FAQ
Clinical controversy: The MENDS trial (maximizing efficacy of targeted sedation and reducing neurological dysfunction)
Introduction
Dexmedetomidine is a selective alpha2 receptor agonist indicated for use as a sedative in mechanically ventilated patients in the intensive care unit (ICU). Its labeled use is for treatment duration less than 24 hours; however, the literature describes prolonged infusions. One advantage of dexmedetomidine compared to other sedative agents is that it does not cause respiratory depression.
Literature review
Pandharipande and colleagues conducted a randomized, double-blind, controlled trial to investigate the hypothesis that dexmedetomidine would be associated with less delirium and coma in ventilated ICU patients compared to lorazepam. The trial took place in 2 centers and subjects were adults in either a medical or surgical ICU who required mechanical ventilation for at least 24 hours. Of note, patients with neurological disease were excluded from participation. Patients were randomized to a continuous infusion of either lorazepam 1 to 10 mg/hour (n = 51) or dexmedetomidine 0.15 to 1.5 mcg/kg/hour (n = 52) for up to 120 hours. Doses were started at the low end of the range and titrated based on response at the bedside. The goal of sedation was based on the Richmond Agitation-Sedation Scale (RASS) and set by the physicians caring for the patients. Fentanyl was given to treat pain and for patients who were not adequately sedated. Propofol (intravenous bolus) was given for urgent levels of agitation. The use of a sedative-free period was not standardized and left to the treating physician’s discretion. The primary composite outcome was the number of coma-free and delirium-free days (days alive without either). Delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU) and coma assessment was based on the RASS score (-4 or -5). Achievement of sedation goals was also evaluated as a main outcome. Secondary outcomes included length of stay (hospital and ICU), neurological testing after ICU discharge, 28-day mortality, duration of mechanical ventilation, and 12-month survival. Cost was also evaluated.
The groups were matched at baseline with an average age of 60 years and Acute Physiology and Chronic Health Evaluation II score (APACHE II) of 29. Sepsis was the most common diagnosis (37% to 39% of patients) followed by other pulmonary causes (22% to 23%). The median infusion rates were dexmedetomidine 0.74 mcg/kg/hour and lorazepam 3 mg/kg/hour. Results for the intent-to-treat population revealed that dexmedetomidine recipients had more days free of delirium and coma compared to lorazepam (7 vs. 3, respectively, p=0.01). Coma occurred in 33 (63%) of 52 dexmedetomidine and 47 (92%) of 51 lorazepam recipients (p<0.001). There was no significant difference in the incidence of delirium (41 [79%] of 42 dexmedetomidine vs. 42 [82%] of 51 lorazepam recipients, p=0.65). There was no significant difference found for any of the secondary endpoints. Dexmedetomidine-treated patients were at their desired sedation goal more often than those treated with lorazepam (p=0.04 for nurse goal and p=0.008 for physician goal); however, they received more fentanyl than lorazepam recipients (575 mcg/day vs. 150 mcg/day, p=0.006). The only side effect that differed significantly between groups was the incidence of bradycardia (9 [17%] of 52 dexmedetomidine vs. 2 [4%] of 51 lorazepam recipients, p=0.03). Cost of the hospitalization was higher in the dexmedetomidine group, but not significantly.
The authors concluded that dexmedetomidine was more effective than lorazepam in achieving sedation goals and led to more days alive and free of coma and delirium.
Editorialists’ comments
The MENDS trial has been criticized for the lorazepam dosing strategy, namely that a continuous infusion was used instead of repeated bolus injections. Pharmacists who authored some of the editorial letters comment that lorazepam has a long half-life (8 to 15 hours), and oversedation is likely to occur when a continuous infusion is used. This could also lead to the higher incidence of coma. Also criticized was the titration of 0.15 mcg/hour of dexmedetomidine and 1 mg/hour of lorazepam. The criticism is based on the different half-lives of the medications, and that these doses do not represent equivalent increases. Other comments include the fact that the difference in the primary endpoint was largely due to a difference in incidence and numbers of days of coma, not delirium and the non-standardized approach to sedation interruption.
Conclusion
Based on the MENDS trial, dexmedetomidine appears to be a promising agent for ICU sedation, even beyond its labeled use of 24 hours. However, more data from properly designed trials are warranted to better define its impact on the occurrence of delirium and coma in this population.
References
Precedex [package insert]. Lake Forest, IL: Hospira; 2004.
Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298(22):2644-2653.
Dotson B, Peeters MJ. Sedation with dexmedomidine vs lorazepam in mechanically ventilated patients [letter]. JAMA 2008;299(13):1540.
Wunsch H. Sedation with dexmedomidine vs lorazepam in mechanically ventilated patients [letter]. JAMA 2008;299(13):1540-1541.
Barletta JF, Devlin JW. Sedation with dexmedomidine vs lorazepam in mechanically ventilated patients [letter]. JAMA 2008;299(13):1541-1542.
Pandharipande PP, Girard TD, Ely EW. In reply: sedation with dexmedomidine vs lorazepam in mechanically ventilated patients [letter]. JAMA 2008;299(13):1542.