This study investigates the accuracy of a composite index, the A-Line(R) auditory evoked potentials index version 1.6 (AAI1.6; Danmeter A/S, Odense, Denmark), as a measure of cerebral anesthetic drug effect in a model for predicting a calculated effect site concentration of propofol (CePROP). The AAI1.6 algorithm extracts information from the midlatency auditory evoked potentials, the spontaneous electroencephalographic activity, and the detection of burst suppression. The former version of this monitor, the A-Line auditory evoked potential index version 1.5, is only based on fast extracted midlatency auditory evoked potential information.
After institutional ethics committee approval (University Hospital, Ghent, Belgium), informed consent was obtained from 13 patients (10 women, 3 men) with an American Society of Anesthesiologists physical status of I, aged 18-65 yr, who were scheduled to undergo ambulatory gynecologic or urologic surgery. The authors evaluated for Bispectral Index, A-Line auditory evoked potential index, version 1.5, AAI1.6 scaled from 0 to 100 and AAI1.6 scaled from 0 to 60, the interpatient stability at baseline, the detection of burst suppression, prediction probability, and correlation with CePROP, during a constant infusion of 1% propofol at 300 ml/h. The authors developed pharmacodynamic models relating the predicted CePROP to each measure of cerebral anesthetic drug effect.
Bispectral Index had the lowest interindividual baseline variability. No significant difference was found with prediction probability analysis for all measures. Comparisons for correlation were performed for all indices. The AAI1.6 scaled to 60 had a significantly higher correlation with CePROP compared with all other measures. The AAI1.6 scaled to 100 had a significant higher correlation with CePROP compared with the A-Line auditory evoked potential index version 1.5 (P < 0.05)
The authors found that the application of AAI1.6 has a better correlation with a calculated CePROP compared with a solitary fast extracting midlatency auditory evoked potential measure. Whether this improvement in pharmacodynamic tracing is accompanied by an improved clinical performance should be investigated using clinical endpoints.
PROCESSED analysis of the electroencephalogram or midlatency auditory evoked potentials (MLAEPs) is increasingly accepted as surrogate endpoint for quantification of anesthetic cerebral drug effect. For the electroencephalogram, the Bispectral Index (BIS) incorporated in the A-2000 BIS® monitor (Aspect Medical Systems, Newton, MA) has been proven to have a high sensitivity and specificity to measure anesthetic drug effect.1–3For MLAEPs, Jensen et al. 4developed a new method for extracting the MLAEP from the electroencephalogram by using an autoregressive model with an exogenous input (ARX), allowing fast extraction of the raw MLAEP signal. A new monitoring variable called the A-Line® ARX Index, version 1.5 (AAI1.5), is incorporated in a recently commercialized monitor called the A-Line® (Danmeter A/S, Odense, Denmark). Various investigators have illustrated its clinical usefulness and limitations.2,3,5,6
In previous work, we compared the performance of both systems and found that the correlation between the changes in anesthetic drug effect as measured by BIS or AAI1.5and the propofol effect site concentration (CePROP) were accurate, except at baseline and during excessive levels of anesthetic drug effect, as detected by the increasing level of burst suppression.7For BIS, better baseline stability (minimal variability in the absence of drugs between individuals) was observed as compared with AAI1.5.7Excessive levels of anesthetic drug effect remained detectable by the BIS monitor from a burst suppression ratio of 40%, whereby no changes in AAI1.5were observed during increasing levels of burst suppression.7This lack of information is caused by the fact that (1) burst suppression ratio does not participate in the calculation of AAI1.5and (2) at patient-specific levels of anesthetic drug effect, the amplitude (latency) of the raw MLAEP wave is reduced (increased) in such a way that it becomes nearly a straight line, limiting its discriminating power.8,9
In a recent editorial in Anesthesiology, Kalkman and Drummond10stated that it might be proven ultimately, if we deem the grail of depth of anesthesia monitoring worth pursuing, that the optimal monitor of depth of anesthesia will be one that integrates parameters extracted from both spontaneous and evoked cerebral electrophysiologic signals. Following this philosophy, the first step is to prove that this monitor has a good correlation with cerebral anesthetic drug effect during the administration of a hypnotic drug.10Therefore, we hypothesized that the construction of a composite index calculated from the combination of a fast extracted MLAEP, electroencephalogram, and burst suppression might offer a broader range of information on the calculated effect site of propofol—as a pharmacodynamic endpoint of cerebral anesthetic drug effect—compared with an index based on solitary MLAEP or electroencephalographic input. Recently, an upgrade version of the A-Line® has been developed, producing such a composite index, called the A-Line® auditory evoked potential index, version 1.6 (AAI1.6; Danmeter).
This study compares the accuracy of the BIS, AAI1.5, and AAI1.6in their ability to predict a progressively increasing CePROP. Therefore, we evaluated for all measures the stability at baseline (minimal variability in the absence of drug between individuals),11accurate detection of burst suppression,12prediction probability,13,14and correlation with the CePROP. We also developed pharmacodynamic models relating the predicted CePROPto each measure of cerebral anesthetic drug effect.
Materials and Methods
After institutional ethics committee approval (University Hospital, Ghent, Belgium), informed consent was obtained from 13 patients (10 women, 3 men) with an American Society of Anesthesiologists physical status of I, aged 18–65 yr, who were scheduled to undergo ambulatory gynecologic or urologic surgery. Exclusion criteria included weight less than 70% or more than 130% of ideal body weight, neurologic disorder, and recent use of psychoactive medication, including alcohol.
An 18-gauge intravenous line was positioned at a large left forearm vein. Every patient received approximately 100 ml crystalloid fluid during the study period. No fluid load was given before induction. No patient received preoperative medication. No other drugs, including opioids, were given during the study period. All patients maintained spontaneously ventilating (even at high levels of burst suppression) via a facemask delivering 100% oxygen at 6 l/min.
Heart rate and noninvasive blood pressure, arterial oxygen saturation, and capnography were recorded at 1-min intervals using an S-5 monitor (Datex, Helsinki, Finland). Capnography was monitored by putting the side stream sample line in the facemask of the patient. This implies the occurrence of an error for quantification of the partial pressure of carbon dioxide, but it enables monitoring of respiratory rate and free airway. A silent operation room was obtained for all patients.
At the start of the study period, 1% propofol was administered at 300 ml/h via a computer-assisted continuous infusion device (RUGLOOP**). This system captures all monitored data while driving a Fresenius Modular Infusion Pump connected to a Fresenius Base A (Fresenius Vial Infusion Systems, Brézins, France) via an RS-232 interface. During the propofol infusion, the corresponding CePROPis calculated in a time-synchronized way by RUGLOOP using a three-compartment model enlarged with an effect site compartment, previously published by Schnider et al. 15,16The calculated CePROPwas computed to yield a time to peak effect of 1.6 min after bolus injection,17as also published by Schnider et al. 15,16and clinically confirmed by Struys et al. 18The propofol infusion was continued at the same speed until burst suppression levels of 80% or higher were achieved. However, infusion was stopped earlier if the mean arterial blood pressure became lower than 50 mmHg.
Before the drug administration was started, all patients were asked to close their eyes and relax for 2 min. During that time, signal quality, impedance of the electrodes, and the adequate detection of all parameters by RUGLOOP were verified. Baseline measures were performed during the first 5 s after starting the pumps, when CePROPwas 0 in all patients. Averaging of the data was performed using a 10-s interval.
Electroencephalographic and MLAEP Data Collection
BIS-XP (version 4.0) was derived from the frontal electroencephalogram (At-Fpzt) and calculated by the A-2000 BIS® monitor using four BIS® sensor electrodes (Aspect Medical Systems, Inc.). The BIS value ranges from 0 to 100. The smoothening time of the BIS monitor was set at 15 s.
We recorded raw electroencephalographic data including the MLAEP data with a prototype version of the A-Line® monitor. Three electrodes (A-Line® AEP electrodes; Danmeter A/S) were positioned at mid forehead (+), left forehead (reference), and left mastoid (−). Impedance was always lower than 5 kOhm. In this protocol, MLAEP was elicited by a bilateral click at 9 Hz, with a 2-ms duration and an adaptable click intensity set automatically by the monitor according to the measured signal-to-noise ratio (SNR) of the raw MLAEP signal.19Artifact rejection and 25- to 65-Hz band-pass filtering was conducted previously to the extraction of the MLAEP.
All raw MLAEP data were stored on a compact flash card (SanDisk, Sunnyvale, CA) connected to the prototype A-Line®. Post hoc , both AAI1.5and AAI1.6were extracted from these data on a time synchronized basis.
The AAI1.5is calculated using a fast extracting method called ARX, enabling us to extract information from the MLAEP within 2–6 s. This protocol has been published elsewhere.2The AAI1.5value ranges from 0 to 100.
The AAI1.6is a composite index using three sources of information resulting in an index value ranging between 0 and 100. First, an ARX is used to extract information from the raw MLAEP wave during periods with high SNR. The method used is based on the AAI1.5protocol and is described elsewhere.4When the MLAEP is reduced to a flat line, the SNR becomes too low to extract a useful AAI calculation. At that time, the electroencephalographic-based information will determine the AAI1.6calculation. Finally, when burst suppression patterns are detected, this information becomes the major factor in the calculation of the composite index. The AAI1.6is mathematically formulated as
where AAI1.5is the result of the ARX model. E30–47 Hzand E10–20 Hzare the results of a power analysis in the raw electroencephalographic spectrum using higher and lower frequencies, respectively. BS is the percentage of burst suppression patterns detected during the last 30 s. k0, k1, and k2are functions of the SNR, the detection of iatrogenic artifacts (translated in a signal quality index), and the auditory stimulus intensity. The SNR is determined during the averaging process of the raw signal. It evaluates the detection quality of the signal under investigation. For MLAEP, the occurrence of the electroencephalogram, electromyogram, and other artifacts will induce a lower SNR. For the electroencephalogram, only electromyographic and iatrogenic artifacts will be taken into account. The signal quality index is calculated based on the number (and type) of artifacts during a certain period of time. If the amount of artifacts per period of time is higher than a percentage of this time, no AAI1.6is calculated because it is not reliable. If the number of artifacts per period of time is less than this value, an index is calculated, but the signal quality index bar is decreased on screen, indicating a lower accuracy of the calculated index. When this occurs, an artifact code is transferred to the RUGLOOP program automatically. These data were deleted post hoc from further analysis.
The burst suppression parameter is defined as the percentage of time where the power of the electroencephalogram is smaller than 5 μV over a period of time. However, the calculation of burst suppression differs between monitors. For BIS and AAI1.5, the burst suppression algorithm details are published previously.7
In the AAI1.6, the burst suppression detection algorithm is based on a maximum likelihood cumsum algorithm, with variable probability functions, using a preprocessed signal after artifact detection and filtering. The main property of this method is that low-amplitude signal criteria are based on probabilities and not on a fixed number. Second, the signal has no fixed segmentation, allowing a higher time resolution for detecting changes in comparison with other methods as applied in AAI1.5and BIS. Finally, burst suppression is evaluated over a window of 30 s in AAI1.6, instead of 22 s in the former version.
Because it might be hypothesized that no additional information on loss of consciousness is revealed for AAI1.6values between 60 and 100,3the A-Line® monitor offers the possibility to adjust the range of the index toward a 0–60 scale (defined as AAI1.660). However, by setting all values higher than 60 to 60, it has to be proven that no information on cerebral anesthetic drug effect is lost, which is crucial when using the monitor in a pharmacodynamic protocol or in a clinical setting. Therefore, applicable performance measurements (baseline variability, individualized Spearman rank correlation, prediction probability analysis) were calculated on both scales.
The significance level was set at 5% unless otherwise reported.
The baseline variability is calculated by computing the coefficient of variance on the electroencephalographic data points obtained during the first 5 s of the protocol, before any drug has been delivered. In this setting, the baseline variability will mainly reflect interpatient variability because of the short duration of measurement.
Comparison between AAI1.5and AAI1.6.
A Pearson correlation was calculated between AAI1.5and AAI1.6.
Burst Suppression Detection and Parameter Correlation.
The relations between the burst suppression and each measure of anesthetic drug effect are plotted. A Spearman rank correlation was calculated. For each scatterplot, a model was fitted to the data using curve estimation function from Sigmaplot2000® for Windows® (SPSS Inc., Chicago, IL). The curve estimation function produces curve estimation regression statistics and related plots for different curve estimation regression models including linear, logarithmic, inverse, quadratic, cubic, power, compound, S-curve, logistic, growth, and exponential. A separate model is produced for each dependent variable, together with its regression coefficients, predicted values, residuals, and predictive intervals. After this, the most appropriate regression model can be selected.
The ability of the different indicators to describe the anesthetic drug effect was evaluated using prediction probability (PK), which compares the performance of indicators having different units of measurements. PKwas calculated using a custom spreadsheet macro PKMACRO, developed by Smith et al. 13,14The PKvalue was calculated for every individual patient and for all parameters studied. We evaluated the predictive capacity of BIS, AAI1.5, and AAI1.6for detecting the calculated CePROP, which has a known correlation with the anesthetic drug effect.18The calculated CePROPreached at every 5 s was used as an endpoint for PKcalculation. CePROPwas calculated with a precision of two decimals. A PKof 1 for BIS, AAI1.5, or AAI1.6would mean that BIS, AAI1.5, or AAI1.6always decreases (increases) as the patient reaches higher (lower) drug concentrations according to the CePROP. Such an indicator can perfectly predict the anesthetic drug concentration. Alternatively, a PKvalue of 0.5 would mean that the indicator is useless for predicting anesthetic drug concentration. The jackknife method was used to compute the SE of the estimate, based on the assumption that all assessments were independent.13,14After having evaluated normal distribution, a Student t test with Bonferroni correction was used to evaluate significant difference between PKmeans.
Individualized Spearman Rank Correlation.
As an additional nonparametric approach, the Spearman rank correlations between CePROPand BIS, AAI1.5, or AAI1.6(both scales) were individualized by computing the correlation first for every patient i separately, defined as R i. The reported Spearman rank correlation, R , is a weighted average of the R i(weighted according to the number of observations for each patient). In this way, R retained its usual interpretation. The confidence intervals on R were obtained by the bootstrap method in which the hierarchical nature of the data were incorporated by resampling within patients. Equality of two correlation coefficients was tested at the 5% level of significance by constructing the 95% confidence intervals of the difference (confidence intervals were also computed with the bootstrap technique). All bootstrap calculations were based on 10,000 simulation runs.
The relation between CePROPand the electroencephalographic measures of anesthetic drug effect were analyzed using a sigmoid Emaxmodel,
where Effect is the electroencephalographic effect being measured (BIS, AAI1.5, or AAI1.6[both scales]), E0is the baseline measurement when no drug is present, Emaxis the maximum possible drug effect, Ce is the calculated effect site concentration of propofol, Ce50is the effect site concentration associated with 50% maximal drug effect, and γ is the steepness of the concentration–response relation curve. The model parameters were estimated using NONMEM V (Globomax LLC, Hanover, MD). Interindividual variability was modeled using a log-normal distribution,
where Piis the parameter value (E0, Emax, y or Ce50) in the i th patient, Ptvis the typical value of the parameter in the population, and η is a random variable with a mean of 0 and a variance of ω.2Individual variability is reported as ω, the SD of η in the log domain, which is approximately the coefficient of variance in the standard domain. Residual intraindividual variability was modeled using a standard additive error model.20
The population characteristics were as follows: weight, 64.0 ± 3.8 kg; age, 38 ± 6.0; height, 168 ± 7.8 cm; sex, 10 women and 3 men. All patients remained within a safe hemodynamic and respiratory clinical state.
All measured data were included in the analysis. Figure 1shows the raw data over time for the four electroencephalographic measures (BIS, AAI1.5, AAI1.6, AAI1.660) and CePROP. All patients remained in a hemodynamic and respiratory safe condition during the study period.
The interpatient baseline variability was calculated for all studied electroencephalographic measures (BIS, AAI1.5, AAI1.6, AAI1.660). The coefficient of variance on the first 5 s of measurement before administration of propofol is shown in table 1.
AAI1.5and AAI1.6(both scaled between 0 and 100) were compared as shown in figure 2. This shows a strong correlation between both AAI versions (Pearson correlation R = 0.91209833, P < 0.001). We notice a large variability at high values of both parameters and a tendency for AAI1.5to remain on a higher value at higher levels of CePROPin comparison with AAI1.6. For AAI1.5, no data lower than 7 are observed in contrast to AAI1.6.
The relations between the percentage of burst suppression and BIS, AAI1.5, and AAI1.6are plotted in figure 3together with the most appropriate curve estimation. For BIS, a cubic polynomial regression curve was considered to be the best fit. For AAI1.5and AAI1.6, a sigmoid regression curve with three parameters was selected as the best fit. For AAI1.660, identical results to AAI1.6were found. Therefore, no graph is presented. The Spearman rank correlations between burst suppression and BIS, AAI1.5, and AAI1.6are −0.728, −0.551, and −0.871, respectively.
The PKvalues for BIS, AAI1.5, AAI1.6, and AAI1.660are shown in table 2. The individualized Spearman rank correlations between CePROPand BIS, AAI1.5, AAI1.6, and AAI1.660are also included in table 2.
Figure 4shows the behavior of the four electroencephalographic measures versus CePROPfor all patients. With increasing CePROP, all measures decreased. The relations of CePROPto BIS, AAI1.5, AAI1.6, and AAI1.660are modeled and shown in figure 5. The typical parameter values for each population model including the coefficient of variance (as a measure for interindividual variability in the standard domain) are found in table 3. The SD for each model (as a measure of the intraindividual variability in the log domain) was 5.63 for BIS, 13.67 for AAI1.5, 7.24 for AAI1.6, and 4.02 for AAI1.660.
This study shows that the application of a composite index (AAI1.6) based on MLAEPs and spontaneous electroencephalography optimizes the prediction of CePROPas compared with a solitary fast extracting MLAEP measure (AAI1.5). Comparing several monitors for cerebral hypnotic drug effect demands a systematic approach. The methodology used in this trial is based on a former publication from Vanluchene et al. ,7where spectral entropy is compared with BIS and AAI1.5.
The A-Line® monitor offers the possibility to reduce the upper scale limit to 60, based on the rationale that values between 60 and 100 suffer from a high interpatient variability and offer no additional information on loss of consciousness.2Although this adjustment might be interesting on a clinical level, it is crucial to prove whether this scale is applicable to pharmacodynamic studies investigating subhypnotic levels of anesthesia (when consciousness is not lost), without losing any information on the propofol drug concentration. Therefore, we also investigated the performance accuracy of the AAI1.660as an individual index.
High baseline variation, as defined by the coefficient of variance, might decrease the predictive ability of the electroencephalogram-derived measures when used to detect cerebral drug effect, as stated by Bruhn et al. 11BIS showed the lowest baseline variability. In contrast, AAI1.5and AAI1.6showed a high but comparable coefficient of variance. We found a major improvement in baseline variability in AAI1.660in comparison to AAI1.5and AAI1.6. Although it is potentially interesting when applying the A-Line® monitor clinically to monitor loss of consciousness, one might question that it does not make sense to reduce baseline variability by cutting of data higher than 60, if this new scale causes a decreased sensitivity for the detection of subhypnotic levels of anesthetic drug effect. This reduced upper limit only makes sense if the other performance measures reveal a beneficial effect.
Burst suppression is a benign electroencephalographic pattern frequently seen in healthy brain at deep levels of anesthesia. Because the detection of burst suppression represents an important component to the level of hypnotic effect, it might be helpful to take into account burst suppression analysis when measuring deep levels of anesthetic drug effect because it might optimize the discriminating power of the investigated index at these levels. For BIS, burst suppression is included in the algorithm. Various authors have found that above a burst suppression ratio of 40%, a linear correlation exists between BIS and burst suppression ratio, indicating that the burst suppression ratio is the only determinant factor for BIS values below 30.7,21Our results for BIS, as shown in figure 3, are in agreement with these previously published findings. If burst suppression was excluded from the algorithm, BIS would become very resistant at excessive levels of anesthetic drug effect. In contrast, the calculation of the AAI1.5is only based on the MLAEP. As already observed in previous work, the MLAEP flattens at patient-specific levels of anesthetic drug effect, thereby limiting its discriminating power.7–9This phenomenon results in a maximum decreased AAI1.5“plateau” level higher than 0. As shown in figures 2 and 4, the lowest observed AAI1.5values are ceiled around 7. Beyond this level, no additional information on cerebral drug effect can be obtained. When taking in consideration that the ED95for loss of consciousness is around 19 for AAI1.5, the discriminating power might become very low after loss of consciousness. For AAI1.6, the electroencephalogram and burst suppression are included as a component of the composite index as described in the Materials and Methods section. This results in an increased discriminating power at deep levels of anesthetic drug effect. As shown in figure 3, the absolute values of AAI1.6are able to decrease to 0 at increasing levels of burst suppression. This improvement between AAI1.5and AAI1.6is also reflected in the statistically significant better individualized Spearman rank correlation for AAI1.6(table 2).
When studying performance accuracy, the question is how well the observed measure, which is the electroencephalographic response, predicts the unobserved “underlying” state of the patient, which is represented by the CePROP. Therefore, PKwas calculated for BIS, AAI1.5, AAI1.6, and AAI1.660. The underlying theoretical background of PKcalculations has been published elsewhere.7In our study, we did not obtain any significant difference between PKvalues, although AAI1.6tended to have the highest median value.
As an additional analysis for correlation between parameters and CePROP, we calculated the Individualized Spearman rank correlation coefficients for each measure. This weighted nonparametric statistical approach depicts the nonlinearity in the system much more accurately as compared with PKanalyses. Results confirm the significant increase in correlation between AAI1.6versus CePROPin comparison to AAI1.5, thereby proving that the combination of MLAEP and derived measures from the spontaneous electroencephalogram (power spectrum analysis and burst suppression calculation) increases the accuracy to measure cerebral anesthetic drug effect. Initially, no difference was found between BIS and AAI1.5or between BIS and AAI1.6when scaled to 100. However, when the upper limit of the scale was reduced to 60, remarkable results were observed. Figure 4shows that a high variability and a high amount of nonlinearity are observed in all measures when scaled to 100. For AAI1.6, one can say that the signal between 60 and 100 nearly behaves as “random noise.” By eliminating this part of the AAI1.6range, the high variability resulting in a high level of nonlinearity is drastically reduced. This results in a very high individualized Spearman rank correlation as shown in table 2. However, one can raise the question of whether a constant number around 60 offers more information compared with the complete scale, both when predicting propofol anesthetic drug effect and when evaluating a clinical level of sedation before loss of consciousness is obtained. This must be studied in further research. We were not able to evaluate the clinical level of sedation in this population because we wanted to avoid any stimulation during induction.
Figure 5shows the pharmacodynamic modeling for all measures versus CePROP. Previously, the relation between measures of anesthetic drug effect and CePROPwas observed following a sigmoid Emaxmodel. Therefore, in our study, the relation between the measures of anesthetic drug effect and CePROPwas also modeled using a sigmoid Emaxmodel, and the model parameters were estimated using a population approach. In NONMEM, the parameters in the individual are weighted in a Bayesian manner toward the mean for the population, based on the variance of the individual parameters. Examining our raw data, we found for all parameters a single sigmoid regression to be adequate for describing the range of concentrations used in this study. When looking at figure 5, one can conclude that the smoothest regression is found in AAI1.660. This is reflected in an optimization of both the interindividual and the intraindividual variability in the population. In table 3, the coefficients of variation of the typical values of the cerebral drug effect measures reveal a major decrease in the interindividual variability of the slope (γ) when AAI1.660is compared to AAI1.6. Simultaneously, a decrease in intraindividual variability at baseline is observed for AAI1.660, reflected by the lower SD compared with AAI1.6. However, we want to stress the fact that the regression analysis for AAI1.660should be interpreted cautiously because of the effect of rejection of data on the NONMEM analysis. It might cause a distortion on the data input in such a way that the behavior of the population regression is closer to the a priori chosen Emaxmodel. Further research is needed to clarify whether this result is an artificial overestimation of the performance parameters or whether AAI1.660is indeed able to maintain a high performance as a hypnotic drug effect monitor.
We conclude that the use of the composite index AAI1.6, which combines information from the MLAEP, spontaneous electroencephalogram, and burst suppression, increases the correlation with the cerebral drug effect of propofol as compared with the AAI1.5, which is a solitary fast extracted MLAEP index. By adjusting the upper scale limit to 60, the performance measures are optimized even more. However, the implications of this newly chosen upper scale limit should be further explored on both the clinical and the pharmacodynamic level.