Sedation induced anti-inflammatory effectsPrevious preclinical studies had shown that sedation with dexmedetomidine does improve mortality from endotoxic shock in rats compared with a non-sedated group [22]. trichostatin a clinical trials Based upon the inflammatory and apoptosis biomarkers we would anticipate superior benefits of sedation with dexmedetomidine vs midazolam in the acute phase of sepsis; possible reasons why this putative benefit was not borne out by the mortality data may relate to the ‘hyper-aggressive’ septic state that appears primarily to be TNF-�� dependent (as mortality benefits were associated with reduced TNF-�� levels). It is noteworthy that midazolam and dexmedetomidine reduced TNF-�� levels by a similar amount although previous clinical trials have suggested that dexmedetomidine was superior to midazolam in this regard [24].

Dexmedetomidine has also been shown to improve mortality and reduce inflammatory cytokine levels induced by CLIP in mice when dexmedetomidine was started prior to the sepsis [23] though the dosing schedule in this study was irregular. In our study the sedatives were commenced by infusion shortly before provoking sepsis and therefore the levels were unlikely to be therapeutic as sepsis was induced.The anti-inflammatory effects of dexmedetomidine have now been shown against endotoxin (compared with saline) [22], in single CLIP [23], in double CLIP (compared with midazolam; Figures Figures2,2, ,3)3) and in critically ill humans (compared with propofol [25] or midazolam [24]).

How dexmedetomidine induces its anti-inflammatory effect is currently unclear though it may be related to its central sympatholytic effects [23,30] and relative stimulation of the cholinergic anti-inflammatory pathway [16,17]. Inflammation also appears to alter the effects of ��2 adrenoceptor stimulation shifting them from a pro- to an anti-inflammatory effect [35].The effect of the sedatives on IL-6 require further consideration as IL-6 levels are predictive of mortality in septic humans [36] and animals [37]. Therefore, the reduction of IL-6 levels by dexmedetomidine relative to midazolam and saline may prove crucial in future studies. The achieved significance value of P = 0.05 means the results are of borderline significance though we suspect this is due to a reduced sample size in the midazolam group.

Power analysis based on our results suggests that six animals per group are required to achieve power to find a statistical difference of P < 0.05. Therefore our study was designed with appropriate power but a loss of two animal samples in the midazolam group, leaving a sample size of four animals in that group, may have been responsible for our result that is of borderline Carfilzomib significance. The superiority of dexmedetomidine’s ability to reduce IL-6 levels has already been shown in humans [24,25]; however, it should be noted that dexmedetomidine was administered immediately after the septic insult in this study.