Investigations of the Bispectral Index Monitor in Pediatric Anesthesia: First Things First

The ideal “depth of anesthesia” monitor would be simple to use, not require calibration, and function with high specificity and sensitivity in predicting patient response without being influenced by the subject’s age, gender, concurrent illness, or use of a specific anesthetic or combination of drugs. Such a device remains the “holy grail” of monitoring for anesthesiologists (1). In October 1996 the Food and Drug Administration approved the use of an electroencephalogram (EEG)-based monitor of anesthetic effect that integrates various EEG descriptors into a single dimensionless, empirically calibrated number, the Bispectral Index (BIS) (1–4). The developers of the BIS monitor first established a large database of EEG activity in healthy adult volunteers at various clinically important end points and hypnotic drug concentrations. Bispectral and power spectral variables from these EEG data were fitted in a multivariate statistical model to produce a BIS number on a scale where 0 = EEG silence and 100 = EEG of a fully awake adult (5). The BIS values correlated well with a validated sedation scale (the Observer’s Assessment of Awareness/Sedation [OAA/S]) and with responsiveness to verbal commands in subsequent clinical trials with propofol, sevoflurane, midazolam, and isoflurane (6–10). However, intraoperative changes in BIS were not always reflections of the depth of anesthesia with ketamine, nitrous oxide, or xenon, and could be affected by electromyelogram activity from the scalp and pacer-generated electrical activity (11–16). In addition, the BIS monitor was not effective in predicting movement response to noxious stimuli, which was primarily mediated at the spinal cord level, whereas the EEG-based BIS values reflected cortical activity and the hypnotic component of anesthesia (3,5,17–21). Studies of the relationship between BIS and memory formation during anesthesia have raised hopes that titrating drugs to achieve a specific BIS value may reduce the incidence of intraoperative awareness (5,7). This speculation has raised a considerable degree of recent interest in the lay press (22) and the manufacturers of this device are still gathering scientific evidence in support of this claim. Until this is available, the best application of information provided by the BIS monitor in adults will continue to be debated. However, there is good evidence that titrating anesthetics to a BIS value is associated with the administration of smaller doses of anesthetics and earlier awakening in the healthy adult patient population (4,8,23,24). It is not surprising that investigators would turn their attention to the use of the BIS monitor in other patient populations, including children (25–27). In this issue of Anesthesia & Analgesia, Bannister et al. (28) have described a study in which they titrated anesthetic gas concentrations to achieve a targeted BIS value in children during sevoflurane–nitrous oxide anesthesia, and compared the resulting anesthetic use and recovery characteristics with those seen with standard care. They studied two pediatric patient populations, younger children (aged <3 yr) undergoing hernia repair and older children (3–18 yr) undergoing tonsillectomy and adenoidectomy. Bannister et al. (28) noted that sevoflurane concentrations and recovery times were smaller in the older children undergoing tonsillectomy/adenoidectomy in the BIS-monitored group. However, emergence and recovery characteristics were not affected by titrating anesthetics to a given BIS value in the younger children. What conclusions can we draw from this finding of a difference in younger and older patients? Is this yet another example that pediatric patients are different from adults, or are there confounding factors in the study design that could explain the age-related differences? The BIS value is based on adult EEG data and may not apply to the pediatric patient population, particularly to children less than 6 mo of age and perhaps up to 5 yr. Brain maturation and synapse formation continues after birth for up to 5 yr of age, with most of it occurring in the earlier part of life (29). EEG changes with maturation have been noted from birth through puberty, but data on EEG changes produced by anesthetic drugs in this patient population are not available (30). It is therefore essential that studies confirming the validity of BIS in different age groups of children be performed before the use of this device is extended to the pediatric patient population. Denman et al. (25) have listed the problems of validating the BIS monitor in infants and children. These include the absence of a “gold standard” for sedation or sleep, difficulties in distinguishing purposeful actions from nonspecific startle responses, and ethical problems in recruiting children as volunteers. However, BIS values increase when discontinuing anesthetic administration in children and can predict voluntary patient movement in response to commands during the intraoperative wake-up test for scoliosis surgery in older children (27). Denman et al. (25) has shown that BIS values in children undergoing surgery were inversely proportional to the end-tidal concentration of sevoflurane. There was a concentration-response difference between infants and older children consistent with data that the minimum alveolar concentration for preventing movement with skin incision was larger in infants (25). Davidson et al. (31) performed a similar study in 23 infants and 21 older children undergoing circumcision during a sevoflurane-nitrous oxide anesthetic supplemented by a penile nerve block placed before surgery. They noted an increasing BIS value in older children when the end-tidal concentration of sevoflurane was decreased from 0.9% to 0.7% and 0.5% after the completion of surgery. No such relationship could be established in infants. However, failure to show this may reflect the relatively small number of patients studied (31). The concomitant use of regional anesthesia by Bannister et al. (28) introduced a potentially confounding factor in the age-related comparison of BIS values. The younger subjects in this study underwent inguinal hernia repair and received a caudal epidural block in addition to a sevoflurane anesthetic, where-as the older patients underwent tonsillectomy/adenoidectomy procedures where regional blockade was not possible. There are conflicting data on the effect of epidural and spinal block on sedation scores and BIS values in adults who have received no other medications. Pollock et al. (32) noted that unmedicated volunteers undergoing spinal anesthesia had significant changes in sedation scores when the full OAA/S rating scale was used. However, changes in BIS values were noted only in the unblinded part of this study. In contrast, Morley et al. (33) noted increases in BIS values after spinal anesthesia but not after epidural anesthesia, whereas no changes were noted in the responsiveness component of the OAA/S scores. Other studies have shown decreased requirements for intraoperative sedation in adults after regional blockade (34,35). Interestingly, Bannister et al. (28) found it difficult to adjust sevoflurane concentrations to achieve the target BIS value in children less than 6 mo of age who had effective caudal epidural anesthesia. In this subset of patients, the BIS values remained low despite early discontinuation of sevoflurane, whereas it was possible to achieve a desired BIS value with sevoflurane in the older patients who did not have epidural anesthesia. It is unclear if there are dose-related changes in BIS values in infants with other sedatives and inhaled anesthetics in the absence of regional blockade. It is also possible that BIS responses to changes in the dose of sedative drugs in infants and younger children differ from those in older children and adults. The difficulty in interpreting the results of BIS studies in children reinforces the need for establishing the validity of the BIS monitor in assessing sedation in the pediatric patient population. It should be relatively easy to perform a study in sedated children of various age groups, where BIS values are compared with a validated sedation scale such as the responsiveness component of the OAA/S or the University of Michigan sedation scale (36). Other scales, such as the Ramsay scale, COMFORT, Sedation-Agitation-Scale, and the Motor Activity Assessment Scale, have been validated in pediatric and adult intensive care patient populations undergoing positive pressure ventilation but may not be readily applicable to the sedated child who is breathing spontaneously via a natural airway (5,37–39). This author suggests that the validation of the BIS monitor in the pediatric patient population should be a priority before other studies are performed to determine the clinical usefulness of this device in children. Questions raised by the study of Bannister et al. (28) regarding the effect of regional blockade on BIS values in anesthetized children should be addressed only after the validity of the BIS monitor in assessing hypnosis and sedation in various pediatric age groups has been established. In clinical investigations, as in other matters, first things should come first.