Key Point

Dexmedetomidine is as safe as midazolam for long-term sedation of mechanically ventilated patients—with less risk of delirium.

HONOLULU—Long-term sedation with dexmedetomidine is safe and reduces the risk of delirium in mechanically ventilated ICU patients, according to results from the Safety and Efficacy of Dexmedetomidine Compared to Midazolam (SEDCOM) study presented by Richard R. Riker, MD, of the Maine Medical Center in Portland, at the Society of Critical Care Medicine’s 37th Critical Care Congress.

Dexmedetomidine, a selective α₂-adrenergic receptor agonist, has sedative, analgesic, anxiolytic, and sympatholytic properties without depressing respiratory function. It was approved by the FDA in 1999 for use as a sedative for up to 24 hours. The current study was undertaken at the request of the FDA to provide information regarding the safety and efficacy of dexmedetomidine for long-term sedation.

Dr. Riker noted that delirium affects 60% to 80% of mechanically ventilated patients and is associated with a threefold higher mortality rate over the following six months. In addition, delirium has been linked to prolonged cognitive impairment and increased utilization of health care resources.

With regard to sedatives, both midazolam and lorazepam are associated with oversedation and hypotension, while propofol may cause hypotension, triglyceride elevations, pancreatitis, and the potentially fatal propofol infusion syndrome. Dexmedetomidine is associated with hypotension and bradycardia. “So there is no perfect sedative out there,” Dr. Riker stated.

STUDY METHODS

The double-blind SEDCOM study evaluated the safety and efficacy of dexmedetomidine compared with midazolam in intubated, mechanically ventilated ICU patients requiring sedation for longer than 24 hours. Intubated adults anticipated to require more than 72 hours of mechanical ventilation were eligible for inclusion in the study. Prior to initiation of the study drug, the patient had to be within the target sedation level, which was a Richmond Agitation-Sedation Scale (RASS) score between -2 and 1. Among the patients excluded from the study were those who already had been intubated for longer than four days or admitted for trauma or burns; those with documented central nervous system pathology, unstable cardiac conditions, advanced liver disease, or active hepatitis; and those who were dialysis-dependent.

Patients were assessed at baseline for delirium using the Confusion Assessment Method for the ICU (CAM-ICU) and randomized to either dexmedetomidine or midazolam on a two to one basis, but they could receive midazolam boluses if they were out of the target sedation range. Additionally, fentanyl boluses or transition fentanyl infusion was allowed to manage pain.

Of the 420 eligible patients, 244 patients in the dexmedetomidine arm and 122 in the midazolam arm received the study drugs; their data were used to assess safety information. Patients who received a study drug for more than 24 hours—194 in the dexmedetomidine arm and 103 in the midazolam arm—were included in the efficacy evaluable analysis.

The two study arms were similar with regard to age, gender, weight, APACHE score, liver and renal function, and baseline CAM-ICU status (56% and 54% were CAM-ICU positive in the dexmedetomidine and midazolam arms, respectively). Pre–study drug sedation was with a benzodiazepine for 80% of patients in both groups, propofol in approximately 28% of patients, and dexmedetomidine in less than 1% of patients. Similar sedation levels were achieved in both arms; patients were sedated within the target RASS range of -2 to 1 for 80.8% and 81.0% of the treatment time in the dexmedetomidine and midazolam arms, respectively.

DEXMEDETOMIDINE FAVORED

“If you look at day 1 through day 8, you can see a dramatically higher incidence of delirium in the group receiving midazolam,” Dr. Riker said. Specifically, the incidence of delirium in the dexmedetomidine group was 54% versus 75% in the midazolam group.

A similar difference was seen in the subgroups of patients who were initially CAM-ICU negative or CAM-ICU positive. In the CAM-ICU negative group, delirium occurred in 33% of dexmedetomidine-treated patients and 55% of midazolam-treated patients, while among those who were initially positive, 70% and 95% of patients in the dexmedetomidine and midazolam groups, respectively, experienced delirium. Duration of delirium was shorter in the dexmedetomidine group—1.4 days versus 2.7 days for midazolam, a 48% reduction.

Time to extubation also favored dexmedetomidine, with the median time to extubation being 94 hours with dexmedetomidine and 138 hours with midazolam—a reduction of 32% in ventilator time for the dexmedetomidine group. Time to readiness for ICU discharge was shorter with dexmedetomidine—6.2 days versus 8.0 days with midazolam, a reduction of 21%. Nursing assessments found that patients treated with dexmedetomidine had a statistically significant greater ability to communicate and to cooperate than those treated with midazolam.

SIMILAR RATES OF ADVERSE EVENTS

Safety analysis found that while there was a higher incidence of treatment-related emergent adverse events in the dexmedetomidine group, there were no between-group differences in rates of moderate or severe adverse events.

“There was a significantly higher incidence of bradycardia among those treated with dexmedetomidine and a higher incidence of tachycardia in the midazolam group,” Dr. Riker remarked. The ICU death rate was approximately 18% in both arms.

“Compared to midazolam at equivalent levels of sedation, dexmedetomidine use is associated with a significant decrease in the incidence and duration of delirium, in the time to extubation, and in the ICU length of stay,” Dr. Riker concluded.

—Laurel McKee Ranger

Suggested Reading
Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753-1762.
Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003;289(22):2983-2991.
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.

Return to table of contents