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Anesth Analg 2004;98:1644-1649 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000117223.84646.36
William J. Greeley Section Editor |
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Abstract |
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Bispectral index (BIS) was developed to monitor anesthetic depth in adults, but has been investigated for use in children, using sevoflurane. We examined the concentration-response relationship between BIS and isoflurane. Thirty children undergoing cardiac catheterization received continuous intraoperative BIS monitoring and had BIS values recorded at 6 steady-state end-tidal isoflurane (EtIso) concentrations between 1.5% and 0.5% and at first arousal. The mean (SD) values for BIS were as follows: 1.5%, 32.3 ± 11.7; 1.3%, 34.7 ± 12.5; 1.1%, 40.5 ± 13.3; 0.9%, 48.0 ± 13.7; 0.7%, 55.9 ± 14.4; and 0.5%, 61.8 ± 13.1. There was an inverse correlation between EtIso and BIS (r = –0.634; P < 0.01). There were significant differences (P < 0.0001) in mean BIS values between adjacent EtIso in all cases except 1.5% versus 1.3%. An inhibitory sigmoid Emax model best described the BIS-isoflurane concentration relationship, with an 50% effective dose of 0.85% (95% confidence interval, 0.72%–0.98%). The mean value of BIS at first arousal was 78.5 ± 12.3. The relationship between EtIso and BIS is qualitatively and quantitatively similar to that described for isoflurane in adults and sevoflurane in children. These results add to the body of evidence that BIS is adequately calibrated for use in children older than 1 yr.
IMPLICATIONS: This observational study of children undergoing cardiac catheterization characterizes the concentration-response relationship between bispectral index and isoflurane and demonstrates that bispectral index seems adequately calibrated for monitoring the depth of isoflurane anesthesia in pediatric patients.
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Introduction |
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Depth of anesthesia is a dynamic balance between the effect-site concentration of hypnotic and analgesic drugs and the intensity of surgical stimulation. Awareness during surgery is a feared complication of anesthesia but excessive depth of anesthesia is equally undesirable, given the narrow therapeutic index of anesthetic drugs and the reduced physiological reserve of some patients.
Bispectral analysis of the adult electroencephalogram (EEG) has been used to develop an algorithm, which generates the bispectral index (BIS). BIS is a statistical construct whose values are associated with quantified probabilities of reduced awareness and memory formation in adults undergoing anesthesia (1–6).
There is no evidence that awareness is less of a problem during pediatric anesthesia (7), although preverbal patients cannot complain of it afterwards, whereas slightly older patients may mistake conversations heard during emergence or recovery for intraoperative events or vice versa. For these reasons, a reliable monitor of anesthetic depth may be valuable to pediatric anesthesiologists. However, because young children have different EEG patterns than older children and adults, and because there is little information on the effects of various anesthetics on the pediatric EEG, it cannot be assumed that BIS will be accurately calibrated for use in children.
A number of studies have suggested that BIS may be adequately calibrated for children older than 12–24 mo (8–11). All these studies have used sevoflurane. The aim of this study was to investigate the concentration-response relationship between BIS and end-tidal isoflurane concentrations (EtIso).
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Methods |
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After obtaining local research and ethics committee approval, 33 patients scheduled to undergo elective cardiac catheterization were recruited. All parents gave informed consent before participation, and, where appropriate, children gave their assent. We excluded children aged younger than 12 mo or older than 17 yr, those who had preexisting neurological abnormality, seizure disorder, developmental delay, were receiving treatment with antiepileptic or stimulant medication, or who had a hearing deficit. Patients were premedicated with midazolam 0.5 mg/kg, given orally 30 min before the induction. Anesthesia was induced using either IV thiopental 5 mg/kg or inhaled sevoflurane 8% in oxygen. All patients received rocuronium 0.6 mg/kg IV and had the trachea intubated. Standard monitoring was used in all cases. Anesthesia was maintained with isoflurane and 70% nitrous oxide in oxygen. Positive-pressure ventilation was titrated to achieve an end-tidal carbon dioxide concentration of 4.0–4.5 kPa (30–34 mm Hg). Once arterial access had been obtained for cardiac catheterization, invasive arterial monitoring and periodic arterial blood gas sampling were used as additional monitoring.
As soon as consciousness was lost, a pediatric BIS sensor (Aspect Medical Systems, Newton, MA) was placed on the patient’s forehead and connected to a BIS A-2000 monitor (Aspect Medical Systems). Sensor 1 was placed in the midline above the nasion and Sensor 3 midway between the outer canthus of the eye and the tragus of the ear. Impedance was <5 k
. BIS was recorded continuously, with a smoothing window of 15 s and an update rate of 2 s. Data were downloaded every 5 s to a laptop computer for subsequent analysis.
After tracheal intubation, isoflurane was titrated to generate an EtIso of 1.5%. Total flow through a pediatric circle system (Tyco Healthcare, Gosport, Hampshire, United Kingdom) was 6l min–1 throughout the study period. In all patients, at least 20 min elapsed before the first set of BIS values were recorded for EtIso = 1.5%. By this time, no residual sevoflurane was detectable. Thereafter, isoflurane delivery was decreased stepwise to an EtIso of 1.3%, 1.1%, 0.9%, 0.7%, and 0.5%. Once each new EtIso was reached, we allowed 10 min of equilibration time before recording values for BIS at that concentration. All EtIso were measured using a Hewlett-Packard 88S/M1026A gas analyzer (Agilent Technologies UK Ltd., Stockport, Cheshire, United Kingdom) to within an accuracy of 0.1%.
At the end of the procedure, isoflurane and nitrous oxide were discontinued. Neostigmine 50 µg/kg and atropine 20 µg/kg were given IV to reverse residual neuromuscular blockade. A standardized verbal stimulus (speaking the patient’s name) was given at 1-min intervals. Actual BIS values were noted at 1-min intervals, offset from the verbal stimulus by 30 s. BIS was also recorded at the first sign of recovery of consciousness, defined as coughing, eye opening, or purposeful movement. Recovery of consciousness within 30 s of stimulus was defined arbitrarily as "provoked" arousal; after 30 s but before the next verbal stimulus was "spontaneous" arousal.
The Aspect monitor downloads a BIS reading every 5 s. To obtain a representative BIS value at each steady-state EtIso, we averaged the 12 BIS readings generated over 1 min. For each patient, we obtained 6 averaged BIS values; one for each of the 6 steady-state EtIso concentrations. Individual plots of BIS against EtIso were generated for each patient. Distribution of BIS values at each steady-state EtIso was tested for normality with the Kolmogorov-Smirnov (K-S) test. Repeated-measures analysis of variance (ANOVA) with the Greenhouse-Geisser F statistic and Bonferroni-corrected t-tests were used to analyze differences in BIS between adjacent ETIso. Statistical analysis was performed using SPSS version 11.0 (Chicago, IL). The concentration-response relationship between BIS and isoflurane was explored using Kinetica version 4.1 pharmacokinetic-pharmacodynamic modeling software (Franklin, OH). Prearousal and arousal data were compared with paired Student’s t-test.
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Results |
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BIS data at all 6 EtIso were obtained in 30 of 33 children. In the other 3, the procedure was completed much sooner than expected and before data collection was complete. Results are presented for the 30 children on whom full data sets were recorded. Table 1 indicates patient ages, weights, and surgical procedures.
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The mean values for BIS and the results of K-S tests of normality are shown in Table 2. There was a monotonic inverse correlation between EtIso and BIS (Pearson’s r = –0.634; P < 0.01), i.e., BIS increased as EtIso decreased. The nonsignificant K-S tests indicate that distribution of BIS values at each EtIso was approximately normal.
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The difference in mean BIS values at different EtIso values was highly significant: F (5, 145) = 124.2; P < 0.001 (repeated-measures ANOVA with Greenhouse-Geisser test). A posteriori Bonferroni-corrected t-test comparisons between adjacent EtIso revealed significant differences in all cases except between 1.5% and 1.3% (Table 2).
The individual concentration-response relationships for each patient are illustrated in Figure 1. We further characterized the concentration-response relationship between BIS and isoflurane by testing three possible pharmacodynamic models for comparison of goodness-of-fit to the data.
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1. A simple linear model:
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2. An inhibitory sigmoid Emax model:
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3. A simple inhibitory sigmoid Emax model, in which n = 1:
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where E = effect (BIS), E0 = baseline effect (set at 100), Emax = maximum effect (set at zero), C = end-tidal concentration, EC50 = EtIso at 50% of maximum effect, n = sigmoidicity factor (slope function), and S = slope of the relationship between concentration and effect when a linear relationship is assumed.
In all goodness-of-fit tests applied, the inhibitory sigmoid Emax model best described the concentration-response relationship. Figure 2 shows the population concentration-response curve. The model estimate of the EC50 for isoflurane was 0.85% (95% confidence interval [CI], 0.72%–0.98%).
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Arousal data were available for 24 of 30 patients. One patient was transferred to the cardiac surgery theater still anesthetized. Two patients woke up in response to extraneous stimuli (removal of transesophageal echocardiography probe) at BIS values of 75.6 and 72.6. In three patients, data were not recorded. Mean BIS (± SD) at first arousal in all 24 patients was 78.5 ± 12.3 compared with 75.1 ± 16 in the preceding minute (95% CI, –0.4–7.3 for the difference between means; P = 0.08). Fourteen patients were roused within 30 s of hearing their name spoken, defined arbitrarily as "provoked" arousal. The mean prearousal BIS in this subgroup was 74.6 ± 18.3; on arousal, mean BIS was 78.3 ± 12.2 (95% CI, –2.9–10.1 for the difference between means; P = 0.25). Ten patients roused spontaneously. The subgroup mean prearousal BIS was 75.7 ± 13.1, increasing to 78.8 ± 13.2 on arousal (95% CI, –0.8–7.0 for the difference between means; P = 0.11).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study examined the applicability, or otherwise, of BIS monitoring to anesthetized children, given that the algorithm is derived from adult EEG data. Our data can be compared with adult data on BIS using isoflurane and with pediatric data on BIS using sevoflurane.
We have demonstrated that BIS increases as EtIso decreases. The relationship is monotonic but nonlinear and is best characterized by an inhibitory sigmoid Emax model. This model is often found best to describe dose-response relationships. The mean values of BIS at successive isoflurane concentrations are significantly different from each other, although interindividual variability is large. The gradual inverse relationship between BIS and isoflurane concentration in children supports the concept that BIS reflects changes in effect-site concentration of hypnotic drugs, which occur with a wash-in, washout exponential profile.
Our investigation of the concentration-response relationship between BIS and isoflurane has yielded results that are very similar to those obtained in adults receiving isoflurane/nitrous oxide anesthesia. Olofsen and Dahan (12) reported that an inhibitory sigmoid Emax model best described the dynamic relationship between EtIso and BIS. Their model estimates of BIS at the same EtIso values, from 0.5% to 1.5%, are 75, 52, 44, 37, 34, and 30. These are well within the CI of our data, with the exception of the BIS value for EtIso = 0.5%. This finding suggests that the BIS algorithm processes raw pediatric EEG data in a similar way to adult data to generate similar values at similar isoflurane concentrations, which supports the hypothesis that BIS is adequately calibrated for use in children older than one year old. The direction of discordance at EtIso = 0.5% between studies is counterintuitive, given that, if anything, depth of anesthesia at this value should be greater in adults than in children and the BIS correspondingly lower. It may be attributable to statistical or physiological phenomena. With regard to the latter, as Olofson and Dahan (12) themselves discuss, differences between populations in the time course of the effects of isoflurane on neuronal processes and on the cortical-subcortical interactions that contribute to the BIS may partly account for the difference. In addition, our patients had a variety of anatomical cardiac anomalies, with potential for an altered time course of equilibration between alveoli and brain, such that the effect-site concentration of isoflurane may have been larger in our patients than in Olofson and Dahan’s (12) at the same end-tidal concentration; such an effect would become greater with each step change in inspired isoflurane concentration. In our study, the last readings were taken after 5 step changes of anesthesia, compared to 2 step changes in Olofson and Dahan’s (12) study.
Previous investigators have assessed BIS in children receiving sevoflurane-based inhaled anesthesia. Although sevoflurane is now the anesthetic of choice for inhaled induction, isoflurane is still widely used to maintain anesthesia. BIS is used as a pharmacodynamic end-point, i.e., as a measure of hypnosis, and should be independent of the hypnotic used to produce that state, as has been demonstrated in adults (4). Minimum alveolar anesthetic concentration (MAC)-equivalent values of different volatile anesthetics should therefore generate similar BIS values, with other variables being equal.
Our findings are qualitatively and quantitatively similar to those from sevoflurane studies. Denman et al. (8) reported BIS values in 55 children undergoing routine general anesthesia with a variety of IV and inhaled anesthetics to be similar to those recorded in historical adult controls. They also characterized the sevoflurane-BIS relationship in 11 infants and 11 children and described a monotonic inverse relationship in both groups. Using an inhibitory sigmoid Emax model, they calculated an EC50 of 1.25% sevoflurane for children older than two years of age. McCann et al. (11) also described the inverse correlation between BIS and end-tidal sevoflurane concentration in preschoolers and derived an EC50 of 1.48% using non–steady-state data. These studies used 60%–70% nitrous oxide, which has a MAC-sparing effect of 24%–40% on sevoflurane (13,14). We used 70% nitrous oxide, which has a 40% MAC-sparing effect on isoflurane (15). Thus, the EC50 of 0.85% that we report is approximately equipotent with that reported for sevoflurane. Davidson et al. (10) measured BIS in 24 children older than 12 months at end-tidal sevoflurane concentrations of 0.9%, 0.7%, and 0.5% in oxygen and found a monotonic inverse relationship. Moreover, at 0.9%, the mean BIS was 60.9, similar to our approximately equipotent 0.5% isoflurane value of 62. The value predicted by Denman et al.’s (8) concentration-response graph is also approximately 62. Thus, it would seem that the BIS concentration-response relationships for isoflurane and sevoflurane are similar in children.
The emergence values for BIS in our study (78.5 ± 12.3) are also comparable to those found in earlier pediatric studies: Denman et al. (8) reported a mean (SD) BIS of 83.5 ± 11.6 at emergence (and 80 in adults). Degoute et al. (16) reported a mean BIS of 86.7 on recovery of consciousness from sevoflurane-alfentanil anesthesia in children aged 3.5–13 undergoing tympanoplasty. McCann et al. (11) reported a BIS of 88 ± 11 at "first purposeful movement" in their study of preschoolers undergoing tonsillectomy. Our mean value of 78.5 may be slightly lower because, consistently in our patients, the first sign of lightening anesthesia was coughing or gagging on the endotracheal tube. This airway reflex occurs at a greater depth of anesthesia (MAC-ET) than true awakening (MAC-awake). Despite prospectively including eye-opening and purposeful movement in our definition, we were unable to determine BIS values at these end-points for two reasons. First, coughing or gagging is undesirable in cardiac catheter patients because it increases the risk of hemorrhage from the relatively large femoral vessel puncture wounds, so tracheal extubation becomes a clinical priority. Second, once the patient is coughing, motor activity in facial muscles precludes further interpretation of BIS values. For both these reasons, we terminated our study at the first sign of intolerance of the endotracheal tube. It is interesting to note that the BIS values of 72.6 and 75.6 in 2 patients who responded to inadvertent airway stimulation by removal of a transesophageal echocardiography probe were close to the mean BIS value for awareness of the endotracheal tube; given our results, such a response would be predictable in future.
It might be argued that 10 minutes of equilibration time between step changes in isoflurane concentrations may not have been long enough to allow complete alveolar-brain equilibration. We did use high flows in a small circle circuit to maximize the equilibration of alveolar isoflurane tension with new inspired gas concentration. As a result, the inspired-alveolar gradient for isoflurane was consistently <0.2. However, our patients had a heterogeneous selection of complex congenital heart conditions, with attendant variable pulmonary blood flow, making it difficult to guarantee the time course of alveolar-brain equilibration. In all patients, EtIso remained stable at the desired level for a full 10 minutes before readings were taken.
Patients undergoing cardiac catheterization were chosen for this study because of the need for a constant surgical stimulus. Previous studies of BIS in children have been subject to criticism because of the potential effects of surgical stimulation on anesthetic depth. The only true constant stimulus is no stimulus at all; this group of patients represented the closest we could get to that without resorting to regional anesthetic supplementation, which itself might confound the results of a concentration-response study. During cardiac catheterization, the only significant stimulus comes from insertion of femoral arterial or venous sheaths, which occurs at the start of the procedure. We deliberately recorded BIS at the highest isoflurane concentration first to cover this potential stimulus.
The same primary anesthesiologist cared for all our patients, thus ensuring a standardized technique. All patients received midazolam premedication. A randomized, controlled trial to examine the effect of oral midazolam premedication found no difference in intraoperative BIS values between the premedicated and unpremedicated groups (17); moreover, BIS values during sevoflurane-nitrous oxide maintenance were very similar to a previous study using the same anesthetic concentrations in unpremedicated children. We deliberately excluded infants from our study population. Previous studies indicate that BIS is difficult to interpret in this age group, in which EEG differences are maximal compared with adults. We therefore felt that they should be studied separately.
In summary, we have demonstrated a monotonic inverse relationship between EtIso and BIS in a pediatric population. The relationship between BIS and isoflurane is qualitatively and quantitatively similar to that seen in adults receiving isoflurane and in children receiving sevoflurane. These findings add to the small body of research that suggest that BIS monitoring may be adequately calibrated for use in children older than one year and may be useful as a monitor of anesthetic depth in this population.
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Acknowledgments |
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We thank Dr. Dyfrig Hughes and Ms. C. MacLeod for conducting population pharmacodynamic modeling and Dr. Roger Thornington for his cooperation with the clinical phase of the study.
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References |
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- Leslie K, Sessler DI, Schroeder M, et al. Propofol blood concentration and the Bispectral Index predict suppression of learning during propofol/epidural anesthesia in volunteers. Anesth Analg 1995; 81: 1269–74.[Abstract]
- Liu J, Singh H, White PF. Electroencephalographic bispectral index correlates with intraoperative recall and depth of propofol-induced sedation. Anesth Analg 1997; 84: 185–9.[Abstract]
- Liu J, Singh H, White PF. Electroencephalogram bispectral analysis predicts the depth of midazolam-induced sedation. Anesthesiology 1996; 84: 64–9.[Web of Science][Medline]
- Glass PS, Bloom M, Kearse L, et al. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997; 86: 836–47.[Web of Science][Medline]
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[Abstract/Free Full Text] - Kearse LA Jr, Rosow C, Zaslavsky A, et al. Bispectral analysis of the electroencephalogram predicts conscious processing of information during propofol sedation and hypnosis. Anesthesiology 1998; 88: 25–34.[Web of Science][Medline]
- Davidson AJ. Awareness and paediatric anaesthesia. Paediatr Anaesth 2003; 12: 567–8.
- 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: 872–7.
[Abstract/Free Full Text] - 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: 877–81.
[Abstract/Free Full Text] - Davidson AJ, McCann ME, Devavaram P, et al. The differences in the bispectral index between infants and children during emergence from anesthesia after circumcision surgery. Anesth Analg 2001; 93: 326–30.
[Abstract/Free Full Text] - McCann ME, Bacsik J, Davidson A, et al. The correlation of bispectral index with endtidal sevoflurane concentration and haemodynamic parameters in preschoolers. Paediatr Anaesth 2002; 12: 519–25.[Web of Science][Medline]
- Olofsen E, Dahan A. The dynamic relationship between end-tidal sevoflurane and isoflurane concentrations and bispectral index and spectral edge frequency of the electroencephalogram. Anesthesiology 1999; 90: 1345–53.[Web of Science][Medline]
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[Abstract/Free Full Text] - Brosius KK, Bannister CF. Effect of oral midazolam premedication on the awakening concentration of sevoflurane, recovery times and bispectral index in children. Paediatr Anaesth 2001; 11: 585–90.[Web of Science][Medline]
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