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PEDIATRIC ANESTHESIOLOGY

Bispectral Index and Middle Latency Auditory Evoked Potentials in Children Younger Than Two-Years-Old

Adelaida Lamas, MD^*, Jesús López-Herce, MD^*, Luis Sancho, MD^*, Santiago Mencía, MD^*, Ángel Carrillo, MD^*, Maria José Santiago, MD^*, and Vicente Martínez, MD

From the *Pediatric Intensive Care Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain; and Centro de Estudios Sociosanitarios (CEES), Castilla-La Mancha University, Cuenca, Spain.

Address correspondence and reprint requests to Jesús López-Herce, MD, Sección de Cuidados Intensivos Pediátricosm, Hospital General Universitario Gregorio Marañón, Dr Castelo 47, 28009 Madrid. Spain. Address e-mail to pielvi{at}ya.com.

Abstract

BACKGROUND: We analyzed the values of the bispectral index (BIS) and midlatency auditory evoked potentials (MLAEP) and their correlation with the modified Ramsay score (RS) during wakefulness and natural sleep in healthy children without pharmacological sedation.

METHODS: Fifty-three healthy children younger than 2-yr-old were studied. Children were evaluated simultaneously using the modified RS, the BIS, and MLAEPs. Each patient was studied only once. The correlation and agreement were studied. The correlation among the three methods was determined using the Spearman Rank Correlation test and the agreement among the methods was assessed using by Cohen’s Kappa test.

RESULTS: There was a moderate-to-good correlation (r) among the three methods (P = 0.01): BIS and MLAEP (r = 0.574), BIS and RS (r = –0.504), and MLAEP and RS (r = –0.624). However, the level of agreement () was only poor to fair: BIS and MLAEP ( = 0.392), BIS and RS ( = 0.270), and MLAEP and RS ( = 0.409). All the correlations were lower in children between 1 and 6 mo-of-age. When the children were asleep (RS: 3–5), the BIS values were higher in children younger than 1 mo-of-age than in children older than 6 mo-of-age (P after Bonferroni correction = 0.028).

CONCLUSIONS: The BIS, MLAEP, and RS have a good correlation in children younger than 2 yr not receiving pharmacological sedation, though the level of agreement was poor.

Sedation is important in the care of children, both during general anesthesia for surgery or painful procedures as well as in the pediatric intensive care unit. The state of sedation depends on many physical and psychological factors. It can be modified by the presence of the parents, the consciousness level, the presence of pain, and the administration of sedative medications.1 Evaluation of the level of sedation in small children is complicated because they present marked physiological alterations with minor stimuli and they are unable to communicate verbally.Until recently, the control of the level of sedation could only be made by clinical sedation scores.2–4 However, sedation scores are subjective, though some include autonomic variables that vary with different stimuli and others require stimulation.4

The bispectral index (BIS) and the midlatency auditory evoked potentials (MLAEP) are objective, noninvasive methods that provide an indirect measurement of the depth of sedation through analysis of the electroencephalogram (EEG).5,6 Each monitor produces a single numeric value on a scale from 0 to 100, which reflects a patient’s state of hypnosis. These methods have been developed and validated in adult patients during anesthesia, but only a few studies have applied these technologies to critically ill patients.7–10 Some studies have analyzed the utility of the BIS11–17 and MLAEP18,19 in anesthetized and critically ill children; however, there are very few data on the use of BIS in healthy children20 and none on the use of MLAEP.

The objective of the present study was to analyze the BIS and MLAEP values during the periods of wakefulness and natural sleep in normal, small children not receiving pharmacological sedation.

METHODS

We conducted a prospective, observational study from June to November 2005. The study was approved by the IRB. Healthy children younger than 2-yr-of-age were included in the study after obtaining informed consent from their parents. The sample size was chosen for convenience. The subjects were classified into three age groups: younger than 1 mo, 1–6 mo, and older than 6 mo. A minimum of 15 individuals were included in each age group. None of the children had received pharmacological treatment with sedative-analgesic medication. Each child was studied only once.

Measurement of consciousness level was made throughout the day at different times, during periods of wakefulness and natural sleep, using the BIS, MLAEP, and Ramsay scale score (RS) simultaneously. Table 1 shows the modified RS. The BIS scores were recorded by connecting the A-2000 XP BIS monitor (Medical Aspect Systems, software 3.30, Newton, MA) with four electrodes (BIS Quatro) to children older than 1-yr-of-age and three electrodes (BIS Pediatric) to children younger than 1-yr-of-age. After cleaning the skin, the sensors were positioned on the forehead at the base of the nose, at the lateral end of the supraciliary arc and in the preauricular region. The data were analyzed only if the signal quality index, representing the percentage of segments of EEG measured in the previous 60 s, was over 60%. The BIS values recorded were the electromyography activity (EMG-BIS), which reflects the electrical power of muscle activity and high frequency artifacts, and the suppression ratio (SR-BIS), defined as the percentage of time over the previous 63-s period during which the EEG is considered to be in a suppressed state.

The MLAEP scores were recorded using the A-Line ARX Index monitor (AAI 1.5, ALARIS Medical Systems; software 1.5, Code 0033UM00, Danmeter A/S, Odense, Denmark) with three sensors (code ALE-001). The sensors (A-Line MLAEP electrodes; Danmeter A/S) were positioned on the mid-forehead (positive), left or right forehead (reference), and in front of the ear. These sensors were placed on the contralateral side to the BIS sensors. The MLAEP was elicited with bilateral click stimuli of 70 decibels and 2 ms duration with a special headphone. The MLAEP values recorded were the EMG-MLAEP and the SR-MLAEP. The MLAEP monitor generates a signal that is one-hundredth the power of the EEG signal detected by the BIS; this means that there is no interference between the two monitors and they can therefore be used simultaneously.

The BIS and MLAEP scores were registered by one investigator followed immediately by the determination of the RS by a second investigator who was blinded to the BIS and MLAEP scores.

The level of consciousness was classified into two categories according to the scores obtained from three methods and based on the values obtained in previous studies in adults7,21: Awake (RS of 1–2, BIS >80, and MLAEP >60) and sleep or light-moderate sedation (RS of 3–5, BIS 80, and MLAEP 60).

The presence of correlation was determined using the Spearman Rank correlation test (r) and was stratified by age and sex. Evaluation of the agreement among the three methods was performed using Cohen’s Kappa test (). Hypotheses about means were tested using the ANOVA, and subsequent t-tests for pairs of means were corrected using the Bonferroni and Dunnett’s C methods. Data are expressed as mean ± sd in the case of a normal distribution. P < 0.05 was considered significant in all tests, Spearman Rank values (r) more than 0.4 were considered moderate to excellent, and kappa values () more than 0.4 represented acceptable agreement. The ability of BIS and MLAEP to discriminate between the two sedation levels classified according to the RS score was tested using receiver operating characteristic (ROC) curve statistics. The cut-off points were determined at the point of greatest sensitivity and specificity for discrimination. Logistic regression models using the BIS and MLAEP cut-off points were developed to evaluate the prediction ability of sedation levels (deep versus light sedation) in accordance with the RS classification. Data analysis was performed using the SPSS statistical package for Windows (software version 13.0, SPSS Inc., Chicago, IL).

RESULTS

Fifty-three children were included in the study, 28 (52.8%) were boys and 25 (41.1%) girls. The mean age was 131.7 days (sd: 118.5), median 45, and range 1–720. Twenty-two (41.5%) were <1-mo-old, 15 (28.3%) between 1 and 6 mo and 16 (30.1%) were >6-mo-old. The global values of the RS, BIS, and MLAEP and the values classified by age group (<1 mo, 1–6 mo, and >6 mo) are shown in Table 2. RS values vary between 1 and 5. The mean BIS and MLAEP values were higher in children younger than 1-mo-of-age than in older children. RS values were similar in the three age groups. Statistically significant differences between children <1 mo old and children 1–6 mo old were only found in the BIS values (P = 0.047). There were no significant differences between the sexes. There were no differences in the SR or EMG among age groups in either the BIS or the MLAEP.

Thirty-five children had RS scores of 1 or 2 (normal level of consciousness or nonsedation) and 18 had RS values between 3 and 5 (light-moderate sedation or natural sleep). Twenty-eight children (52.8%) had BIS score >80 (normal level of consciousness) and 25 (47.2%) BIS scores between 60 and 80 (light-moderate sedation). Thirty children (56.6%) had MLAEP values >60 (normal level of consciousness) and 23 (43.4%) between 30 and 60 (light-moderate sedation).

No adverse effects were observed during the BIS and MLAEP monitoring in the study. A small group of young infants had some skin redness immediately after sensor removal, but this resolved in <24 h.

Correlation and Agreement Between the Methods of Evaluation the Level of Consciousness
The overall correlation among the BIS, MLAEP, and RS values varied between moderate and good, except in the children between 1 and 6 mo old (Table 3). There were no differences in the degree of correlation between the sexes.

A moderate correlation was found between the BIS and the MLAEP in children with RS scores of 1 or 2 (r = 0.507; P = 0.01), but no correlation was found in those with RS scores of 3–5 (r = 0.335).

After classification into the two categories of consciousness, a moderate agreement was found between the AEP and RS values ( = 0.409) but not between the BIS and MLAEP or between the BIS and RS scores ( = 0.392 and 0.270, respectively). The RS classified a larger percentage of children as in a normal state of consciousness or nonsedation than did either the BIS or the MLAEP (Table 4).

Comparison of the BIS and MLAEP Values According to the Level of Consciousness Evaluated by the RS
The BIS and MLAEP values of the children with RS scores of 1–2 (fully awake) were significantly higher than those of children with RS 3–5 (natural sleep). Statistical significance was not reached in all groups (Table 5). When we compared the BIS and MLAEP values among the different age groups according to the RS score, children <1 mo old had higher BIS and MLAEP scores than the other age groups. In sleeping children (RS: 3–5), the differences between the BIS values were only significant between children <1 mo and children > 6 mo old (P after Bonferroni correction P = 0.028). The MLAEP measurements showed no statistically significant differences among any of the groups (Table 5).

Predictive Capacity of BIS and MLAEP According to the RS
When the level of consciousness was classified in two levels by the RS (fully awake and asleep), the calculated cut-off point for the BIS between the two levels was 84.5 (sensitivity of 63%, specificity of 78%, and area under the curve 0.75) and for the MLAEP was 61.5 (sensitivity of 65%, specificity of 78%, and area under the curve 0.84) (Fig. 1).

View larger version (16K): [in this window] [in a new window]   Figure 1. Receiver operating characteristic analysis (ROC) curve for bispectral index (BIS) and midlatency auditory evoked potentials (MLAEP) classifying the children either fully awake or asleep according to the Ramsay scale score.

Two logistic regression models using the previously defined cut-off points for BIS and MLAEP as explanatory variables were correctly able to predict the level of sedation defined according to the RS in 67.9% and 69.8% of the children, respectively.

DISCUSSION

The clinical sedation scales used to evaluate the level of sedation and consciousness have limitations: they are subjective and, in general, are not sufficiently sensitive to detect changes between the different levels of consciousness.4,22 The modified RS is simple, quick, and shows a good correlation with other clinical sedation scores; hence, it is frequently used in adults and children.2,14,15,22 However, it has never been validated in children and it requires the use of auditory and painful stimuli, increasing the risk of subjectivity in its evaluation.4

The BIS monitor analyzes the level of cerebral electrical activity and determines the patient’s level of consciousness by analyzing free wave frequencies of the EEG.5,7 A number is assigned between 0 (isoelectric or complete suppression of EEG) and 100 (fully awake), making interpretation simple and available to any bedside caregiver. The BIS has been validated in adults during anesthetic procedures, and intraoperative studies have demonstrated that adequate anesthesia correlates well with values <60; BIS values of 40–60 are typical during the maintenance of general anesthesia.5,7,23,24 In children, there are only a few studies that have analyzed its utility during anesthesia,11,12,25 in critically ill children13,16,26,27 or during invasive and noninvasive procedures.15,28–30 Nevertheless, the reference values come from studies in adults and cannot be extrapolated directly to children; validation of the BIS in children of different ages is therefore necessary before it can be used in clinical studies.31

The monitor for the MLAEP uses a repeated auditory stimulus transmitted by headphones and provides values automatically using an online analysis. This value reflects the morphology of auditory potential curves and is calculated from differences in amplitude between successive segments of the curve. The signal is amplified and processed in a computer, providing values between 0 and 100. Studies in adults have demonstrated that MLAEP values correlate well with the depth of sedation.6,32 In adults, the fully awake state corresponds to MLAEP values >60, light sedation to values of 30–60, deep sedation to values of 30–15, and very deep sedation state to values <15. MLAEP have been used to measure the depth of anesthesia during surgery in adults33 and in critically ill patients9,10; however, only a few studies have used MLAEP in children during anesthetic procedures,17,34 only one in critically ill children,18 and none has evaluated the use of MLAEP in small children. Our study is the first to assess the normal values of BIS and MLAEP in small children not receiving pharmacological sedation, as well as their correlation and agreement with a clinical scale.

The BIS values in awake children in our study correspond with previously published values for a nonsedated or fully awake state.7 In our study, the MLAEP values for fully awake children were always more than 60. Although there are no previous studies that have analyzed the MLAEP values in small children receiving no medication, these data are similar to the results published by Weber et al. in preschool children during anesthesia17 and also during anesthetic procedures in adults.21

In our study, fully awake children (RS: 1–2) had significantly higher BIS and MLAEP values than sleeping children (RS: 3–5), which indicates that BIS and MLAEP values decrease during periods of natural sleep. Although the BIS was designed based on the EEG of adult patients under pharmacological sedation and not during natural sleep, some studies in adults have found that the value decreases during natural sleep, reaching 40–4535; the BIS can also detect the onset of naturally occurring sleep,36 though it was not able to differentiate the different stages of physiologic sleep.37 In a study performed in 15 children between 1 and 16-yr-of-age, the BIS was sensitive enough to reflect the changes on the EEG trace that accompany the various stages of natural sleep.20 In this study, children in deep sleep had BIS values similar to the ones reached during very deep sedation. This demonstrates that the BIS can detect changes in the consciousness level, independently of its origin, thus explaining why it is possible to find low BIS values during pharmacological sedation and during natural sleep. In our study, the same effect has been observed with MLAEP. There are no previous studies with which to compare our data.

The correlation between the BIS and the RS in studies in adults is extremely variable. The coefficients of correlation are good in general anesthesia,24 but the results are contradictory in critically ill patients.9,38,39 In children, the correlation has also been high variable; a good level of correlation has been found (r = –0.78) in procedural sedations in the emergency department,14 but the results are discordant in critically ill children.13,40 Two studies in critically ill adult patients found a good correlation between MLAEP and RS values.9,10 The results of our study demonstrated a significant correlation among BIS, MLAEP, and RS values. The correlation between BIS and MLAEP values was better in fully awake children older than 6 mo. More studies are necessary in children with deeper levels of sedation to confirm these findings.

The mean signal quality index-BIS was 70, and we considered the BIS values reliable because the minimum value accepted in previous studies is 50.8,16,40,41 The SR-BIS was always 0, but the SR-MLAEP was higher in children <6-mo-old and particularly in children <1-mo-old. It is not possible to determine the cause of the difference in the suppression rate between the two methods, but it could be speculated that the MLAEP monitor was more sensitive in children under 6-mo-old, in whom the EEG is immature and, therefore, the percentage of EEG suppression time higher than in older children. The EMG of both monitors showed a high activity, a finding compatible with the situation of fully awake or natural sleep in children who have not received muscular blockade or sedative drugs.

When we grouped the children as fully awake or asleep, the level of agreement among the three methods was low, and only moderate agreement was found between the MLAEP and RS values. RS classified a percentage of children as fully awake who, according to the BIS and MLAEP values, had light-moderate sedation. This lack of agreement could possibly be explained by an inability of the BIS and MLAEP to detect changes in the consciousness level in small children, as the EEGs in children and adults are different. Nevertheless, a correlation was found among the BIS, MLAEP, and RS values in our patients. We think that the agreement among the three methods could be lacking because the passage through the different stages of sleep to the fully awake state is progressive and it is difficult to find an exact RS score that corresponds to BIS and MLAEP values to discriminate between the different levels of consciousness. However, since BIS scores were generally higher in newborns, some of these discordant observations may reflect the need for different thresholds for different ages within the infant and toddler age group.

The study of the ROC curve found that the cut-off points for the BIS and MLAEP to differentiate between sleeping and awake children according to the RS were similar to those established previously. However, the logistic regression study demonstrated that the predictive capacity of the BIS and MLAEP to differentiate between sleep and wakefulness as defined by the RS is relatively low. This is probably due to the difficulty in finding a clear point of separation between these two states of consciousness, as we have commented above. The best combination of sensitivity and specificity were seen when a higher BIS value was used as the cut-point between sleep and wakefulness, suggesting that the poor agreement (as measured by Kappa) may have been due, in part, to the use of a less than optimal threshold for classification of level of consciousness. However, even at a threshold of 80, more subjects were classified as "awake" by the RS than by BIS; this discrepancy would have been exacerbated had a higher BIS threshold for wakefulness been chosen. Since BIS scores were generally higher in newborns, some of these discordant observations may reflect the need for different thresholds for different ages within the infant/toddler age group.

Our results are the first data obtained using BIS and MLAEP monitors in unsedated, healthy, small children. These data could be sufficient to establish the normal values of the BIS and MLAEP in unsedated small children, fully awake or asleep, and it would be useful to compare these measurements with those from children under sedation and/or with neurological pathology.

We conclude that the BIS and MLAEP have a good correlation with the RS in children younger than 2-yr-of-age who have not received sedative drugs. However, the agreement with the clinical scales used to assess wakefulness and natural sleep is poor. Further studies are necessary to validate these methods in small children with different levels of deep sedation.

ACKNOWLEDGMENTS

We thank Heide von Bormann for her help with the preparation of the manuscript, Monserrat Solera for the help with the statistical analysis, and the nursing staff for their collaboration.

Footnotes

Accepted for publication October 8, 2007.

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