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Does a Sedation Strategy Including Dexmedetomidine Decrease Mortality and the Need for Mechanical Ventilation in Sepsis

Dexmedetomidine is an alpha 2-adrenergic receptor agonist that has proven useful as a light sedative with analgesic properties in postoperative care. It has also been shown to have the ability to suppress inflammatory reactions in animal models, making it an intriguing agent for use in patients with sepsis. In 2010, a subgroup analysis of the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial revealed an improved 28-day mortality rate in septic patients who received dexmedetomidine rather than lorazepam. The DESIRE trial (Dexmedetomidine for Sepsis in Intensive Care Unit (ICU) Randomized Evaluation) was therefore designed as an investigator-initiated, multicenter, open-label randomized trial to determine whether the use of this agent for sedation reduced mortality or the number of ventilator days in septic patients. This study was conducted across 8 ICUs in Japan from February 2013 to January 2016, and 201 patients were enrolled. Adult patients with sepsis who required either invasive or noninvasive mechanical ventilation were eligible. Patients with liver disease, severe heart failure or acute myocardial infarction, drug or alcohol dependence, psychiatric illness or cognitive dysfunction were excluded. The data were analyzed using an intention to treat principle, and the analysis was powered on the basis of the MENDS data for coprimary outcomes of 28-day mortality and ventilator-free days. Both the control group (propofol, midazolam, and analgesia without dexmedetomidine) and the study group (dexmedetomidine with analgesia and other sedatives as needed) had the goal of light sedation: a Richmond Agitation-Sedation Scale (RASS) of 0 (calm) during the day and 2 (lightly sedated) at night. This and the weaning protocol used for all patients likely contributed to the outcome of the study. Neither 28-day mortality (22.8% in the dexmedetomidine group and 30.8% in the control group, P = 0.20) nor ventilatorfree days of the evaluated 28 days (20 in the study group and 18 in the control group, P = 0.20) were significantly improved with the use of this drug for sedation. Of the many secondary outcomes evaluated, only the rate of well-controlled sedation (17% to 50% vs. 20% to 39% in the control group, P = 0.01) was statistically significant between the 2 groups. Interestingly, the rate of delirium was not statistically significantly lower in the group receiving dexmedetomidine. The subgroup analysis of the MENDS trial did offer hope that the use of dexmedetomidine in septic patients could improve mortality and lessen the burden of mechanical ventilation. As the authors cite, this current study is small, used a lower dose of dexmedetomidine than is used in other countries, had older patients, and these patients had overall lower APACHE II (Acute Physiology and Chronic Health Evaluation) scores when compared with the patients in the MENDS trial. Moreover, the strict adherence to a weaning protocol and overall light sedation policy might both have contributed to the lack of effect on delirium as well as days of mechanical ventilation. Finally an 8% reduction in 28-day mortality was found, but this study was likely underpowered for mortality. Further trials using this novel sedative are warranted.