The bispectral index (BIS) monitor was developed

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1 Validation of the Bispectral Index Monitor During Conscious and Deep Sedation in Children Nicole Brown McDermott, MD, Tamitha VanSickle, MD, Dominika Motas, MD, and Robert H. Friesen, MD Department of Anesthesiology, The Children s Hospital and the University of Colorado School of Medicine, Denver, Colorado In this study, we tested the validity of the bispectral index (BIS) monitor during conscious and deep sedation of children by comparing it with the University of Michigan Sedation Scale (UMSS), a validated observational pediatric sedation scale. Eighty-six children 12 yr of age were enrolled in this observational study. The subjects underwent conscious or deep sedation administered by nonanesthesiologists for diagnostic or therapeutic procedures in four departments in a children s hospital. Sedation medications varied among departments and were not controlled by the study protocol. An independent observer derived a UMSS score at 10-min intervals for 1 h during sedation; personnel administering sedation medications and performing the procedures were blinded to the BIS and UMSS scores. Significant correlation between BIS scores and UMSS scores was found (r 0.704, P ), including in subjects 6 moofage(n 6) (r 0.761, P 0.001). Poor correlation was found when ketamine or an oral combination of chloral hydrate, hydroxyzine, and meperidine were used for sedation. We conclude that BIS correlates well with UMSS scores and may be a valid measure of conscious and deep sedation in children. (Anesth Analg 2003;97:39 43) The bispectral index (BIS) monitor was developed by correlating electroencephalogram (EEG) recordings from healthy adult volunteers with clinical data indicative of hypnosis. This large database was then used to calculate a numeric scale from 100, equaling an EEG pattern of an awake and alert adult, to 0, indicating an isoelectric EEG pattern. The goal of the BIS monitor was to provide an objective, quantitative measure of the level of hypnosis for all patients. Denman et al. (1) and Bannister et al. (2) showed a correlation between BIS value and end-tidal sevoflurane concentration in children during general anesthesia. However, there are no current studies of EEG changes in children in the presence of sedative drugs, so a need exists for validation of the BIS value in pediatric populations (3,4). Until recently, there have been limited tools to reliably measure the depth of sedation in children. With the development and validation of the University of Michigan Sedation Scale (UMSS) for children (5), the ability to conduct a study Accepted for publication February 28, Address correspondence and reprint requests to Robert H. Friesen, MD, Department of Anesthesiology, The Children s Hospital, 1056 E. 19th Ave., Denver, CO Address to friesen.robert@tchden.org. DOI: /01.ANE A2 to determine the validity of the BIS monitor in children has become more feasible. Therefore, the goal of this study was to determine the validity of the BIS during conscious and deep sedation (6) in children 12 yr of age. We hypothesized that the BIS score is a valid measure of the depth of conscious and deep sedation in children. Methods This study was approved by our IRB. Parental written informed consent and child assent (when appropriate for age) were obtained for each subject. Eighty-six children aged 12 yr were enrolled in this observational study. Subjects were undergoing elective diagnostic or therapeutic procedures involving conscious or deep sedation in the cardiac catheterization laboratory, gastrointestinal endoscopy suite, computerized tomography scanner, or the dental clinic. Patients with endotracheal tubes in place, on ventilatory support, or with known EEG abnormalities were excluded. The study did not dictate choice or dosage of sedation medications. The sedation medications were administered according to protocols followed by the departments in which the procedures took place by the International Anesthesia Research Society /03 Anesth Analg 2003;97:

2 40 PEDIATRIC ANESTHESIA McDERMOTT ET AL. ANESTH ANALG BIS MONITORING IN SEDATED CHILDREN 2003;97:39 43 Although drug dosage varied somewhat among patients, the general drug regimens used in each department are displayed in Table 1. The physicians administering or supervising the administration of sedation medications were not anesthesiologists and were not investigators in this study. All personnel involved in performing the diagnostic or therapeutic procedures and in administering sedation medications were blinded to UMSS and BIS scores. The UMSS score is a 5-point observational scale for the depth of sedation: 0 awake and alert, 1 minimally sedated (tired/sleepy, appropriate response to verbal conversation and/or sound), 2 moderately sedated (somnolent/sleeping, easily aroused with light tactile stimulation or a simple verbal command), 3 deeply sedated (deep sleep, arousable only with significant physical stimulation), 4 unarousable (5). An independent observer derived and recorded the UMSS score every 10 min for 1 h during the procedure and recorded the doses and times of administration of sedation medications. A disposable pediatric BIS adhesive sensor was placed on each child s forehead and connected to a BIS monitor (model A2000; Aspect Medical Systems, Newton, MA) as directed by the manufacturer before sedation medications were administered and before each procedure began. BIS was monitored for 1 h during the procedure. The BIS monitor screen was covered during the procedure to ensure that observers were blinded to the BIS score. The protocol called for a second independent observer who was unaware of the UMSS score to record the BIS score every 10 min, and this was achieved in 37 subjects. However, because of manpower problems, a second observer was unavailable for 49 subjects; in those cases, the first observer derived and recorded the UMSS score and then immediately uncovered the BIS screen momentarily to record the BIS score. We recognized the possibility that this could introduce bias that could affect subsequent UMSS scores by providing BIS feedback immediately after deriving a UMSS score, so correlation with and without the second independent observer was performed. The BIS monitor also displays electromyogram (EMG) activity in graphic form on a scale of db. This EMG score was recorded by the observer at 10- min intervals along with the BIS score. Correlation between paired UMSS and BIS scores was determined by applying the Spearman rank correlation test. The number of noncorrelating data pairs (BIS 90 and UMSS 2; BIS 85 and UMSS 3) observed with each type of sedation were compared using one-way analysis of variance with Tukey- Kramer post hoc multiple means comparisons. Using 2 analysis, the number of noncorrelating data pairs was compared among groups within the categories of age (0 6 mo versus 6 mo) and location in the hospital. EMG activity scores of patients with and without noncorrelating data pairs were compared using an unpaired t-test. P 0.05 was considered to be statistically significant. Results Significant correlation was found between BIS scores and UMSS scores (r 0.644, P 0.001) (Fig. 1). Correlation was significant in subjects 6moofage(n 6) (r 0.761, P 0.001) (Fig. 2). Sixty-nine of the 516 paired data points were deemed noncorrelating pairs (when BIS 90 and UMSS 2, and when BIS 85 and UMSS 3) (see the right upper quadrant of Fig. 1). The incidence of noncorrelating pairs was significantly more frequent in subjects who had received IV ketamine (n 5 subjects) or the oral combination of chloral hydrate, hydroxyzine, and meperidine (n 12 subjects) (P 0.003) (Fig. 3). When data from subjects receiving these two sedation regimens were removed from analysis, the correlation between BIS scores and UMSS scores improved (r 0.704, P ) (Fig. 4). The incidence of noncorrelating pairs was not significantly different among subjects grouped by age (P 0.213) or location in the hospital (P 0.158). Mean EMG activity was similar in subjects with ( se db) and without ( se db) noncorrelating data pairs (P 0.95). Correlation was significant whether one or two independent observers were used. When two observers were used (one to record the BIS score and the other to derive the UMSS score), r (P ). When one observer was used, r (P ). Discussion The results of this study demonstrate that the BIS may be a valid monitor of depth of conscious and deep sedation in the spontaneously breathing child. BIS scores correlated significantly with their paired UMSS scores. In this series, the BIS was also valid in a small group of infants aged less than six months. We believe that these results are important because the BIS has several potential advantages over observational scoring systems. It is objective and easy to use. Unlike observational scales, assessment does not need to be interrupted during procedures to avoid patient movement because the BIS requires no verbal interaction or physical stimulus to the patient that may disrupt the procedure. Inter-observer variability is not an issue. If our results are confirmed by other studies, the BIS could become a useful monitor during sedation of children, not only to measure depth of sedation, but also to guide dosing of sedation drugs.

3 ANESTH ANALG PEDIATRIC ANESTHESIA McDERMOTT ET AL ;97:39 43 BIS MONITORING IN SEDATED CHILDREN Table 1. Conscious and Deep Sedation Drug Regimens Used in Four Hospital Locations n Age Regimen Location (subjects) (mo) Intravenous pentobarbital 3 5 mg/kg Computerized tomography scanner (8 42) Intravenous midazolam mg/kg with either fentanyl 1 3 g/kg or meperidine mg/kg Oral combination of chloral hydrate mg/kg, meperidine 2 mg/kg, and hydroxyzine 2 mg/kg Cardiac catheterization laboratory (1 144) Gastroenterology endoscopy suite Dental procedures clinic (24 94) Intravenous or intramuscular ketamine 2 6 mg/kg Cardiac catheterization laboratory 5 30 (3 71) Age is expressed as median (range). Figure 1. Correlation between bispectral index (BIS) and University of Michigan Sedation Scale (UMSS) scores in all 86 subjects (516 data pairs) (r 0.644, P 0.001). Choosing a scoring system for comparison to the BIS was not straightforward, because a gold standard does not seem to exist in pediatric practice. Scoring systems for depth of sedation in children are few, and each has disadvantages. The Ramsay score (7) and the Observer s Assessment of Alertness/ Sedation Scale (8) have been applied in pediatric studies, but were designed for adults. The COMFORT score (9) has application in children who are sedated, intubated, and mechanically ventilated. The UMSS is a validated observational scale that has been shown to be reproducible among observers (5). Although the UMSS was validated in children of a narrower age range during less-invasive procedures than those of our study, both the subjects and setting were more similar to ours than were those of other scoring systems. The chief disadvantage of the UMSS (shared with other observational scores) is that determination of a UMSS score of 3 or 4 requires observation of a response to significant physical stimulation (5). In many cases, the stimulation was provided by the procedure itself, but the application of additional noxious Figure 2. Correlation between bispectral index (BIS) and University of Michigan Sedation Scale (UMSS) scores in 6 subjects aged 6 mo (36 data pairs) (r 0.761, P 0.001). stimulation could have disrupted the clinical procedures for which the sedation was given. Thus, the observers were reluctant to apply vigorous physical stimuli to sedated children and did not assign a UMSS score of 4 to any patient. It is plausible that some subjects with low BIS scores who were assigned UMSS 3 should have been UMSS 4, indicative of general anesthesia. When evaluating our data, some of the paired values were noted to be noncorrelating, i.e., UMSS scores of 2 or 3 indicated adequate sedation, but high BIS scores indicated wakefulness or inadequate sedation. We considered possible explanations for this discrepancy, including sedation drug regimen, age, and EMG activity. Regarding sedation drug regimen, adults receiving ketamine had high BIS scores during adequate anesthesia (10,11). Narcotics can provide sedation without hypnosis. High BIS scores were measured during sedation procedures that were observed to be satisfactory when an oral sedative combination similar to that of this study was used for pediatric dental procedures

4 42 PEDIATRIC ANESTHESIA McDERMOTT ET AL. ANESTH ANALG BIS MONITORING IN SEDATED CHILDREN 2003;97:39 43 Figure 3. The incidence of noncorrelating data pairs (bispectral index [BIS] 90 and University of Michigan Sedation Scale [UMSS] 2; BIS 85 and UMSS 3) was significantly more frequent with sedation regimens 3 and 4 (P by analysis of variance with Tukey-Kramer multiple means comparisons). % percentage of data pairs that were noncorrelating; 1 IV pentobarbital; 2 IV midazolam plus fentanyl or meperidine; 3 oral chloral hydrate, hydroxyzine, and meperidine; 4 IV or IM ketamine. (12). However, BIS and observed sedation scores did correlate when oral midazolam was administered to children aged years (13). Analysis of our data demonstrated that patients receiving IM or IV ketamine or the oral combination of chloral hydrate, meperidine, and hydroxyzine were significantly more likely to have noncorrelating data pairs than were patients receiving other sedation drug regimens (Fig. 3). Age is a potential issue because the BIS algorithm was developed using adult EEG data, and BIS scores in infants less than six months of age have been noted to be unreliable during general anesthesia (2). Although our study was not designed to vigorously test the effect of age on BIS, noncorrelating data pairs did not occur in any subject less than six months of age. Excessive EMG activity has been shown to inhibit the ability of BIS to measure depth of hypnosis and may cause the BIS to report falsely increased numbers (14). The presence of noncorrelating data pairs was not associated with EMG activity in our subjects. A weakness of our study is that, because of manpower limitations, a second independent observer was not always available to record the BIS scores. When only one observer was used, the observer derived a UMSS score and then immediately uncovered the BIS monitor and recorded the BIS score. This could have resulted in bias of the observer when determining the UMSS score at the next 10-minute interval. If this bias had been present, we would expect better correlation of BIS and UMSS scores in subjects with only one Figure 4. Correlation between bispectral index (BIS) and University of Michigan Sedation Scale (UMSS) scores of 69 subjects (414 data pairs) after exclusion of subjects who received ketamine or oral combination of chloral hydrate, hydroxyzine, and meperidine (r 0.704, P ). observer. Because this did not occur, bias does not seem to have influenced our conclusion. This study addresses the need for validation of the BIS monitor in children and represents the initial step in developing a protocol for use of the BIS during sedation of children. We conclude that the BIS monitor may be a valid tool for measuring depth of sedation in pediatric patients, depending on the sedation regimen used. Further investigations of the clinical applicability of the BIS should be pursued. References 1. Denman WT, Swanson EL, Rosow D, et al. Pediatric evaluation of the bispectral index (BIS) monitor and correlation of BIS with end-tidal sevoflurane concentration in infants and children. Anesth Analg 2000;90: Bannister CF, Brosius KK, Sigl JC, et al. The effect of bispectral index monitoring on anesthetic use and recovery in children anesthetized with sevoflurane in nitrous oxide. Anesth Analg 2001;92: Kissin I. Depth of anesthesia and bispectral index monitoring. Anesth Analg 2000;90: Watcha MF. Investigations of the bispectral index monitor in pediatric anesthesia: first things first. Anesth Analg 2001;92: Malviya S, Voepel-Lewis T, Tait AR, et al. Depth of sedation in children undergoing computed tomography: validity and reliability of the University of Michigan Sedation Scale (UMSS). Br J Anaesth 2002;88: American Academy of Pediatrics. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89: Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974;2: Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the observer s assessment of alertness/sedation scale: study with intravenous midazolam. J Clin Psychopharmacol 1990;10:

5 ANESTH ANALG PEDIATRIC ANESTHESIA McDERMOTT ET AL ;97:39 43 BIS MONITORING IN SEDATED CHILDREN 9. Ambuel B, Hamlett KW, Marx CM, Blumer JL. Assessing distress in pediatric intensive care environments: the COMFORT scale. J Pediatr Psychol 1992;17: Sakai T, Singh H, Mi WD, et al. The effect of ketamine on clinical endpoints of hypnosis and EEG variables during propofol infusion. Acta Anaesthesiol Scand 1999;43: Suzuki M, Edmonds HL Jr, Tsueda K, et al. Effect of ketamine on bispectral index and levels of sedation [letter]. J Clin Monit Comput 1998;14: Religa ZC, Wilson S, Ganzberg SI, Casamassimo PS. Association between bispectral analysis and level of conscious sedation of pediatric dental patients. Pediatr Dent 2002;24: Brosius KK, Bannister CF. Oral midazolam premedication in preadolescents and adolescents. Anesth Analg 2002;94: Greif R, Greenwald S, Schweitzer E, et al. Muscle relaxation does not alter hypnotic level during propofol anesthesia. Anesth Analg 2002;94: Attention Authors! Submit Your Papers Online You can now have your paper processed and reviewed faster by sending it to us through our new, web-based Rapid Review System. Submitting your manuscript online will mean that the time and expense of sending papers through the mail can be eliminated. Moreover, because our reviewers will also be working online, the entire review process will be significantly faster. You can submit manuscripts electronically via There are links to this site from the Anesthesia & Analgesia website ( and the IARS website ( To find out more about Rapid Review, go to and click on About Rapid Review.