 in the saline group, 232 �� 40 in the midazolam group, and 244 �� 93 in the dexmedetomidine group.

Thus the reduction in mortality effect in the sedative group was associated with a reduction in TNF-�� levels in both sedated groups (Figure (Figure22).Figure 2Plasma TNF-�� levels immediately prior to (0 hours) and after (2, 4 and 5 hours) induction of severe sepsis by double caecal ligation and puncture in rats (n = 4 to 6). (a) The actual change in levels is shown. (b) The total difference in levels …Cytokine signalling: IL-6In contrast to sedation with midazolam, dexmedetomidine reduced IL-6 levels relative to the saline group (P < 0.05; Figure Figure3).3). At two hours the saline (188 �� 37 pg/ml), midazolam (176 �� 40 pg/ml), and dexmedetomidine groups were similar (50 �� 11 pg/ml). At four hours the IL-6 levels in the dexmedetomidine group (181 �� 15 pg/ml) were significantly lower than midazolam (312 �� 39 pg/ml) and saline (282 �� 70 pg/ml) groups.

At six hours the IL-6 levels in the dexmedetomidine group (262 �� 38 pg/ml) were again lower than midazolam (371 �� 14 pg/ml) and saline (455 �� 96 pg/ml) groups. The mean area under the curve was 1135 �� 187 in the saline group, 1132 �� 90 in the midazolam group, and 771 �� 100 in the dexmedetomidine group.Figure 3Plasma IL-6 Brefeldin_A levels immediately prior to (0 hours) and after (2, 4 and 5 hours) induction of severe sepsis by double caecal ligation and puncture in rats (n = 4 to 6). (a) The actual change in levels is shown.