In the absence of knowledge of the mechanisms whereby DEX improves patient outcome, it will be necessary to postulate testable hypotheses; hypothesis-testing data can provide the basis for designing future comparative Wortmannin efficacy trials for sedation for the wide-range of ICU patients.The ��2 adrenoceptor agonists and benzodiazepines have different molecular targets (��2 adrenoceptors and gamma-aminobutyric acid type A (GABAA) receptors, respectively) and neural substrates for their hypnotic effects that may play a critical role in maintaining sleep architecture in critically ill patients [22,24]; improved sleep may potentially improve delirium outcomes and immune function [25-27]. In addition, benzodiazepines and ��2 adrenoceptor agonists exert opposing effects on innate immunity, apoptotic injury and mortality in preclinical models of infection [27].

Benzodiazepines increase mortality in animal models of bacterial infection [28-30] likely by impairment of neutrophil [31] and macrophage function [32], whereas GABAA receptor antagonists are under investigation as anti-infective agents [33]. Contrastingly, ��2 adrenoceptor agonists enhance macrophage phagocytosis and bacterial clearance [34-36], while exerting minimal effect on neutrophil function [37], and are associated with improved outcomes in animal models of bacterial sepsis [38]. DEX per se exerts superior anti-inflammatory and organ-protective properties compared with other sedatives [22,39,40] and is neuroprotective in models of hypoxia-ischemia [41] and apoptosis [42], and thus may prevent sepsis-induced brain and other organ injury.

The anti-apoptotic effects of DEX are greater than midazolam [40,42] and may be useful, given Brefeldin_A that sepsis-related mortality has been associated with apoptotic injury [43]. Sympatholysis has also been shown to improve outcome in sepsis [44]; in line with previous reports [22], presumptive evidence for the more profound sympatholytic actions of DEX over its benzodiazepine comparators was suggested by the higher incidence of bradycardia and reduced tachycardia in both the MENDS [21] and SEDCOM [23] studies.Multiple levels of evidence thus converge to support our hypothesis that sedation with DEX may lead to better outcomes for patients with sepsis than benzodiazepine sedation. We therefore conducted an a priori-planned subgroup analysis among patients from the MENDS trial to determine if sedation with DEX compared with LZ in septic and non-septic patients affected clinical outcomes, including duration and prevalence of acute brain dysfunction and 28-day mortality.