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Anesth Analg 2006;103:902-907 © 2006 International Anesthesia Research Society doi: 10.1213/01.ane.0000237282.76394.6b
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Abstract |
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There is a debate regarding whether opioids, as a component of general anesthesia, are adequately reflected in the assessment of anesthesia based on derivatives of the electroencephalogram. To test the hypothesis of a possible quantitative contribution of remifentanil on middle latency auditory evoked potentials, we studied its interaction with propofol anesthesia in 45 unpremedicated male patients undergoing elective lower limb orthopedic surgery. They were allocated randomly to three groups. The first two groups received remifentanil either with a high (8 ng mL–1) or a low (3 ng mL–1 target concentration using target-controlled infusion (TCI). The third group received spinal anesthesia instead of remifentanil. Anesthesia was induced by a stepwise increase in propofol concentration using TCI. The auditory evoked potential index (AEPex) and calculated propofol effect site concentrations were determined at loss of consciousness and the reaction to laryngeal mask airway insertion was noted. The propofol infusion was then converted to a closed-loop TCI using an AEPex value of 40 as the target. We found no significant contribution of remifentanil alone on the auditory evoked response, whereas increasing concentrations of remifentanil led to a significant decrease of the calculated propofol effect site concentrations (P = 0.023) necessary for unconsciousness. Prediction probability for AEPex was inversely related to the remifentanil concentration and was best for the control group, which received propofol alone. These results support previous findings of a quantitative interaction between remifentanil and propofol for loss of consciousness but question the specific contribution of remifentanil to auditory evoked potentials.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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A well-known advantage of combining an opioid and a general anesthetic over the use of single drugs is the synergistic increase in effect or providing the same effect with a reduced concentration of either drug. Opioids reduce the amount of propofol required for surgical anesthesia (1,2) and remifentanil reduces the MAC of isoflurane in a dose-dependent manner, similar to other µ agonists (3). These studies were based on movement response to noxious stimulation to assess the type of interaction of various clinical end points.
Middle latency auditory evoked potentials (MLAEP) and their derivatives are increasingly used as a surrogate measure of the level of anesthesia (4). In particular, auditory evoked potentials (AEP) have been shown to provide good discrimination of the transition from asleep to awake and vice versa during propofol anesthesia (5). However, the effect of opioids in general and remifentanil, in particular, on the auditory evoked response (AER) in the context of surgical anesthesia remains controversial.
AEP have been introduced as an input signal for closed-loop propofol anesthesia (6). Using this system, which is able to obtain an unbiased indicator of propofol requirements, we tested the hypothesis of a possible dose-dependent interaction of remifentanil with propofol on the AER during induction and maintenance of anesthesia.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Patients
After obtaining University Hospital Ethics Committee approval and written, informed consent, we prospectively studied 45 unpremedicated patients scheduled for lower limb orthopedic surgery under general anesthesia. They were randomly allocated to three groups of 15 patients each: A large-dose remifentanil group (Group 1) with remifentanil given to a target blood concentration of 8 ng mL–1, a small-dose remifentanil group (Group 2) with remifentanil given to a target blood concentration of 3 ng mL–1, and a control group, which instead of remifentanil received spinal anesthesia as the analgesic component (Group 3). Patients with impaired renal or hepatic function, reduced hearing threshold, or a known history of chronic drug or alcohol abuse were excluded, as well as those who were obese (body mass index > 30 kg m–2).
Remifentanil
Remifentanil was administered by a target-controlled infusion (TCI) device to rapidly achieve, and then maintain, the predefined blood concentrations. This infusion device is based on a prototype "Diprifusor" system used in previous studies (7). Incorporating the pharmacokinetic data set for remifentanil published by Minto et al. (8) the "Diprifusor" system was modified to a "Remifusor" and used to administer a remifentanil solution with a concentration of 20 µg mL–1. Remifentanil TCI is a validated technique (9) and is licensed for clinical use in Europe (GlaxoSmithKline, Uxbridge, UK). All patients received propofol by TCI once the remifentanil blood concentration was in equilibrium with the calculated effect site concentration (Ceffect) after 8 min. In the control group, spinal anesthesia was established with 3.0–3.5 mL of 0.5% plain bupivacaine administered via a 26-G needle at the L2/3 interspace and the adequacy and level of the local block was ensured before propofol was infused.
Closed-Loop System
Propofol was administered by a closed-loop system (CLAN) based on AEP to ensure an unbiased level of anesthesia in all three groups. The electroencephalogram (EEG) of the AER was obtained from three disposable silver-silver chloride electrodes (Ziprep, Aspect Medical Systems, Natick, MA) placed on the right mastoid (+), middle forehead (–), and Fp2 as reference. The custom-built amplifier had a 5-kV medical grade isolation, common mode rejection ratio of 170 dB with balanced source impedance, input voltage-noise of 0.3 µV, and current input noise of 4 pA (0.05 Hz-1 kHz rms). A third-order Butterworth analog band-pass filter with a bandwidth of 1–220 Hz was used. The auditory clicks were of 1 ms duration and 70 dB more than hearing threshold. They were presented to both ears at a rate of 6.9 Hz. The amplified EEG was sampled at a frequency of 1778 Hz by a high accuracy, low distortion 12-bit analog to digital converter (PCM-DAS08, Computer Boards, Mansfield, MA) and processed in real time on a microcomputer (Tecra 700 CDT, Toshiba, Tokyo, Japan). AEP were generated by averaging 256 sweeps of 144 ms duration. The time required to update a full signal was 36.9 s, but a moving time average technique allowed a faster response time to any change in the signal every 3 s. The AEP index (AEPex), which reflects the morphology of the AEP waveform, is a mathematical derivative and is calculated as the sum of the square root of the absolute difference between every two successive 0.56-ms segments (10). The 3-s average of the AEPex was entered into a proportional integral (PI) control algorithm. The algorithm calculated the required alteration in the target blood concentration of propofol from the difference between the measured AEPex and the control value of the AEPex. The new value for the target propofol concentration was transmitted to the TCI system, which used a pharmacokinetic model to achieve and maintain the required target concentration set by the PI control algorithm.
Induction and Maintenance
The value for the AEPex was recorded in the awake patient and the anticipated AEPex to control satisfactory anesthesia was entered into the CLAN system. This target was set to be 40, a value that has been proven to guarantee satisfactory anesthesia in a previous study (11). Anesthesia was induced by setting the propofol target concentration to 4 µg mL–1 and increased by 0.5 µg mL–1 every 30 s until loss of consciousness (LOC). Thus during induction, the propofol TCI infusion systems was started manually and operated individually until the target AEPex value of 40 was achieved and maintained for at least 60 s. The CLAN system was then started and controlled the administration of propofol to maintain an AEPex of 40 ± 10% in all patients. Thereafter, control of anesthesia was achieved by transmitting the target blood propofol concentration calculated by the PI algorithm to the infusion system and maintaining the measured AEPex close to the selected value of 40. During the induction sequence, the presence or absence of an eyelash reflex and the patient's response to a verbal command to squeeze the investigator's hand were recorded. LOC was defined clinically as the point at which there was no response to verbal command and absence of an eyelash reflex. The anesthesiologist was blinded to both the remifentanil target concentration and the obtained EEG signals. A laryngeal mask was inserted and pressure-controlled ventilation (Pmax = 15 mm Hg) with 30% oxygen in air was adjusted to keep end-tidal CO2 between 35–45 mm Hg. Respiratory and cardiovascular monitoring was performed according to the institution's standard practice and consisted of continuous ECG, noninvasive oscillometric arterial blood pressure monitoring, pulse oxymetry, and end-tidal CO2. The core temperature was kept greater than 35.5°C using warming devices. No neuromuscular blocking drugs were given.
Study End Points
During the experiment, the AEPex, calculated remifentanil and propofol Ceffect, and the presence or absence of voluntary movements were obtained at the following measurement points: (MP 1) baseline values in the awake patient, before starting the remifentanil infusion; (MP 2) at the beginning of the propofol infusion, i.e., after equilibration of remifentanil with the Ceffect; (MP 3) at LOC; (MP 4) during the insertion of the laryngeal mask; and (MP 5) 2 min after insertion of the laryngeal mask. These time points were compared with the values obtained 2 min after skin incision (MP 6) when anesthesia was controlled by the CLAN system in maintenance mode. In summary, the protocol started in open-loop for induction and was converted into closed-loop feedback control for maintenance. The detailed study plan is expressed in Figure 1.
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Statistical Analysis
Descriptive data are presented as means (±sd) and in the case of skewed data (visual examination) median values with interquartile range, which are graphically expressed in box-whiskers plots. Power analysis to estimate sample size was performed prospectively to detect a difference in calculated propofol Ceffect of at least 0.5 µg mL–1 with a power of 0.8. The ability of AEPex to correctly predict the transition from consciousness to unconsciousness was calculated using the prediction probability (Pk). Pk was calculated using the PKMACRO as described by Smith et al. (12), for assessing prediction accuracy when indicator value and patient state are polytomous ordinal, and both variables are measured experimentally. As a nonparametric measure, Pk is independent of scale units and does not require knowledge of underlying distributions or efforts to linearize or to otherwise transform scales. Prediction probability has a value of one when the indicator perfectly predicts observed anesthetic depth, and a value of 0.5 when the indicator predicts no better than a 50:50 chance. The jackknife method was used to compute the standard error of the estimate. Comparison of the Pk values was performed with the PKDMACRO (12). The AEPex threshold used to calculate sensitivity of movement response was a change of more than 10 on the AEPex scale compared to the prestimulation value.
Statistical assessment for between-group differences was calculated with Mann–Whitney U-test and the Kruskall–Wallis test, respectively. Analysis of variance (ANOVA) was calculated to detect within-group differences across subsequent time points with a Bonferroni-Holm correction for repeated measures. Probability values <0.05% were considered statistically significant. Calculations were performed with SPSS® v.8.0 (SPSS Science, Chicago, IL) and STATISTICA v.5.5a (StatSoft, Tulsa, OK).
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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All 45 patients were successfully studied. Biometric data of the study population are summarized in Table 1. The mean values for weight and, consequently, for body mass index and lean body mass were slightly lower in Group 1. However, the pharmacokinetic data set for remifentanil used in this study compensates for total body weight and related differences (13).
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We observed only a minor direct contribution of remifentanil to the depression of AER (Fig. 2), which was not shown to be significant. After equilibration of remifentanil with its Ceffect, the AEPex was not statistically different from either the preinduction values or from the control group (spinal group). Subsequently, after propofol anesthesia was commenced, there was a significant decrease in AEPex values when patients lost consciousness in the spinal group (P = 0.038), whereas in the low remifentanil group the decrease was less pronounced, and in the high remifentanil group only slightly less compared with the preinduction value. A similar disparity in AEPex between the groups receiving remifentanil and the spinal group was observed at the time of laryngeal mask insertion. A consistent feature for both these end points is the large spread of individual AEPex values, especially in the high remifentanil group, compared with propofol alone (control group).
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During the induction phase, the calculated propofol Ceffect for LOC decreased significantly (P = 0.023) with increasing remifentanil concentrations, whereas the respective AEPex values increased (P = 0.036) (Fig. 3). Accordingly, prediction probability Pk for AEPex was inversely related to the remifentanil concentration and best for the control group, which received propofol alone (Table 2). The stimulus of the laryngeal mask insertion led to a marked increase in AEPex in 8 of 15 patients in the spinal group with a magnitude of 17%–65% compared to preinduction values, whereas in the remifentanil groups fewer patients responded with less pronounced AEPex increases. The sensitivity and specificity of a 10-point increase in AEPex to predict movement of a patient was higher in the spinal group receiving propofol only, compared to the low and high remifentanil groups, where sensitivity, expressed as the correct identification of movers by an increase on AEPex, was lower (Table 3). Calculated propofol Ceffect had no predictive value for movement response.
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Subsequently, during the maintenance phase, there was no difference of mean AEPex values after skin incision, as a result of the CLAN system automatically adjusting propofol administration to maintain the target AEPex value in all groups. The mean propofol Ceffect in the control group (Group 3) was 4.2 µg mL–1 (95% CI 3.1–4.8) and thus slightly higher compared with 2.7 µg mL–1 (95% CI 1.9–4.1) in Group 1, and 2.8 µg mL–1 (95% CI 2.0–3.9) in Group 2, respectively, both receiving remifentanil.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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General anesthesia is understood as a balance of hypnosis produced by general anesthetics such as propofol on the cortical level, and analgesia mediated by opioids on a lower brainstem or spinal level. Propofol suppresses consciousness, memory formation, and learning, whereas opioid analgesics diminish the spinothalamic input of noxious stimuli (14). Contemporary approaches to monitor the cerebral effects of anesthesia and stimulation are predominantly based on derived parameters of the EEG. However, the dose-dependent interaction between hypnotics and analgesics is not well described in the EEG (15) and, thus, there is still a lack of a calibrated measure of combined drug effects.
In the present study we used MLAEP, which represent a functional EEG with similar pattern response to different anesthetics (16) and, expressed as an AEPex, are able to discriminate between the anesthetized and the awake state in the presence (17) and absence (11) of surgical stimulation. The latter study found 100% specificity for AEPex values of 37 for being unconscious and 61 for being awake, whereas threshold AEPex values of 45 still had 85% sensitivity and 87% specificity, respectively.
We found no relevant contribution of remifentanil to MLAEP in the awake patient, nor did remifentanil alone lead to a significant degree of sedation, whereas a few patients required verbal prompting to breathe as a sign of increased drug effect. Furthermore, the decrease of AEPex values after propofol was added and after patients subsequently lost consciousness, was less pronounced in patients receiving remifentanil compared with propofol alone. This is in contrast to the conclusion drawn from a study by Crabb et al. (18) in which they observed a significant and dose-related effect of remifentanil on the Pa and Nb amplitude of the AER during isoflurane anesthesia. However, the patients who actually showed a relevant reduction in amplitudes in this study received remifentanil in concentrations up to 25 ng mL–1, which is three times the concentration given to our "high" group (8 ng mL–1). In a subsequent experiment, the authors could not find any effect of remifentanil on the Pa and Nb amplitudes or latencies in the absence of stimulation (19). This study was designed to clarify whether the changes in MLAEP in response to remifentanil are due to a direct depressant effect of opioids on the AER itself, or an indirect effect on suppression of arousal associated with noxious stimulation. In this respect, their findings were comparable with our results.
However, the interaction with a hypnotic adds more complexity. Whereas a reduction in propofol requirements in the presence of increasing remifentanil concentrations could be expected and explained by supra-additivity found in previous interaction studies (1–3), the finding that the relative decrease of AEPex was significantly less with remifentanil in increasing concentrations requires further discussion. If we assume that the MLAEP represents a graded measure of sedation and unconsciousness, it will, in the absence of any nociceptive input, predominantly correlate with sedative and hypnotic drugs. It has been shown, by Iselin-Chaves et al. (20) in a volunteer study, that MLAEP changes correlate well with increasing sedation produced by propofol, and that these changes are independent of the presence of alfentanil. In this study, Pa and Nb latencies were identified as the best predictors of LOC. Although the addition of alfentanil decreased the Cp 50 for LOC, it did not significantly affect the MLAEP wave amplitudes and latencies 50 for the same end point.
These findings are also supported in a study by Tooley et al. (21). They found that adding alfentanil reduced the propofol infusion rate to produce unconsciousness, but did not influence the MLAEP (Nb latency) itself. Similar results using the EEG bispectral index were found by Lysakowski et al. (22) in a study determining the effect of propofol in the presence of fentanyl, alfentanil, remifentanil, and sufentanil given by TCI (22). However, there are well-known differences between AEPex and bispectral index that preclude a direct comparison.
In contrast to these studies, our results, though similar in essence, were obtained in an unbiased protocol, minimizing operator-related influence. Furthermore, the experimental design allowed us to study both the phases of dynamic nonequilibrium during induction and of equilibrated steady state during maintenance in the same patients. It also facilitates comparing and assessing the interaction pattern and its combined effect on the surrogate marker of depth of anesthesia, both in the absence and presence of surgical stimulation.
On the other hand, we have to consider some limitations of our study. The induction of general anesthesia is dynamic. Thus, the observed clinical end points are in a continuum and therefore may be less distinctive in a clinical population. We studied nonequilibrium conditions during early induction, which gradually converted into equilibrium later in the maintenance period. Using TCI in plasma control, the initial divergence between plasma and Ceffect can be significant. In particular, the closed-loop system itself, which administered propofol on the basis of AEPex by a PI algorithm, could have influenced the results, especially in the later period of induction, as the stepwise increase in propofol blood concentration and its feedback circle to be updated to a new target concentration may have lagged behind the actual AEPex value and the respective Ceffect (23). This could have led to a situation where a patient was already adequately anesthetized, as indicated by the current AEPex value, while its propofol Ceffect was still increasing. Insufficient synchronization may be seen as another design problem of our study. The time required to reach a full update of the AEP signal is 36.9 s, slightly longer than our induction sequence to ramp up propofol every 30 s. To make this less relevant, we used a moving-time average technique, which allowed a faster response time to any change in the signal. As the AEPex was calculated on the basis of a 3-s interval update of the AEP, any change in clinical situation during this short time may have been underestimated by the respective AEPex value. However, both the equilibration and synchronization problems may be considered less relevant in the light of multiple measurements and during different levels of stimulation.
In conclusion, we have demonstrated that remifentanil shows no significant direct contribution to the suppression of the AER during induction of propofol anesthesia. Furthermore, it is likely that a large-dose remifentanil technique may lead to situations where the clinical impression about the underlying depth of anesthesia is ambiguous and not very well reflected by a surrogate marker of anesthetic depth, such as the AER.
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Footnotes |
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Accepted for publication June 20, 2006.
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REFERENCES |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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[Abstract/Free Full Text] - Wright DR, Thornton C, Hasan K, et al. The effect of remifentanil on the middle latency evoked response and haemodynamic measurements with and without the stimulus of orotracheal intubation. Eur J Anaesthesiol 2004;21:509–16.[Web of Science][Medline]
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