October 2009
Reviewer: Jeff C. Huffman, MD
Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery
Background: Delirium after cardiac surgery is associated with increased length of hospitalization, increased complication rates, and mortality. Despite the clear links between delirium and poor outcomes after heart surgery, there are few interventions that appear to reduce the incidence of delirium in this setting. The authors of this study aimed to determine whether patients undergoing elective valve surgery who received postoperative sedation with dexmedetomidine (a selective a-2 agonist) brand name Precedex (Hospira, Inc.) had lower rates of delirium than those who had standard postoperative sedation.
Methods: This was a randomized, prospective study performed at a single tertiary care medical center. Subjects were enrolled prior to their elective cardiac valve operation; exclusion criteria included dementia, preoperative use of psychotropic medications, and a substance use disorder. Subjects were randomly assigned to one of three agents for postoperative sedation: dexmedetomidine, midazolam, or propofol; though subjects were blinded, because of the different appearances and half-lives of the agents, the investigators/clinicians were not blinded to subjects’ group assignment. Postoperatively, subjects were assessed daily (between 1600-1900) by a neuropsychiatrist who assessed the patient for delirium using DSM-IV-TR criteria. The three groups were compared with respect to the primary outcome (delirium incidence) and secondary outcomes (length of stay, adjunctive treatment requirements, and estimated cost of postoperative care).
Results: 118 of 179 eligible patients were randomized (n=40 dexmedetomidine; n=38 propofol; n=40 midazolam). Several patients in each group did not receive the intervention due to circulatory arrest, protocol violation, or physician request and ultimately 30 patients in each group received the intervention and were not lost to follow-up. The incidence of delirium in each group was dexmedetomidine 3% (n=1), propofol 50% (n=15), and midazolam 50% (n=15). When intent to treat analysis was used, these incidences were: dexmedetomidine 10%, propofol 44%, midalozam 44%. On logistic regression accounting for baseline characteristics, postoperative sedation treatment was the factor most strongly associated with the development of delirium.
Patients in the dexmedetomidine group received significantly less adjunctive medication (narcotic analgesics) for postoperative sedation. ICU and hospital stays were generally shorter, medications to treat delirium lesser, and estimated health care costs smaller in the dexmedetomidine group, although these differences did not reach significance.
Discussion: Despite having many flaws, this study is quite intriguing given the incredibly large reduction in delirium associated with use of dexmedetomidine. First, the flaws: the investigators were not blinded to subjects’ treatment condition, different patients had different surgeries (and 9 patients underwent CABG as a secondary procedure), about half of the 179 eligible patients never received the intervention, secondary analyses were not performed using intent-to-treat analysis, the cost estimates appear to have been quite rudimentary (assigning cost based solely on unit location and intubation status), and the ultimate size of the study may have been too small to assess the secondary outcomes with adequate statistical power. Therefore, this is best conceptualized as a true pilot study. Fortunately, the authors did carefully standardize the protocol for surgery and postoperative assessment, subjects did seem to receive similar treatments/protocols between groups with regard to their surgery, subjects received a careful clinical assessment for delirium, and the authors did control for some important baseline variables in their analysis.
The decreased incidence of delirium associated with dexmedetomidine has some theoretical basis. Both midazolam and propofol appear to have activity at GABA-A receptors, and agents that act at this receptor (e.g., other benzodiazepines) are associated with development/worsening of delirium. In contrast, dexmedetomidine is a “clean” agent that blocks only norepinephrine, may promote a more normal sleep-wake cycle, and (as in this study) is associated with reduced use of narcotics postoperatively, which may in itself reduce rates of delirium.
This study seems to have been just the beginning: since presentation of these results, there have been several randomized studies of dexmedetomidine in this setting.1,2 For example, a large randomized study of 375 patients with expected mechanical ventilation compared the use of dexmedetomidine and midazolam for sedation during intubation.2 The authors found that, at equivalent levels of sedation, dexmedetomidine-treated patients spent less time on the ventilator and experienced significantly less delirium.
Further, some centers are using this agent specifically for treatment of delirium, with promising results;3 these findings may be the most relevant for psychosomatic medicine specialists, given that we are usually not called to help prevent delirium. Instead we are typically called much later, to help manage emergent/persistent delirium. Additional study of dexmedetomidine is needed, but it seems clear that this agent may be the most promising development in the prevention and treatment of delirium in quite a long time.
References
- 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;298:2644-53.
- Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489-99.
- Reade MC, O'Sullivan K, Bates S, Goldsmith D, Ainslie WR, Bellomo R. Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial. Crit Care 2009;13:R75.