General Anesthesia Dexmedetomidine Reduces Propofol and Remifentanil Requirements During Bispectral Index–Guided Closed-Loop Anesthesia: A Double-blind, Placebo-Controlled Trial Morgan Le Guen,*† Ngai Liu,*†‡ Felix Tonou,§ Marion Augé,* Olivier Tuil,* Thierry Chazot,* Dominique Dardelle,║ Pierre-Antoine Laloë,¶ Francis Bonnet,§# Daniel I. Sessler,** and Marc Fischler*† (Anesth Analg, 118:946–955, 2014) *Department of Anesthesiology, Hôpital Foch, Suresnes; †UVSQ–UFR des Sciences de la Santé Simone Veil, Montigny-le-Bretonneux; ‡Outcomes Research Consortium, Cleveland, Ohio; §Department of Anesthesiology and Intensive Care, Hôpital Tenon, Paris; and ║Pharmacy, Hôpital Foch, Suresnes, France; ¶Department of Anesthesiology, Leeds General Infirmary, Leeds, United Kingdom; #UPMC, Paris, France; and **Department of Outcomes Research, Cleveland Clinic, Cleveland, OH. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/SA.0000000000000089 D exmedetomidine (DEX) is an α 2 -adrenergic agonist and can be used as an adjunct to anesthetics, including propofol or volatile anesthetics. Automated titration of propofol and remifentanil with a dual-loop controller maintains bispectral index (BIS) values between 40 and 60 better than manual control. It automates anesthetic administration and is a way to quantify the anesthetic- sparing effect of an adjuvant such as DEX. This randomized, double-blind, placebo-controlled clinical trial was performed to determine the extent to which DEX could reduce the require- ment for propofol and remifentanil by decreasing dual-loop administration of the drugs during induction and maintenance of general anesthesia. Patients were scheduled for nonhemorrhagic elective sur- gery and were allocated 1:1 to DEX (100 μg/mL) or isotonic saline placebo just before anesthesia induction. The final concentration of DEX was 2 μg/mL, given as a bolus of 1 μg/kg over 10 minutes followed by a continuous infusion of 0.5 μg/kg per hour until skin closure. A comparable volume of saline was given to patients in the placebo group. After the 10-minute bolus infusion of study drug, induction was done by a closed-loop BIS-guided system that coadministered propofol and remifentanil. The controller was able to provide a user interface to key in patient’s demo- graphic data, to calculate effect-site concentrations of propofol and remifentanil, to steer the infusion pumps, to display the cal- culated effect-site concentration in real time, and to continuously record BIS, effect-site concentrations, and hemodynamic data at 5-second intervals. Minimal and maximal effect-site concentra- tions were set at 1 and 5 μg/mL for propofol and at 3 and 12 ng/mL for remifentanil during maintenance. Propofol and remifentanil requirements were compared using nonparametric statistical tests; P < 0.05 was considered statistically significant. SPSS version 11.0 (SPSS, Inc, Chicago, Ill) was used. Of 70 patients screened, 66 were allocated to either the DEX or saline group. Complete data for analysis were available from 28 patients per group. Patient demographic and surgical character- istics were comparable; 40% of the whole cohort underwent lapa- roscopic procedures. Bispectral index values in the saline group before and at the end of the bolus infusion were 95 and 94, respec- tively, and those for the DEX group were 95 and 85, respectively. Anesthetic induction times were 156 and 240 seconds in the DEX and saline groups, respectively (P = 0.003). Dexmedetomidine patients required 23% less propofol (95% confidence interval [CI], 8–38; P = 0.002) and 25% less remifentanil (95% CI, 9–41; P < 0.02). During maintenance, DEX patients required 29% less propofol (95% CI, 11–40; P = 0.005; 2.2 vs 3.1 mg/kg per hour) but comparable amounts of remifentanil. The initial postoperative request for morphine was a median of 4 hours in the DEX group compared with 1 hour in patients given saline. Pain scores at rest or at mobilization were similar during the first 6 hours postopera- tively. The ephedrine requirement in each group was similar during anesthesia induction and maintenance. The rates of postoperative shivering, pruritus, and nausea/vomiting were comparable in the 2 groups. Manual intervention of the practitioner on the closed- loop system was required only once in each group. No patient re- ported intraoperative awareness with explicit recall. The use of an automated system to administer anesthetics showed that DEX infusion reduced propofol and remifentanil requirements during induction and propofol requirement during maintenance. No notable adverse effects occurred. The investi- gators concluded that DEX could be a useful adjuvant to reduce anesthetic requirements to provide postoperative analgesia. COMMENT Dexmedetomidine is a highly selective central nervous sys- tem α 2 -adrenergic agonist that possesses sedative, hypnotic, anal- gesic, anxiolytic, and sympatholytic effects. These effects are mainly attributable to stimulation of α 2 adrenoceptors in the locus coeruleus in the brainstem and in the substantia gelatinosa of the dorsal horn of the spinal cord. One of the advantages of DEX is that it exhibits pronounced sedative and analgesic effects without respiratory depression and is associated with increased hemodynamic stability, thus making it an ideal anesthetic adjuvant in various clinical settings. In an effort to quantify the sparing ef- fects of DEX on intraoperative general anesthesia administered with intravenous propofol and remifentanil, the authors con- ducted this randomized, double-blind, placebo-controlled clinical trial using an automated dual closed-loop administration algo- rithm and assisted by BIS monitoring. A highly inventive and simple study design was followed. A practical protocol was designed that involved anesthetic in- duction and maintenance with a closed-loop BIS-guided system that coadministered propofol and remifentanil to the study group and saline to the control group. Age, sex, height, and weight were used to calculate the effect-site concentration of propofol and remifentanil. The input variable for the closed-loop system was a BIS value between 40 and 60. The system titrated propofol and remifentanil accordingly to maintain these BIS values and, if nec- essary, a bolus of either anesthetic was administered to attain this BIS range. Depending on error size from the set point of BIS 50, the controller determined a new concentration of either 280 www.surveyanesthesiology.com Survey of Anesthesiology • Volume 58, Number 6, December 2014 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.