Dexmedetomidine Reduces Delirium Compared With Midazolam in ICU Patients Sedated for More Than 24 Hours

Emma Hitt, PhD

February 04, 2008

February 4, 2008 (Honolulu) — Compared with midazolam, dexmedetomidine significantly decreases incidence and duration of delirium, time to extubation, and length of stay in intensive care unit (ICU) patients when given for more than 24 hours, according to the findings of a randomized, multicenter trial.

Richard Riker, MD, from the Maine Medical Center in Portland, reported the findings here yesterday in a late-breaking session at the 37th Critical Care Congress of the Society of Critical Care Medicine.

Dexmedetomidine, an alpha-2 agonist, was approved in 1999 for up to 24 hours of use in the ICU setting. The US Food and Drug Administration mandated the current trial to evaluate the safety and efficacy of this agent when used for longer than 24 hours. Dexmedetomidine, unlike some other sedatives, is not associated with respiratory depression and may reduce or prevent delirium.

"Delirium affects 60% to 80% of mechanically ventilated patients and is associated with a 3-fold higher mortality risk over 6 months," Dr. Riker noted during his presentation.

The current study evaluated the safety and efficacy of dexmedetomidine vs midazolam in adult ICU patients expected to require mechanical ventilation for at least 24 hours. Patients were sedated within a target Richmond Agitation Sedation Scale (RASS) range of −2 to +1 at the initiation of the study drug.

Patients were randomly assigned in a ratio of 2:1 to receive dexmedetomidine (n = 244) or midazolam (n = 122), respectively. The overall population was used in the safety analysis, whereas a subset of patients receiving either dexmedetomidine (n = 194) or midazolam (n = 109) for more than 24 hours was evaluated in an intention-to-treat (ITT) analysis.

Patients received dexmedetomidine with an optional loading dose followed by a maintenance dose of 0.2 to 1.4 µg/kg/hr. Midazolam was given with an optional loading dose followed by a dose of 0.02 to 0.1 mg/kg/hr. Daily arousal, RASS, and Confusion Assessment Method for ICU (a measure of delirium) were all assessed. Patients were treated for 30 days or until extubation. Patients outside of the target RASS range could also receive midazolam bolus or fentanyl bolus or IV.

The primary efficacy endpoint was time in the target RASS range. Patient in both groups achieved this endpoint for approximately 80% of the study duration, with no significant difference between groups.

However, delirium was decreased or prevented with dexmedetomidine. From days 1 through 8, a significantly higher incidence of delirium was observed with midazolam compared with dexmedetomidine (P < .05 for trend). Furthermore, patients who were positive for delirium at baseline demonstrated a significantly reduced incidence of delirium over 8 days with dexmedetomidine (P < .05 for trend). Patients in the ITT group receiving dexmedetomidine had, on average, 1.4 days with delirium compared with 2.7 with midazolam (P < .0001). Likewise, the number of delirium-free days was significantly higher with dexmedetomidine than midazolam (P = .0018).

The median time to extubation was also shorter with dexmedetomidine than with midazolam — 93.8 hours vs 138.4 hours, respectively (P = .016) — as was time to readiness for ICU discharge — 6.2 days vs 8.0 days (P = .025). The overall nursing assessment significantly favored dexmedetomidine for patient cooperation and ability to communicate (P = .015).

With respect to safety, the rate of treatment-emergent adverse events was higher with dexmedetomidine (40.6% vs 28.7%; P = .029); however, moderate to severe adverse events, as well as the number of discontinuations, were comparable between groups.

The incidence of bradycardia was higher in the dexmedetomidine group (42.2% vs 18.9%), but the rates of tachycardia and systolic blood pressure of 180 mm Hg or more were higher with midazolam. Infection rates were also higher with midazolam than with dexmedetomidine, potentially because of the longer duration of ICU stay needed with midazolam.

No differences in all-cause mortality were noted between the groups, either at discharge or 30 days after the study drug was stopped.

According to Dr. Riker, the most impressive finding was that the patients on dexmedetomidine had a much lower incidence of delirium whether or not they had delirium at baseline. "Previous studies had hinted at this, but this is the largest multicenter study to incorporate an assessment of delirium and to confirm these results," he told Medscape Critical Care. He added that delirium is associated with worse cognitive outcomes that extend well beyond hospital discharge, "so I think these findings have clear implications for clinical practice."

"Dexmedetomidine is just now coming into widespread use, and many of us have questions," said Heidi J. Dalton, MD, from the Children's Hospital of Pittsburgh, Pennsylvania, who moderated the session." These results with dexmedetomidine are intriguing," she told Medscape Critical Care.

"I will be interested to see if these results can be reproduced in the pediatric setting. It will also be interesting to see if the approved duration of treatment with dexmedetomidine will be lengthened past 24 hours," Dr. Dalton said.

The study was funded by Hospira.

Society of Critical Care Medicine 37th Critical Care Congress: Late-breaker abstract. Presented February 3, 2008.

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