Anesthesiology 2009; 110:1036 – 40 Copyright © 2009, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Effect of Flumazenil on Bispectral Index Monitoring in Unpremedicated Patients Ashraf A. Dahaba, M.D., Ph.D., M.Sc.,* Helmar Bornemann, M.D.,† Peter H. Rehak, Ph.D.,‡ Geng Wang, M.D.,§ Xin Min Wu, M.D.,|| Helfried Metzler, M.D.# Background: Flumazenil is an imidazobenzodiazepine that promptly reverses via competitive inhibition the hypnotic/sed- ative effects of benzodiazepines on -aminobutyric acid recep- tors. Endogenous benzodiazepine ligands (endozepines) were isolated in urine, cerebrospinal fluid, and breast milk of women who had not received benzodiazepines. The bispectral index (BIS), an electroencephalographically derived parameter widely used for monitoring the effects of anesthetic/hypnotic drugs, was shown to correlate to various conditions that could influence electroencephalography. The authors examined the hypothesis that 0.5 mg of flumazenil administered to healthy unpremedi- cated patients during deep surgical remifentanil/propofol an- esthesia would increase the BIS value and might expedite recov- ery from anesthesia. Methods: Sixty healthy unpremedicated patients were ran- domly allocated to the flumazenil or control groups. After study drug administration, the authors compared BIS values and var- ious recovery parameters in the flumazenil and control groups. Results: BIS baseline values in the flumazenil group (38.7  3.8) increased 15 min after flumazenil administration (53.2  4.7), with a significant difference over time (P < 0.0001) be- tween the two groups. Mean recovery parameters time, com- prising time to spontaneous breathing, eye opening/hand squeezing on verbal command, extubation, and date of birth recollection, was significantly shorter (P  0.0002) in the flumazenil group (6.9  2.6 min) compared with the control group (9.8  2.9 min). Conclusions: This study demonstrates that flumazenil given to healthy unpremedicated patients during propofol/remifen- tanil anesthesia significantly increased the BIS value and al- lowed earlier emergence from anesthesia. This may indicate that flumazenil could be used on a case-by-case basis to reverse endogenous or exogenous endozepines that might play a role during anesthesia. FLUMAZENIL is an imidazobenzodiazepine that promptly re- verses via competitive inhibition the hypnotic/sedative effects of benzodiazepines on -aminobutyric acid re- ceptors. 1 Flumazenil was shown to have a beneficial analeptic stimulant effect in hepatic encephalopathy pa- tients; a recent meta-analysis 2 of several double-blind randomized placebo-controlled trials described improve- ment in electroencephalographic signs of hepatic en- cephalopathy after flumazenil administration in patients who had not received sedative/hypnotic medications. 2 En- dogenous benzodiazepines ligands (endozepines) 3 were isolated in urine, 4 cerebrospinal fluid, 5 and breast milk 6 of women who had not received benzodiazepines. It has been suggested that there might be a beneficial analeptic stimu- lant effect as a result of flumazenil’s displacement of these endogenous benzodiazepine ligands. The bispectral index (BIS), an electroencephalographi- cally derived parameter widely used for monitoring the effects of anesthetic/hypnotic drugs, was shown to cor- relate to various conditions that could influence electro- encephalography. 7 Meanwhile, there is paucity of infor- mation regarding the effects of central nervous system (CNS) stimulants on BIS monitoring when they are added to general anesthesia. Because flumazenil is a readily available medication that might exert a stimulant effect expediting anesthesia recovery, we tested the hypothe- sis that flumazenil administration in unpremedicated pa- tients during steady-state deep surgical anesthesia would lead to an increase in BIS value as a surrogate parameter suggesting a lighter plane of anesthesia. Our primary endpoint was the effect of flumazenil administration on deep surgical propofol/remifentanil total IV anesthesia of BIS around 40. The secondary endpoints were the differences between the two groups in various anesthe- sia recovery parameters. Materials and Methods Our report of a prospective clinical consecutive ran- domized study was prepared in conformity with the guidelines of the consolidated standards of reporting trials (CONSORT) statement. 8 After approval by the Pe- king University First Hospital (Beijing, People’s Republic of China) ethics committee, all patients who agreed to participate in the study gave written informed consent. Exclusion criteria were body mass index less than 20 or greater than 26 kg/m 2 , treatment with cardiovascular or sedative/hypnotic drugs that might affect BIS monitor- ing, 7 and medical conditions that could affect the level of consciousness such as stroke, stupor, or dementia. Using a computer-generated program, 60 unpremedi- cated patients with American Society of Anesthesiolo- gists classification I-II undergoing upper/lower extremi- ties or general surgical procedures of around 3 h with expected blood loss of less than 1 l were randomly allocated to the flumazenil or control groups. A BIS Quatro sensor (Aspect Medical Systems, Newton, MA) * Associate Professor, † Staff Anesthesiologist, # Professor, Department of Anaesthesiology and Intensive Care Medicine, ‡ Professor, Biomedical Engineer- ing and Computing Unit of the Department of Surgery, Graz Medical University, Graz, Austria; § Associate Professor, || Professor, Department of Anaesthesiology, Peking University First Hospital, Beijing, People’s Republic of China. Received from Department of Anaesthesiology and Intensive Care Medicine, Graz Medical University, Graz, Austria. Submitted for publication July 23, 2008. Accepted for publication November 21, 2008. Support was provided solely from institutional and/or departmental sources. Address correspondence to Dr. Dahaba: Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria, Auenbrugger- platz 29, A-8036, Graz, Austria. ashraf.dahaba@medunigraz.at. Information on purchasing reprints may be found at www.anesthesiology.org or on the mast- head page at the beginning of this issue. ANESTHESIOLOGY’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. Anesthesiology, V 110, No 5, May 2009 1036 Downloaded from anesthesiology.pubs.asahq.org by guest on 07/15/2020