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Efficacy and Safety of Dexmedetomidine for Postoperative Delirium in Adult Cardiac Surgery on Cardiopulmonary Bypass

Background Delirium after cardiac surgery is associated with serious long-term negative outcomes and high costs. The aim of this study is to evaluate neurobehavioral, hemodynamic, and sedative characteristics of dexmedetomidine, compared with the current postoperative sedative protocol (remifentanil) in patients undergoing open heart surgery with cardiopulmonary bypass (CPB). Methods One hundred and forty two eligible patients who underwent cardiac surgery on CPB between April 2012 and March 2013 were randomly divided into two groups. Patients received either dexmedetomidine (range, 0.2 to 0.8 μg/kg/hr; n=67) or remifentanil (range, 1,000 to 2,500 μg/hr, n=75). The primary end point was the prevalence of delirium estimated daily via the confusion assessment method for intensive care. Results When the delirium incidence was compared with the dexmedetomidine group (6 of 67 patients, 8.96%) and the remifentanil group (17 of 75 patients, 22.67%) it was found to be significantly less in the dexmedetomidine group (p<0.05). There were no statistically significant differences between two groups in the extubation time, ICU stay, total hospital stay, and other postoperative complications including hemodynamic side effects. Conclusion This preliminary study suggests that dexmedetomidine as a postoperative sedative agent is as sociated with significantly lower rates of delirium after cardiac surgery.


INTRODUCTION
Postoperative delirium is generally known to develop in up to 57% of cardiac-surgery patients [1]. Given this condition's high incidence rate, the consequences of delirium place a considerable burden on both patients and medical staff because of increased morbidity, higher mortality rates, incomplete functional cognitive recovery, prolonged hospitalization, and increased costs of long-term treatment [2][3][4]. A number of studies have reported that 32% to 84% of delirium patients go unrecognized by the relevant clinical staff [5], and the causes of postoperative delirium have not yet been identified. The known probable risk factors of delirium after cardiac surgery include advanced age, preexisting cognitive decline, atrial fibrillation, perioperative medications, previous delirium, and other metabolic disorders [6]. Among them, major surgery including cardiac operations may increase the risk of delirium due to intricacy of the surgical procedure, − 250 − administration of perioperative anesthetic and other pharmacological substances, and postoperative complications [7,8]. We hypothesized that the administration of dexmedetomidine (highly selective and potent α -2 adrenergic agonist with sedative and analgesic properties) may be associated with a lower incidence of delirium by pharmacological action. It produces sedation with modest analgesic and possible anti-delirium effects with minimal respiratory depression [9,10]. The present study was aimed at the investigation of the postoperative sedative effects of dexmedetomidine associated with a lower in-

1) Study design and patients
All patients undergoing cardiac surgery are prospectively registered in Konkuk University Medical Center. These registries contain baseline characteristics of patients, perioperative evaluation data, and results or other complications of surgery.
All patients fulfilling the inclusion and exclusion criteria and hospitalized for elective open heart surgery were eligible for this study. The study was approved by Konkuk University Medical Center's independent institutional review board, and informed consent was obtained from each patient. A total of 370 patients underwent cardiac surgery from April 2012 to March 2013. We excluded patients who had re-do and emergency surgery, severe pulmonary or systemic disease, left ventricular ejection fraction＜40%, pre-existing renal dysfunction (serum creatinine level＞2.0 mg/dL), and documented preoperative dementia, Parkinson disease, or recent stroke, and who were older than 90 years or younger than 17 years of age. In addition, patients who had psychotropic medications, evidence of progressed heart block, and surgery requiring deep hypothermic circulatory arrest involving thoracic aorta were also excluded. Among them, 142 patients who un-derwent cardiac surgery on CPB were enrolled in this trial.

2) Intraoperative procedures
Anesthesia for the operation was initiated according to the

3) Postoperative administration
Upon return to the CICU, a standardized regimen for postoperative management was followed for all patients; they were started on one of the following two sedative protocols: dexmedetomidine (loading dose, 0.5 μg/kg; maintenance dose, 0.2 to 0.8 μg/kg/hr) or remifentanil (range, 1,000 to 2,500 μg/hr). Infusion rate of drugs was maintained by titration as per the specified protocol to maintain target sedation and adequate analgesia by specially trained nurses who were certified in cardiac intensive care. The efficacy measures for sedation and analgesia were based on the Modified Ramsay Sedation Scale (1-6) and the Numeric Pain Intensity Scale (NPIS: 0-10). We intended to maintain a Ramsay sedation score of 3 (before extubation) and 2 (after extubation).

4) Outcome measures
The primary outcome of the study was the proportion of (defined as heart rate less than 55/min), re-intubation within 48 hours, and renal failure.

5) Statistical analyses
Statistical analyses were performed with PASW SPSS ver.
18.0 (SPSS Inc., Chicago, IL, USA   (Table 3). However, the number of patients requiring an additional infusion of analgesics such as pethidine and ketorolac was significantly higher in the dexmedetomidine group than in the remifentanil group.

DISCUSSION
The present study evaluated the administration of a highly selective α -2 agonist, dexmedetomidine focusing on cardiac postoperative care. The study concluded that sedation with dexmedetomidine was associated with a significantly reduced incidence of postoperative delirium in patients undergoing cardiac surgery with CPB. In general, cardiac surgery, particularly valve surgery, has a high risk of cardiovascular and other complications with a reported incidence of over 30%.
Among others, the occurrence of postoperative cognitive dysfunction in patients undergoing cardiac surgery has been attributed to the synergistic effect of microemboli, hypoperfusion, and fast rewarming during CPB [7,8]. However, it is still obscure whether postoperative delirium or cognitive decline is actually related to CPB or not. As for the type of cardiac surgery, it has been known that patients undergoing valvular surgery are at a higher risk of delirium than CABG patients, which makes them potentially more vulnerable to postoperative neuropsychiatric deficits [12]. Similarly, a majority of the patients considered in this study were cardiac valve surgery patients. The low prevalence of delirium in this study may be justified by the pre-exclusion of certain patients who had diagnosis of dementia or other psychological problems, psychotropic medication, and stroke history.
In addition, choices of sedatives in the postoperative period may be critical for preventing delirium. The highly sensitive α -2-adrenergic agonist, dexmedetomidine, has recently attracted considerable attention due to its ability to provide adequate postoperative sedation and analgesia without producing excessive hypotension or the need for vasopressors, while reducing the risk of delirium after cardiac surgery. Unlike conventional sedatives such as propofol, midazolam, or morphine, dexmedetomidine can produce anxiolysis and sedation without provoking significant respiratory depression. It seems that this respiratory advantage of dexmedetomidine is directly related to postoperative delirium, as other studies have implied that dexmedetomidine's effects on delirium are not simply due to its opioid-sparing properties [13]. Several studies have reported that prolonged periods of intubation increase the risk of delirium by 1.10 to 7.90 times as compared to shorter periods of intubation [14]. Consequently, dexmedetomidine has another potential advantage in that patients may be extubated in the sedated state and that they may be main-   By chi-square test.
tained under sedation as long as necessary until homeostasis is recovered and pain and anxiety are kept under control [15].
These findings presume that the maximum benefit of dexmedetomidine may be realized in patients at a high risk of de- were no statistically significant differences between the two groups in extubation time, ICU stay, total hospital stay, and other postoperative complications including hemodynamic side effects. However, the events requiring additional analgesics were significantly higher in the dexmedetomidine group than in the remifentanil group.