How midazolam induces an anti-inflammatory effect is unclear but

How midazolam induces an anti-inflammatory effect is unclear but immune cells express both the peripheral benzodiazepine receptor [39] and gamma-amino butyric acid receptors [40] and thus at least two local targets exist for benzodiazepines. For example, midazolam suppressed lipopolysaccharide-induced TNF-�� activity in macrophages, an ARQ197 NSCLC effect that was blocked by the peripheral benzodiazepine receptor antagonist PK 11195 [39]. Midazolam also inhibits lipopolysaccharide-induced up-regulation of cyclooxygenase 2 and inducible nitric oxide synthase in a macrophage cell line. Other markers of immune cell activation (induced by lipopolysaccharide) such as I��B-�� degradation, nuclear factor-��B transcriptional activity, phosphorylation of p38 mitogen-activated protein kinase and superoxide production were also suppressed by the midazolam [41].

Interestingly dexmedetomidine and midazolam appear to exert opposite effects on innate immunity. Dexmedetomidine appears to potentiate macrophage function and phagocytosis [27-29], while, as described above, midazolam inhibits it [39,41,42]. This may be related to opposing effects on p38 mitogen-activated protein kinase signaling in these cells [41,43]. Thus although both sedatives suppressed circulating cytokines, at a local level the effects on macrophages may have been very different. Benzodiazepine induced suppression of immunity has been noted against Salmonella typhimurium with 15 days of diazepam treatment [19] and Klebsiella pneumoniae with three days of diazepam treatment in vivo [20]. In these settings of infection, diazepam treatment increased animal mortality.

Thus longer treatment times may be needed to show impairment of immune responses by midazolam than used in this study. We consider that differing effects on innate immunity may explain why critically ill patients sedated with dexmedetomidine experienced fewer infections than those patient sedated with midazolam in a recent randomized controlled trial of 366 critically ill patients [44]. Further studies addressing the relative effects of longer dosing schedules and different doses of the two sedatives on innate immune responses are in progress. It is interesting to note that daily interruption of sedative infusions appear to be associated with fewer infective complications [45]; this may be related to the reduced dose of sedatives resulting in less inhibition of the immune system. Recently, deep sedation has been associated with increased mortality in the critically ill [46] although it is unclear whether this affected immune responses. In this study we did not measure depth of sedation with electroencephalogram monitoring; however, based on recently published clinical data Drug_discovery [46], future studies should consider this.

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