PERIOPERATIVE MEDICINE Feasibility of Closed-loop Titration of Propofol and Remifentanil Guided by the Spectral M-Entropy Monitor Ngai Liu, M.D., Ph.D.,* Morgan Le Guen, M.D.,* Fatima Benabbes-Lambert, M.D.,† Thierry Chazot, M.D.,* Bernard Trillat, M.Sc.,‡ Daniel I. Sessler, M.D.,§ Marc Fischler, M.D. ABSTRACT Background: This randomized controlled trial describes automated coadministration of propofol and remifentanil, guided by M-Entropy analysis of the electroencephalogram. The authors tested the hypothesis that a novel dual-loop controller with an M-Entropy monitor increases time spent within predetermined target entropy ranges. Methods: Patients scheduled for elective surgery were ran- domly assigned in this single-blind study using a computer- generated list, to either dual-loop control using a proportio- nal-integral-derivative controller or skilled manual control of propofol and remifentanil using target-controlled-infusion systems. In each group, propofol and remifentanil adminis- tration was titrated to a state entropy target of 50 and was subsequently targeted to values between 40 and 60. The pri- mary outcome was the global score, which included the percent- age of state entropy or response entropy in the range 40 – 60, the median absolute performance error and wobble. Data are pre- sented as medians [interquartile range]. Results: Thirty patients assigned to the dual-loop group and 31 assigned to the manual group completed the study. The dual-loop controller was able to provide induction and mainte- nance for all patients. The Global Score of State Entropy was better maintained with dual-loop than manual control (25 [19 – 53] vs. 44 [25–110], P = 0.043), and state entropy was more frequently maintained in the range of 40 – 60 (80 [60 – 85] vs. 60 [35– 82]%, P = 0.046). Propofol (4.1 [2.9 – 4.9] vs. 4.5 [3.4 – 6.3] mg · kg -1 ·h -1 ) and remifentanil (0.18 [0.13– 0.24] vs. 0.19 [0.15– 0.26] g · kg -1 · min -1 ) consumptions and the incidence of somatic side effects were similar. Conclusion: Intraoperative automated control of hypnosis and analgesia guided by M-Entropy is clinically feasible and more precise than skilled manual control. I N 1950, Mayo et al. reported that electrocortical activity could be used to automatically titrate ether administra- tion. 1 Subsequently, various signals including the median frequency of the electroencephalogram power spectrum 2 and * Associate Professor of Anesthesia, Service d’Anesthe ´sie, Ho ˆpital Foch, Suresnes, France. † Assistant Professor of Anesthe- sia, Service d’Anesthe ´sie, Ho ˆpital Foch. ‡ Informatics Engineer, Service d’Informatique, Ho ˆpital Foch. § Professor of Anesthesia, Department of Outcomes Research, Cleveland Clinic, Cleve- land, Ohio.  Professor and Chairman of Anesthesia, Service d’Anesthe ´sie, Ho ˆpital Foch. Received from Service d’Anesthe ´sie and Service d’Informatique, Ho ˆpital Foch, Suresnes, France, and the Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio. Submitted for publi- cation May 18, 2011. Accepted for publication October 10, 2011. Support was provided by the Service d’Anesthe ´sie, Ho ˆpital Foch (Suresnes, France); Vaincre la Mucoviscidose (Paris, France); Alaris Medical (Hampshire, United Kingdom), who loaned the Asena GH infusion pumps to the study; and GE Healthcare (Helsinki, Finland), who loaned the Entropy Module. N. Liu, T. Chazot and B. Trillat have a patent in France for the gain constants in the control algo- rithm (N°BFF08P669, Institut National de la Proprie ´te ´ Industrielle, France). None of the other authors has a personal financial interest in this research. Presented in part as an oral presentation at the American Society of Anesthesiologists annual meeting, October 17, 2007, San Francisco, California. Address correspondence to Dr. Fischler: Service d’Anesthe ´sie, Ho ˆpital Foch, 40 rue Worth, 92150 Suresnes, France. m.fischler@ hopital-foch.org. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the begin- ning of this issue. ANESTHESIOLOGY’s articles are made freely acces- sible to all readers, for personal use only, 6 months from the cover date of the issue. Copyright © 2012, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2012; 116:286 –95 What We Already Know about This Topic • The use of electroencephalography to guide anesthetic ad- ministration remains controversial • M-Entropy analysis provides dual analyses with differential sensitivities to hypnosis and analgesia What This Article Tells Us That Is New • Intraoperative automated propofol-remifentanil anesthesia guided by M-Entropy is clinically feasible and more precise than skilled manual control  This article is accompanied by an Editorial View. Please see: Crosby G, Culley DJ: Processed electroencephalogram and depth of anesthesia: Window to nowhere or into the brain? ANESTHESIOLOGY 2012; 116:235–7. 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