Sedation in intensive care unit (ICU) patients is assumed to facilitate proper care with improved patient comfort and safety, though long-term use is fraught with potential serious adverse effects. The use of dexmedetomidine, a sedative with alpha-2 agonist properties, may enhance patient safety and comfort in long-term sedation, but evidence has been limited and inconclusive. In the April issue of The Journal of American Medicine Association, Jakob and the Dexmedetomidine for Long-Term Sedation Investigators conducted two parallel randomized trials to determine the efficacy of dexmedetomidine versus midazolam or propofol in maintaining sedation, reducing duration of mechanical ventilation and improving patient interaction with nursing care.

The authors conducted two parallel phase 3, multicenter, randomized controlled trials comparing dexmedetomidine with propofol (PRODEX trial) or with midazolam (MIDEX trial) for patients requiring prolonged mechanical ventilation. The combined studies involved 998 patients in 75 ICUs throughout Europe andRussia. Included were patients 18 years or older receiving mechanical ventilation with an expected duration of 24 hours or longer and in need of light to moderate sedation, Block randomization was employed and all patients and study personnel were masked to treatment allocation with a double-dummy design. The primary efficacy outcomes measured were the proportion of time in target sedation range (Richmond Agitation Sedation Scale [RASS] score 0 to -3) without use of rescue therapy and the duration of mechanical ventilation from randomization until patients were liberated. Secondary outcomes included length of ICU stay, ability to cooperate with care and ability to communicate pain.

Both dexmedetomidine/midazolam and dexmedetomidine/propofol were not statistically different in terms of time to desired sedation level. Median duration of mechanical ventilation was shown to be shorter with dexmedetomidine (123 hours; interquartile range [IQR], 67-337) compared to midazolam (164 hours; IQR, 92-380; P = 0.03), but not with dexmedetomidine compared to propofol (P = 0.24). Among the dexmedetomidine group, patient interaction was also improved when compared to both the midazolam and propofol groups. There were no significant differences between groups regarding length of ICU and hospital stays as well as mortality rate. The use of dexmedetomidine was associated with more episodes of hypotension and bradycardia.

The results of this study are consistent with those of the Safety and Efficacy of Dexmedetomidine Compared with Midazolam (SEDCOM) trial. This is the first large-scale study to compare dexmedetomidine with propofol in long-term sedation. Non- inferiority in maintaining the target sedation level with dexmedetomidine compared with propofol and midazolam was achieved. Dexmedetomidine also appeared to reduce the duration of mechanical ventilation compared with midazolam. The fact that patients who received propofol and midazolam were more sedated than those receiving dexmedetomidine (though all were in a broad range of target RASS) might have resulted in improved outcomes stemming from the decreased sedation level and not due to the inherent properties of the agent used. While this well-designed and methodologically rigorous study provides additional evidence to support the use of dexmedetomidine as a first-line sedative in the ICU, further tangible long-term outcome data, as well as confirmation that the benefits are due to choice of sedative, are needed to justify the substantially higher cost of treatment and to consolidate dexmedetomidine’s place in the intensivist’s armamentarium. Dexmedetomidine is scheduled to be available as a substantially cheaper generic preparation within the next year. 

Concise Critical Appraisal is a regular feature authored by SCCM member Samuel M. Galvagno Jr., DO. Each installment highlights journal articles most relevant to the critical care practitioner.

Special thanks to Ayal Romen, MD, who contributed to this installment of Concise Critical Appraisal. Romen is a fellow in pulmonary critical care at the University of Maryland School of Medicine.