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TECHNOLOGY, COMPUTING, AND SIMULATION

Comparative Evaluation of Narcotrend^TM, Bispectral Index^TM, and Classical Electroencephalographic Variables During Induction, Maintenance, and Emergence of a Propofol/Remifentanil Anesthesia

Department of Anesthesiology, University Hospital Eppendorf, Hamburg, Germany

Address correspondence and reprint requests to Gunter N. Schmidt, MD, Department of Anesthesiology, University Hospital Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Address e-mail to guschmid{at}uke.uni-hamburg.de

	Abstract

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In the present study, we sought to compare the abilities of Narcotrend^TM (NT) with the Bispectral Index^TM (BIS^TM) electroencephalographic system to monitor depth of consciousness immediately before induction of anesthesia until extubation during a standardized anesthetic. We investigated 26 patients undergoing laminectomy. Investigated states of anesthesia were: awake, loss of response, loss of eyelash reflex, steady-state anesthesia, first reaction, and extubation during emergence. NT, BIS^TM, spectral edge frequency, median frequency, relative power in , , , ß, and hemodynamics were recorded simultaneously. The ability of all variables to distinguish between awake versus loss of response, awake versus loss of eyelash reflex, awake versus steady-state anesthesia, steady-state anesthesia versus first reaction and extubation were analyzed with the prediction probability. Effects of remifentanil during propofol infusion were investigated with Friedman’s and post hoc with Wilcoxon’s test. Only NT and BIS^TM were able to distinguish all investigated states accurately with a prediction probability >0.95. After start of remifentanil infusion, only hemodynamics changed statistically significantly (P < 0.05). NT and BIS^TM are more reliable indicators for the assessment of anesthetic states than classical electroencephalographic variables and hemodynamics, whereas the analgesic potency of depth of anesthesia could not be detected by NT and BIS^TM.

IMPLICATIONS: The modern electroencephalographic monitoring systems Narcotrend^TM and Bispectral Index^TM are more reliable indicators for the assessment of anesthetic states than classical electroencephalographic and hemodynamic variables to predict anesthetic conditions from before induction of anesthesia until extubation during a standardized anesthetic regime with propofol and remifentanil. The analgesic potency of depth of anesthesia could not be detected by Narcotrend^TM and Bispectral Index^TM.

	Introduction

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The measurement of depth of anesthesia is an unsolved problem because there is not yet a clear definition of depth of anesthesia. In recent years, new monitor systems based on the electroencephalogram (EEG) were developed. The usefulness of these monitor systems is hard to quantify because a "gold standard" is not available. A depth-of-anesthesia monitor should separate different clinical end-points (states) of anesthesia, such as awake, loss of response, and first reaction during emergence. Therefore, not only should statistically significant differences be recommended, but values indicating different states should not overlap (1). Smith et al. (2) presented a statistical method, the prediction probability (P_K), to detect the accuracy of a variable to distinguish between two or more states of anesthesia. A P_K value of 0.5 means that the variable distinguishes between the two states by change (50:50). A P_K value of 1.0 indicates a variable distinguishes between the states correctly 100% of the time with no overlap.

Narcotrend^TM (NT) (MonitorTechnik, Bad Bramstedt, Germany), a new monitor displaying a derived EEG variable, automatically classifies the resting EEG into stages defined by Kugler (3) during the 1980s (4). "Narcotic stages" deescalate from the awake state (stage A) to isoelectric EEG using 14 distinct gradations (3). Adequate depth of anesthesia is indicated by D0, D1, D2, E0, E1, followed by F0 and F1 indicating burst suppression and isoelectric EEG, respectively. Decreasing NT stages during anesthesia were accompanied by decreasing Bispectral Index^TM (BIS^TM) (Aspect Medical Systems, Newton, MA) values (5). In a very recent study, we were able to demonstrate an advantage of NT over BIS^TM during emergence with a stepwise reduction of propofol without surgical stimulation (6). No other investigations of the ability of NT to predict anesthetic state during induction have been conducted. Moreover, no information about the effects of added remifentanil infusion on the NT is available.

The goal of the present study was to compare NT and BIS^TM with classical EEG variables and hemodynamics by analyzing the accuracy of each variable to distinguish between different clinically defined states of anesthesia such as awake, loss of response, loss of eyelash reflex, steady-state anesthesia, first reaction, and extubation during emergence. Our hypotheses are that there is no difference in performance between NT and BIS^TM in differentiation of anesthetic states, and both monitors would be better than classical power spectral EEG or hemodynamics. Moreover, the start of remifentanil infusion during anesthesia with propofol is without an effect on NT and BIS^TM.

	Methods

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After IRB approval and written informed consent, 26 elective patients were included in the study. Selection criteria were patients aged between 18 and 75 yr, ASA risk classification I–II, and laminectomy surgery. No patient with any medication interacting with the central nervous or cardiopulmonary system was included in the study to avoid influences on the EEG and the hemodynamics.

After premedication with 7.5 mg midazolam per os (30 min before induction), anesthesia was induced with 0.5 µg/mL target controlled infusion (TCI) (Diprifusor, Graseby 3500; Graseby Medical Ltd., Hertfordshire, Watford, UK) of propofol followed by a stepwise increase (0.5 µg/mL) until 3.5 µg/mL propofol was reached. After 5 min, 0.3 µg · kg^–1 · min^–1 remifentanil was added. Rocuronium bromide (0.6 mg/kg) was given to facilitate tracheal intubation 10 min after start of remifentanil infusion. Anesthesia was maintained with 3.0 µg/mL propofol and 0.3 µg · kg^–1 · min^–1 remifentanil. After the end of surgery, propofol and remifentanil infusions were stopped. Extubation criteria were sufficient spontaneous breathing and spontaneous eye opening.

Every minute during induction and emergence, the patients were tested in the same sequence: after test of eyelash reflex the patients were asked to squeeze the observer’s hand.

We defined 6 different anesthetic states: awake, loss of response to squeeze the observer’s hand, loss of eyelash reflex, steady-state anesthesia with 3.0 µg/mL propofol and 0.3 µg · kg^–1 · min^–1 remifentanil, first reaction, and extubation after stopping propofol/remifentanil infusion. Comparisons were performed for awake versus loss of response, awake versus loss of eyelash reflex, awake versus steady-state anesthesia, steady-state anesthesia versus first reaction, and steady-state anesthesia versus extubation.

EEG was registered by seven adhesive silver/silver chloride gel-filled electrocardiograph electrodes (Blue-Sensor; Medicotest, Olstykke, Denmark) on carefully prepared skin (Arbo-Prep; Tyco Healthcare, Neustadt, Germany). Electrode placement was performed according to the instructions of the manufacturers of BIS^TM (2 channel reference: At1-Fpz and At2-Fpz, ground Fp2) and NT (1 channel bipolar at the hairless skin of the forehead). Electrode impedance was kept below 5 k. BIS^TM (version 3.3), relative power in (%: 0.5–3.75 Hz), (%: 4.0–7.75 Hz), (%: 8.0–13.5 Hz), ß (%ß: 13.75–30.0 Hz), spectral edge frequency, and median frequency (MF) were recorded by using an A-1000 EEG monitor (Aspect Medical Systems). The signals were bandpass filtered between 0.5 and 30 Hz. Bispectral and spectral smoothing rates were 30 s. For artifact detection, "slow rate, suppression, motion, and height frequency" were enabled. NT stages (version 2.0 AF/F) were registered by using the NT EEG system. All data were stored on disk.

Heart rate (HR), noninvasive mean arterial blood pressure (MAP), and oxygen saturation were measured and registered at every point of measurement (Solar 8000; Marquette Hellige Medical Systems, Milwaukee, WI). End-expiratory CO₂ concentrations were maintained between 35–40 mm Hg during the whole observation time.

For all variables, the 95%, 90%, 75%, 50%, 25%, 10%, and 5% percentiles were calculated for the investigated states. The accuracy to distinguish between the anesthetic states: awake versus loss of response, awake versus loss of eyelash reflex, awake versus steady-state anesthesia, steady-state anesthesia versus first reaction, and steady-state anesthesia versus extubation were analyzed with the P_K. P_K was calculated for all variables using the P_KMACRO as described by Smith et al. (2). The jackknife method was used to compute the standard error of the estimate (SE). A value of P_K = 0.5 means that the variable predicts the states not better than a 50:50 chance. A value of P_K = 1.0 means that the variable predicts the states correctly 100% of the time. A value < 0.5 means that discordance is more likely than concordance. To enable comparison of P_K, we used 1 – P_K when the P_K value was <0.5 (2). To evaluated the accuracy to distinguish all investigated conditions (P_{K all}) we calculated:

P_{K all} = P_Kawake versus loss of response x P_K awake versus loss of eyelash reflex x P_K awake versus steady-state anesthesia x P_K steady-state anesthesia versus first reaction x P_K steady-state anesthesia versus extubation

A variable that distinguishes all conditions perfectly with a P_K = 1.0 results in P_{K all} = 1.0 x 1.0 x 1.0 x 1.0 x 1.0 = 1.0, a variable which predicts all conditions with P_K = 0.5 results in P_{K all} = 0.5 x 0.5 x 0.5 x 0.5 x 0.5 = 0.03125. Changes of all variables after start of remifentanil infusion were tested with the Friedman test for repeated measurements. In case of significant "overall" effects, changes were evaluated in detail a posteriori by Wilcoxon’s test. Bonferroni’s correction was performed to account for multiple testing. Statistical analyses were performed using the SPSS version 9 package (SPSS, Chicago, IL) and P_KMACRO (2).

	Results

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Data evaluation was performed in 26 patients (6 women, 20 men, aged 48 ± 10 [SD] yr, weight 83 ± 16 [SD] kg, height 177 ± 9 [SD] cm; Table 1) with almost-artifact-free signal registration. Length of surgery was 93 ± 37 (SD) (Table 1) min without unusual perturbations, such as blood loss or hypothermia. Patients were extubated tracheally at a propofol TCI of 1.3 ± 0.2 (SD) µg/mL without any complications.

View larger version (35K): [in this window] [in a new window]   Figure 1. NarcotrendTM and Bispectral IndexTM (BISTM) during the induction and emergence of propofol/remifentanil anesthesia. Example of a 54-yr-old man (number 11) before (A) and after (B) discectomy. NarcotrendTM (gray line) and BISTM (black line) changes before, during, and after infusion of propofol (gray boxes at the bottom) and remifentanil (black boxes at the bottom). Gray arrows mark the investigated conditions awake (1), loss of response (2), loss of eyelash reflex (3), steady-state anesthesia (4), first response (5), and extubation (6).

View larger version (23K): [in this window] [in a new window]   Figure 2. Electroencephalograph and hemodynamics during investigated anesthetic states. Mean arterial blood pressure (MAP), heart rate (HR), NarcotrendTM, Bispectral IndexTM (BISTM), spectral edge frequency (SEF), median frequency (MF), relative (%) power in , , , and ß during the investigated states: awake, loss of response, loss of eyelash reflex, steady-state anesthesia, first reaction, and extubation. To demonstrate the scatter of the data, 95%, 90%, 75%, 50%, 25%, 10% and 5% percentiles are represented.

View larger version (38K): [in this window] [in a new window]   Figure 3. Prediction probability (PK) for the comparison of the investigated states. PK value of 1.0 means that the variable predicts the states correctly 100% of the time. PK of 0.5 means that the variable predicts not better than a 50:50 chance. Shown are results for the calculation of PK all = PKawake versus loss of response x PK awake versus loss of eyelash reflex x PK awake versus steady-state anesthesia x PK steady-state anesthesia versus first reaction x PK steady-state anesthesia versus extubation for mean arterial blood pressure (MAP), heart rate (HR), NarcotrendTM, Bispectral IndexTM (BISTM), spectral edge frequency (SEF), median frequency (MF), and relative (%) power in , , , and ß (gray boxes). The results for a variable that distinguishes all conditions with PK all = 0.5 · 0.5 · 0.5 · 0.5 · 0.5 = 0.55 = 0.03125, PK all = 0.65 = 0.07776, PK all = 0.75 = 0.16807, PK all = 0.85 = 0.32768, PK all = 0.95 = 0.59049, PK all = 1.05 = 1 are plotted on the right (white boxes).

View larger version (35K): [in this window] [in a new window]   Figure 4. Remifentanil effects. Mean arterial blood pressure (MAP), heart rate (HR), NarcotrendTM, Bispectral IndexTM (BISTM), spectral edge frequency (SEF), median frequency (MF), relative (%) power in , , , and ß during infusion of 3.5 µg/mL propofol (BL), and their changes 1, 2, 3, 4, 5, 7, 8, and 10 min after start of remifentanil 0.3 µg · kg–1 · min–1. To demonstrate the scatter of the data 95%, 90%, 75%, 50%, 25%, 10%, and 5% percentiles are represented. *Significant changes from BL (Bonferroni corrected; P < 0.05).

	Discussion

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The measurement of depth of anesthesia is still an unsolved problem because there is no definition of what "depth of anesthesia" means exactly. However, a depth-of-anesthesia monitor would be of enormous clinical interest to increase patient safety and to reduce costs by avoiding drug overdosing. At present, there is no "gold standard" for the measurement of depth of anesthesia. The present study was performed using a propofol and remifentanil regime often used in our hospital. We defined six states from awake through extubation. Steady-state anesthesia was a drug-dosing, regime-dependent state, and it is well known that sensitivity to anesthetics is associated with interindividual variations (7). By determining loss of response, loss of eyelash reflex, first reaction, and the state extubation, we also investigated individual anesthetic states.

Data for NT in the literature are rare (5,6,8–10). In a very recent study, we could demonstrate the possibility of NT to distinguish different states during maintenance and emergence of propofol/remifentanil anesthesia, accurately. However, there is no other investigation evaluating the ability of the NT system to predict anesthetic states during induction of anesthesia. In the present study, NT was able to distinguish all states of anesthesia investigated from induction through extubation accurately.

The BIS^TM is the most evaluated variable derived from the spontaneous EEG, but its status as a depth-of-anesthesia monitor is still controversial (1). In a very recent study, we emphasized the potency of BIS^TM to distinguish between patients who were awake and those who were anesthetized with propofol and remifentanil. For the 25 investigated patients, no overlap in the data was found between the awake and anesthetized state (9). During emergence, BIS^TM was not able to distinguish the first reaction during conditions without any external stimulation from the anesthetized state. We hypothesized that this was attributed to the well known 60-second delay of BIS^TM. Interestingly, in the present study, BIS^TM was able to distinguish between all investigated conditions, including steady-state anesthesia versus first reaction, accurately. The reason for the better differentiation in the present study may be attributed to stimuli during the emergence period (repetitive commands to squeeze the observer’s hand). The method used in the present study to record all variables every minute is limited by the delay of the investigated variables. Further studies should be designed to clarify this issue. However, we were not able to use the newest version of BIS (version 3.3 instead of version 4.0) in the present study which may have restricted our results. We used the Aspect A-1000 monitor because it allowed for the possibility of calculating the classical EEG variables.

The present study confirms the limitations of EEG variables to represent the analgesic potency of remifentanil during propofol infusion. These findings are in accordance with the study of Guignard et al. (11) who demonstrated unchanged BIS^TM values during TCI propofol of 4.0 µg/mL combined with 0, 2, 4, 8, and 16 ng/mL remifentanil plasma concentrations. However, quantitative BIS^TM responses to noxious stimuli (laryngoscopy and intubation) were attenuated in relation to increasing remifentanil applications. These findings indicate that BIS^TM is not a reliable indicator for quantitatively predicting responses to painful events, even when BIS^TM changes are related to analgesic components. To explain the unsatisfying indication of the analgesic power by the BIS^TM, Guignard et al. (11) hypothesized that these components are mediated in subcortical brain structures and at the level of the spinal cord that cannot be detected by EEG registration from the surface of the scalp. In a recent study (9), we demonstrated that the BIS^TM and NT were unaffected by decreasing remifentanil concentrations during 3.0 µg/mL TCI of propofol, whereas classical EEG variables have shown statistically significant effects. In the present study, we investigated increasing concentrations of remifentanil during 3.0 µg/mL TCI of propofol. Also, increases in % and decreases in median frequency and % were observed. These findings were not statistically significant. This may be attributable to the larger concentrations of propofol, resulting in deeper NT stages and BIS^TM values. Besides a pronounced analgesic effect, all opioids also provide dosage-related sedative effects. Without propofol, remifentanil infusion resulted in high-amplitude EEG slowing and waves (12). This might be why, during smaller plasma concentrations of propofol (2 µg/mL), increasing remifentanil dosages (0.01–0.1 µg · kg^–1 · min^–1) correlate with decreasing BIS^TM values (13). NT and BIS^TM responses to remifentanil might not be simply dosage related. Moreover, NT and BIS^TM responses also depend on the existence of the hypnotic power from propofol, quantitatively. After propofol infusion resulting in unconsciousness, remifentanil infusion probably does not alter NT and BIS^TM signal analyzing.

In the present study, we used the P_KMACRO to estimate the P_K and SE based on the given data of the 26 patients. It should be mentioned that these estimates are not the true values of P_K and SE, but the estimates can be used for statistical hypothesis testing (2). For example, the estimates of P_K = 1.0 for awake versus steady-state anesthesia in the present study for BIS^TM and NT may very well be estimates of P_K < 1.0 when more patients are investigated.

Both NT and BIS^TM seemed to be reliable monitor systems to reflect the status of a propofol/remifentanil anesthesia, but NT and BIS^TM seemed not to be reliable depth-of-anesthesia monitors, because the analgesic power of anesthesia was not reflected.

	References

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