After obtaining informed consent from either the patient or an approved surrogate, patients were randomized in a double-blind fashion to receive DEX-based (maximum 1.5 mcg/kg/hr) or LZ-based (maximum 10 mg/hr) sedation for up to five days, titrated to target Richmond Agitation-Sedation Scale (RASS) [45,46] ZD6474 scores determined by the managing ICU team each day. Patients were monitored daily for delirium with the Confusion Assessment Method for the ICU [1,47]. A detailed study protocol has been previously described [21]. In this subgroup analysis, we compared the effects of DEX and LZ in patients with sepsis with the effects of these sedatives in patients without sepsis. Patients were classified as being septic if they had at least two systemic inflammatory response syndrome (SIRS) criteria and a known or suspected infection between admission to within 48 hours of enrollment.

A patient was ‘suspected’ to have an infection if the treating physicians stated this in the medical record or started antibiotics or drotrecogin alfa (activated). SIRS criteria and known/suspected infection were recorded by study personnel prospectively, and one author (TG), blinded to study group assignment, also confirmed each case of sepsis by retrospectively examining electronic medical records. Apart from sedation, all other aspects of medical management were according to standardized ventilator management protocols and sepsis treatment algorithms, provided by the critical care team, blinded to the sedative intervention.

Primary and secondary outcomesThe primary outcome of interest was delirium/coma-free days, defined as the days alive without delirium or coma during the 12-day study period [21]. Secondary outcomes of the study included delirium-free Dacomitinib days, daily prevalence of delirium while patients received study drug, coma-free days, lengths of stay on the MV and in the ICU, and 28-day mortality. Ventilator-free days were calculated as the number of days alive and off MV over a 28-day period [48].Delirium was measured daily until hospital discharge or for 12 days using the Confusion Assessment Method for the ICU (CAM-ICU) [1,47]. Efficacy of the study drug was defined as the ability to achieve a sedation score within one point of the desired goal sedation level determined by the managing ICU team each day. Sedation level was assessed using the RASS [45,46], a highly reliable and well-validated sedation scale for use within patients over time in the ICU. Both the RASS and the CAM-ICU instruments are described in more detail at [49].For other outcomes, patients were followed in the hospital from enrollment for 28 days, or until discharge or death if earlier.Statistical analysisData were analyzed using an intention-to-treat approach.