The inflammatory response is initially exaggerated (best exemplif

The inflammatory response is initially exaggerated (best exemplified in meningoccemia or toxic-shock syndrome) at which stage anti-inflammatory therapy may selleck chemicals have some utility [6]. Following this phase of injury a hypo-inflammatory phase ensues that is characterized by the apoptosis of B and T lymphocytes and subsequent failure of the adaptive and innate immune systems [2,3].Sedative agents exert anti-inflammatory effects that may differentially effect this biphasic inflammatory response to sepsis. Initially, their anti-inflammatory effects may prove beneficial by reducing the ‘cytokine storm’; in this case early institution of sedation may contribute to the benefits of early goal-directed therapy. Indeed, anti-inflammatory agents in early, severe sepsis [7-10] or those with high circulating IL-6 levels [8,11] may prove useful.

Equally plausible, the sedative-induced anti-inflammatory effect may exacerbate the subsequent immunosuppression in the secondary hypo-inflammatory phase and potentiate lymphocyte apoptosis [12]. Sedatives affect immune responses directly [13,14] but may also modulate these processes by indirect mechanisms such as through the burden of sleep deprivation [15] and effects on autonomic nervous system activity [16,17].Accumulating evidence suggests that the currently used sedatives may exert a deleterious effect in the presence of infection [14], notably morphine and benzodiazepines increase mortality from bacterial infections in animals [18-20]. Clinical epidemiological evidence also suggests an association between chronic benzodiazepine usage and increased severity of community-acquired pneumonia [21].

In contrast, dexmedetomidine improves mortality from endotoxic shock in rats [22] and cecal ligation and intestinal puncture in mice [23] associated with an anti-inflammatory effect. Clinically, the anti-inflammatory effects of dexmedetomidine have proven superior to both midazolam [24] and propofol [25]. In addition, dexmedetomidine has organ-protective effects and can inhibit apoptotic cell death [26] that plays a pivotal role in the pathogenesis of sepsis [2,3]. Stimulation of ��2 adrenoceptors also enhances the phagocytic ability of macrophages in vitro [27-29] and thus may enhance bacterial clearance by the innate immune system. The sympatholytic effects of ��2 adrenoceptor agonists may be useful as sympatholysis has been shown to improve outcome in septic animals [30].

Finally, dexmedetomidine induces a sedative state more analogous to natural sleep than benzodiazepines and therefore we hypothesize that dexmedetomidine could reduce immune dysfunction related to sleep deprivation [31]. Recently we performed a secondary analysis of data from the MENDS trial [32] revealing a mortality benefit in septic patients sedated with dexmedetomidine GSK-3 relative to lorazepam.

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