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TECHNOLOGY, COMPUTING, AND SIMULATION

Narcotrend Index Versus Bispectral Index as Electroencephalogram Measures of Anesthetic Drug Effect During Propofol Anesthesia

Sascha Kreuer, MD^*, Wolfram Wilhelm, MD DEAA^*, Ulrich Grundmann, MD^*, Reinhard Larsen, MD^*, and Jörgen Bruhn, MD Section Editor

*Department of Anesthesiology and Intensive Care Medicine, University of Saarland, Homburg/Saar, Germany, and the Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany

Address correspondence and reprint requests to Wolfram Wilhelm, MD, DEAA, Department of Anesthesiology and Intensive Care Medicine, University of Saarland, 66421 Homburg/Saar, Germany. Address email to wolfram.wilhelm{at}uniklinik-saarland.de

	Abstract

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The Narcotrend monitor (MonitorTechnik, Bad Bramstedt, Germany) performs an automatic analysis of the electroencephalogram (EEG) during anesthesia based on a visual assessment of the raw EEG. Its newest software version 4.0 includes a dimensionless index that, similar to the bispectral index (BIS), ranges from 100 (awake) to 0. We compared the performance of Narcotrend index and BIS as EEG measures of anesthetic drug effect during propofol anesthesia. Eighteen adult patients scheduled for radical prostatectomy were investigated. An epidural catheter was placed in the lumbar space and electrodes for BIS (version XP; Aspect Medical Systems, Natick, MA) and Narcotrend were positioned as recommended by the manufacturers. Narcotrend index, BIS values, and propofol plasma and effect site concentrations as parallelly simulated by Rugloop software (Department of Anesthesia, Ghent University, Belgium) were automatically recorded in intervals of 5 s. Induction of anesthesia consisted of a fentanyl bolus and a propofol infusion. After endotracheal intubation, patients received 15 mL bupivacaine 0.5% epidurally, and 45 min later propofol dosages were subsequently increased and decreased twice. Simulated propofol effect site concentrations ranged from 2.0 ± 0.4 µg/mL (smallest) to 6.3 ± 1.3 µg/mL (largest) during these subsequent increases and decreases of propofol. In terms of prediction probability (P_K) the performance of the Narcotrend index (P_K = 0.88 ± 0.03) to predict propofol effect site concentrations was comparable to the BIS (P_K = 0.85 ± 0.04). Using the respective EEG index as a measure of drug effect the mean k_e0 was calculated as 0.20 ± 0.05 min^-1 for Narcotrend index and 0.16 ± 0.07 min^-1 for BIS. In the observed propofol concentration range Narcotrend index detected differences in EEG dynamics as well as BIS.

IMPLICATIONS: This study in 18 adult patients undergoing radical prostatectomy describes the relationship between Narcotrend index and bispectral index versus predicted propofol effect compartment concentrations. In terms of prediction probability, the performance of the Narcotrend index and the bispectral index to predict propofol effect site concentrations was comparable.

	Introduction

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The Narcotrend monitor (MonitorTechnik, Bad Bramstedt, Germany) performs an automatic analysis of the electroencephalogram (EEG) during anesthesia. The methods for the automatic classification were developed on the basis of a visual assessment of the EEG which, in its origins, is related to sleep classification. In 1937 Loomis et al. (1) described systematic changes of the EEG during human sleep and defined 5 stages, A–E, to distinguish different EEG patterns. Subsequently, this scale was extended and refined by defining its substages (2) and applying it to the classification of EEGs recorded during anesthesia from stage A (awake) to F (very deep level of anesthesia). Schultz et al. (3) used a scale with the substages A, B_0–2, C_0–2, D_0–2, E_0–1, and F_0–1, named "Narcotrend stages," for visually characterizing and classifying EEG patterns observed during anesthesia with different volatile and IV drugs. Agreement and correlation between visual and automatic assessment of the analyzed raw EEG epochs have recently been reported to be as much as 92% for the Narcotrend monitor (4). With the newest Narcotrend software version 4.0 a dimensionless scale from 100 (awake) to 0, named Narcotrend index, has been introduced similar to the bispectral index (BIS, Aspect Medical Systems, Natick, MA).

In contrast to the well-established and intensively evaluated BIS, published data regarding the Narcotrend monitor are still sparse. Although first studies indicate the favorable use of the Narcotrend to titrate anesthesia in clinical practice (5,6), we studied the performance of Narcotrend index compared to BIS as a measure of anesthetic drug effect during propofol anesthesia. It was the hypothesis of this investigation that Narcotrend and BIS are equivalent in detecting differences in EEG dynamics.

	Methods

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With IRB approval and written informed consent, 18 adult male patients (ASA physical status II, 62 ± 7 yrs, 80 ± 9 kg, mean ± SD) scheduled for radical prostatectomy were studied. Exclusion criteria were a history of any disabling central nervous system or cerebrovascular disease. All patients were premedicated with midazolam 7.5 mg orally on the morning before surgery. In the operating room an IV catheter was inserted into a larger forearm vein and standard monitors were applied. An epidural catheter was placed in the lumbar space. The EEG was recorded continuously using an Aspect A-2000 BIS monitor (version XP; Aspect Medical Systems, Natick, MA) and the Narcotrend monitor (version 4.0). After the skin of the forehead had been degreased with 70% isopropanol, the BIS (BIS-XP sensor, Aspect Medical Systems) and the Narcotrend (Blue sensor; Medicotest, Olstykke, Denmark) electrodes were positioned as recommended by the manufacturers: For the Narcotrend two electrodes were placed on the patient’s forehead with a minimum distance of 8 cm; a third electrode was positioned laterally serving as a referential electrode. Finally, impedances were measured for each set of electrodes to ensure optimal electrode contact defined as 6 k for the Narcotrend and 7.5 k for the BIS as required by the manufacturers.

Induction of anesthesia was started with a fentanyl bolus of 0.1 mg; 5 min later 36 mg · kg^-1 · h^-1 propofol was given for hypnosis using an infusion system (Graseby 3400; Graseby Medical Limited, Watford, UK). After loss of consciousness oxygen was given by face mask ventilation, the propofol infusion was reduced to 16 mg · kg^-1 · h^-1, patients received 0.5 mg/kg of atracurium, the trachea was intubated 3 min later, and the lungs were ventilated to an end-tidal carbon dioxide concentration of 35 mm Hg. Immediately after intubation, patients received 15 mL bupivacaine 0.5% epidurally, whereas the propofol infusion was adjusted according to clinical needs.

To ensure conditions of constant surgical stimulation, only the EEG data obtained during prostata preparation were used for further analysis. In all cases, a waiting period of at least 45 min after induction of anesthesia was maintained to minimize the effects of the fentanyl administered for induction. For study measurements the propofol infusion rate was increased to 26 mg · kg^-1 · h^-1 until a substantial burst suppression pattern was recognized in the raw EEG. Subsequently, the propofol infusion rate was reduced to 0.5 mg · kg^-1 · h^-1 until a BIS value of 50 was reached. Two of these cycles were performed in each patient; complete neuromuscular blockade during the investigation period was ensured by repetitive injections of 0.25 mg/kg atracurium.

Study data were automatically recorded in intervals of 5 s during the 2 concentration curves. BIS values were recorded using the software program Hyperterminal (Microsoft, Redmond, WA). The Narcotrend index was recorded using a modified research laptop version of the Narcotrend software 4.0. The propofol infusion pump (Graseby 3400) was connected via an RS-232 interface to a computer running the software Rugloop (simulation version, Department of Anesthesia, Ghent University, Ghent, Belgium) which automatically calculated and recorded propofol plasma and effect site concentrations using the Diprifusor data set as published by Marsh et al. (7). The synchronization of the data was performed automatically by the software Access 2000 (Microsoft).

The correlation between Narcotrend or BIS and the predicted propofol effect compartment concentration was calculated using prediction probability (P_K). Smith et al. (8) elucidated the prediction probability as follows: Given two randomly selected data points with distinct anesthetic drug concentration, the P_K value describes the probability that the EEG correctly predicts which of the data points is the one with the larger (or smaller) anesthetic drug concentration. As a nonparametric measure, P_K is independent of scale units and does not require knowledge of underlying distributions or efforts to linearize or to otherwise transform scales. Furthermore, P_K can be computed for any degree of coarseness or fineness of the scales. Thus, P_K fully uses the available data without imposing additional arbitrary constraints.

The relationship between ordinal variables x (indicator value, i.e., in our study BIS value and Narcotrend index value, respectively) and y (i.e., in our study propofol effect-site concentration) is described in terms of the rank ordering of the x and y values for pairs of data points. A concordance occurs in our study when the x values and y values for a pair of data points are rank ordered in the way that the data point with the larger propofol effect site concentration exhibits the lower BIS or Narcotrend index value. A discordance occurs when the x and y values are rank ordered in the opposite direction, i.e., when the data point with the larger propofol effect-site concentration exhibits the higher BIS or Narcotrend index value. An indicator-only, or x-only, tie (tie in indicator value but not in propofol effect-site concentration) occurs when the x values are tied but the y values are not (i.e., the same bispectral or Narcotrend index value but different propofol effect-site concentration). Similarly, a y-only tie occurs when the x values are not tied but the y values are (i.e., different BIS or Narcotrend index value but the same propofol effect-site concentration). Finally, a joint tie occurs when there are ties in both x and in y (i.e., the same BIS or Narcotrend index value and the same propofol effect site concentration). Concordances are desired; discordances and indicator-only ties are undesirable. Ties in y (both y-only and joint ties) will not be considered according to the P_K algorithm.

P_K has been defined (8) as P_K = (P_c + 0.5*P_tx)/(P_c + P_d + P_tx), where P_c, P_d, and P_tx are the respective probabilities that two data points drawn at random, independently and with replacement, from the population are a concordance, a discordance, or an x-only tie.

When comparing indicators, however, it is necessary to gather data using the same procedure and over the same distribution of e.g., propofol concentrations; therefore it is recommended to measure the EEG index values simultaneously for the same subjects.

Data Analysis and Statistics
First, we calculated the prediction probability for Narcotrend index and BIS using the propofol effect compartment concentrations as calculated by the Diprifusor data set with a fixed k_e0 value which is integrated in the Diprifusor algorithm.

In a second separate step we estimated an individual k_e0 value for each patient using the fractional sigmoid E_max model for the relationship between effect compartment concentration and the respective EEG parameter (Hill equation) (9) with input from a first-order effect-site model: equation

and E = E₀ * (1-c_eff /(C50 + c_eff))

C_eff is the apparent effect site concentration, C_plasma is the predicted propofol plasma concentration, k_eo is the first order rate constant determining the efflux from the effect compartment, E₀ is the measured baseline effect of each individual, C50 is the concentration that causes 50% of the maximum effect, and describes the slope of the concentration-response relation.

Data from each person were fitted separately. The parameters of the above models were estimated using nonlinear regression with ordinary least squares. The computations were performed on a spreadsheet using the Excel 2000 software program (Microsoft), and the parameters were optimized with the Solver tool within Excel.

We now calculated the prediction probability for Narcotrend index and BIS using the propofol effect compartment concentrations calculated from the predicted plasma concentrations (as obtained from the Diprifusor data set) and the individually optimized k_e0 values. Differences in P_K values between Narcotrend index and BIS were tested with Wilcoxon’s test. Statistical significance was assumed at P < 0.05.

Data are presented as mean and SD. Statistical calculations were performed using SigmaStat 2.03 and SigmaPlot 2000 computer software (SPSS GmbH, Erkrath, Germany).

	Results

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The mean duration of the time period, during which the propofol concentration was systematically varied, was 59 ± 13 min. From this time period 616 ± 113 artifact-free 5-s epochs of the EEG per patient could be included.

The predicted propofol effect site concentrations reached from a smallest concentration of 2.0 ± 0.4 µg/mL to a largest concentration of 6.3 ± 1.3 µg/mL. With increasing propofol plasma concentrations, Narcotrend and BIS decreased (and vice versa) with a time delay (Fig. 1). Plotting the Narcotrend index versus propofol plasma concentration or the BIS versus propofol plasma concentration revealed hysteresis, which collapsed by introduction of the propofol effect-site concentration (Fig. 2). The performance of the Narcotrend index (P_K = 0.88 ± 0.03) as an index of propofol effect-site concentrations, as predicted by the Diprifusor data set, was not significantly different from that of the BIS (P_K = 0.85 ± 0.04). Figure 3 shows the individual P_K values for each patient.

View larger version (23K): [in this window] [in a new window]   Figure 1. Upper graph, time course of Narcotrend (gray dots) and bispectral index (black dots) for patient #1. Each dot represents the EEG parameter value of a 5-s epoch. Lower graph, propofol plasma (gray line) and effect site (black line) concentrations as predicted by the Diprifusor data set for the same patient.

View larger version (26K): [in this window] [in a new window]   Figure 2. Relationship between Narcotrend index (upper graphs) or bispectral index (lower graphs) and the respective propofol plasma (left) or effect site (right) concentrations for patient #1. Each dot represents the EEG parameter value of a 5-s epoch.

View larger version (8K): [in this window] [in a new window]   Figure 3. A comparison of the individual prediction probability (PK) values for Narcotrend and bispectral index. Given two randomly selected data points with distinct anesthetic drug concentration, the PK value describes the probability that the EEG parameter correctly predicts which of the data points is the one with the larger or smaller anesthetic drug concentration. Every black dot represents a patient.

The mean k_e0 individually optimized while using Narcotrend index as a measure of drug effect was 0.20 ± 0.05 min^-1, whereas it was 0.16 ± 0.07 min^-1 when the BIS was used. The estimates of k_e0 for Narcotrend and BIS are summarized in Figure 4.

View larger version (7K): [in this window] [in a new window]   Figure 4. Individual ke0 values of propofol for each patient as calculated using the fractional sigmoid Emax model for the relationship between effect compartment concentration and the respective Narcotrend or bispectral index parameter.

	Discussion

Top Abstract Introduction Methods Results Discussion References

For the data analysis in this study we preferred the P_K value as the objective function instead of the R² value that had been used in previous studies investigating EEG parameters as measures of anesthetic drug effect (10–12). Calculating R² necessitates the use of a specific pharmacodynamic model. A fractional sigmoid E_max model based on the Hill equation is usually used to that purpose. However, in the present study a burst suppression pattern was observed in all patients. The appearance of burst suppression leads to a switch in the BIS algorithm with a possible model misspecification while using a single fractional sigmoid E_max model (13). Therefore, we decided to use the model-independent calculation of the prediction probability P_K. Given two randomly selected data points with distinct anesthetic drug concentrations, the prediction probability P_K is the probability that the EEG parameter correctly predicts which of the data points is the one with the larger (or smaller) anesthetic drug concentration. This method was previously shown to be an adequate alternative to the R² value for estimating the performance of an EEG parameter as a measure of anesthetic drug effect (14) and to predict propofol target concentration (15).

Nonetheless, it should be noted that we used the fractional sigmoid E_max model for estimating individual values for k_e0 because no model-independent method is available to estimate k_e0 for increasing and decreasing anesthetic drug concentrations with a nonzero starting point.

We determined that a k_e0 of 0.25 min^-1 is incorporated in the Diprifusor data set. This is the same k_e0 value that is used in the computer program STANPUMP, based on preliminary work of Dyck et al.,¹ and that has also been used experimentally (16). This k_e0 value is very close to the k_e0 of 0.239 min^-1 of Schüttler et al.,² which has been used by Vuyk et al. (17) and others for their simulations. Our individually optimized k_e0 values are lower. This is in accordance with a mean k_e0 value of 0.20 min^-1 for propofol as reported by Billard et al. (18) with an older BIS version. Interestingly, when investigating volatile anesthetics Olofsen and Dahan (12) found lower k_e0 values for BIS than for spectral edge frequency. We also found lower k_e0 values for BIS than for Narcotrend index. This may be explained by different calculation intervals; i.e., 30 s for BIS XP (19) and 20 s for the Narcotrend (6). With very short calculation intervals of 2 s Schnider et al. (20) reported even larger k_e0 values of 0.456 min^-1 for propofol. Summarizing these results, it appears that the k_e0 value predominantly depends on the length of the calculation interval, whereas other explanations, e.g., a different site of action for BIS and for the other EEG parameters, are less probable.

We did not measure propofol plasma concentrations but relied on the predicted propofol concentrations. The prediction of propofol concentrations by the Diprifusor is based on a three-compartment model and the calculated pharmacokinetic variable set by Marsh et al. (7). In general, pharmacokinetic variable sets are determined from collectives of patients or subjects. However, the pharmacokinetic variable set of a single individual patient can certainly be different, resulting in a prediction error, i.e., the difference between predicted and measured concentrations, of up to 30% (21). Nevertheless, the prediction of propofol concentrations based on pharmacokinetic principles still makes sense. Predicted and measured concentrations are almost always parallel, and the percentage of deviation remains relatively constant during the complete duration of anesthesia (22). Thus, even though the absolute value of the predicted concentrations may be incorrect, the duration and changes undertaken are in relation correctly reflected. Eventually, this is sufficient for our study design, as only the performance of the EEG parameter to reflect the dynamic (the relative and not the absolute) changes in the single patient was the subject of the study. The excellent P_K values obtained in this investigation further support the adequacy of our approach.

Although the algorithms of Narcotrend index (6) and BIS (23) are completely different, both have a common composition based on an optimization of subparameters using extensive databases. The first step in the development of the automatic classification algorithm of the Narcotrend was to build a database of typical examples for all substages from A to F. For this purpose, artifact-free EEG epochs from a large database of one-channel EEG recordings collected from the electrode positions C₃-P₃ during anesthesia with thiopental-enflurane or propofol were selected. Initially, more than 1000 artifact-free EEG epochs with a length of 20 s were visually classified to form the basis for the development of automatic classification algorithms. From these EEG epochs numerous quantitative EEG features from the time and the frequency domain were extracted, e.g., spectral parameters, entropy measures, and autoregressive parameters (24). The extracted EEG parameters were statistically analyzed to identify a subset of EEG parameters that were best suited to discriminate between the different visually determined EEG substages. Age-related changes in the EEG were incorporated. The resulting parameters were combined in multivariate discriminant functions to classify an EEG epoch into one of the EEG substages between A and E. The discriminant analysis yields probabilities for the degree of similarity of an EEG epoch with the typical EEG stages A to E during anesthesia. In addition, algorithms for the classification of stage F were developed based on the proportion and intensity of very flat EEG segments. The algorithms were revised continuously including extensions for the standard use of frontal electrode positions. Obviously these efforts were successful. First studies indicate the favorable use of the Narcotrend to titrate anesthesia in clinical practice with reduction of drug consumption and shortening of recovery times (5,6). In addition, studies using an older version of the Narcotrend software, before the introduction of the Narcotrend index from 0 to 100, showed dose-dependent changes of the Narcotrend stages A to F, during emergence from propofol anesthesia (15) and during emergence from desflurane anesthesia (25). The Narcotrend index appeared to read larger at small propofol concentrations and smaller at larger propofol concentrations than the BIS. This phenomenon underlines that the parameterization of the raw EEG by Narcotrend index and BIS is different and that a simple 1:1 translation of the index values is obviously inadequate. Further investigations are needed to clarify the comparability of Narcotrend index and BIS values and to guide the clinician in interpreting various Narcotrend index values.

In summary, we were able to demonstrate a close quantitative correlation between Narcotrend index and predicted propofol effect compartment concentrations. In this study, the Narcotrend index detected differences in EEG dynamics in the observed concentration range as well as BIS. However, the small size of the study group and its narrow composition, as well as the particular design of the anesthetic, might limit the ability of these data to be extrapolated to other or larger populations.

	Acknowledgments

 
The authors gratefully acknowledge the substantial help of T. Anschütz, technician, Department of Anesthesiology and Intensive Care Medicine, University of Saarland, who developed the Access database used in this investigation.

	Footnotes

 
¹ Dyck JB, Varvel J, Hung O, Shafer SL. The pharmacodynamics of propofol versus age [abstract]. Can J Anaesth 1991;38:A-106.

² Schüttler J, Schwilden H, Stoeckel H. Pharmakokinetic-dynamic modeling of Diprivan [abstract]. Anesthesiology 1986;65:A-549.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999