Department of Anaesthesiology, Charité Campus Mitte, Schumannstraße 20/21, D-10098 Berlin, Germany
* Corresponding author. E-mail: jan.baars{at}charite.de
Accepted for publication July 8, 2005.
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Abstract |
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Methods. In 28 patients, F-waves were recorded during sevoflurane anaesthesia at a frequency of 0.2 Hz at the lower limb. To insert a laryngeal mask, the sevoflurane concentration was initially increased to 4%, which caused a complete extinction of F-waves. The sevoflurane concentration was then reduced until the F-waves recovered. BIS and spectral edge frequency (SEF95) were recorded continuously. The t1/2ke0 and EC50 values of the F-wave persistence and amplitude were calculated using a standard pharmacokineticpharmacodynamic model. During decreasing sevoflurane concentration motor responses to tetanic electrical stimulation (50 Hz, 60 mA, 5 s, volar forearm) were tested in seven patients and MACtetanus was calculated using logistic regression.
Results. Sevoflurane reduces the F-wave amplitude with an EC50 of 0.79 vol% at a far lower concentration than the calculated MACtetanus (1.5 vol%), whereas the F-wave persistence yields an EC50 of 1.4 vol%. Spinal and EEG parameters predicted the motor responses to movement better than chance alone, but did not differ significantly from each other.
Conclusion. F-waves, especially the F-wave amplitude, cannot be used to predict movement to noxious stimuli during sevoflurane anaesthesia because they are almost completely suppressed at subclinical sevoflurane concentrations. Either the particular motoneurone pool (the largest motoneurones) assessed by F-waves is not involved in generating movement to painful stimuli or direct effects on motoneurone excitability are not involved in the suppression of movement to painful stimuli by sevoflurane.
Keywords: anaesthesia, depth, monitoring ; anaesthetics, volatile ; measurement techniques, electrophysiology ; pain ; pharmacokinetics, sevoflurane ; spinal cord, reflexes
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Introduction |
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In this study, we examined the influence of sevoflurane on F-waves and hypothesized that they are also a suitable predictor for movement under anaesthesia. F-waves are low-amplitude motor responses to supramaximal nerve stimulation, and are widely used for diagnostic purposes in neurology (see recent reviews5 6). The neurophysiological mechanism underlying the production of F-wave responses is antidromic activation of the peripheral motor fibres resulting in recurrent discharges (backfiring) of motoneurones. F-waves are a sensitive indicator of changes in motoneurone excitability.7
Inhalation anaesthetics generally depress F-waves. Animal studies using a goat model which permitted isolated administration of isoflurane to the brain and the spinal cord suggest that this effect is mainly caused by direct spinal action but that there may also be additional supraspinal effects.8 Correlation of F-wave persistence and motor responses with electrical stimulation has been reported in humans.9 In this study we used pharmacokineticpharmacodynamic (PKPD) modelling to quantify the relationship between sevoflurane concentration and F-wave amplitude and persistence. To serve as a predictor of movement to noxious stimulation, the suppression of F-waves and suppression of movement to noxious stimulation would have to occur in the same concentration range. A comparison of the pharmacodynamic and pharmacokinetic parameters may also help to evaluate how much of the suppressive effect is directly spinal and how much occurs secondary to cerebral (sedative) effects, which can be traced by processed EEG parameters. In particular, different values of the equilibration half-times would be an argument for different and independent sites for the two effects.
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Material and methods |
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Study design
Patients fasted for at least 6 h before the study. Eighteen patients received oral midazolam 0.1 mg kg1 as premedication 30 min before the study period. The other 10 patients received no premedication. After arrival in the operation room, standard monitoring (non-invasive blood pressure monitoring, electrocardiography and pulse oximetry) and intravenous access via a forearm vein were established. Thereafter baseline recordings of F-waves (Fig.1) and EEG variables were obtained for 10 min before induction of anaesthesia. Patients were instructed to keep their eyes closed and refrain from talking and moving during this period.
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In seven patients, the response to a noxious electrical stimulus was investigated before a neuromuscular blocking drug was administered. In these patients an electrical stimulus (50 Hz, 60 mA, 5 s, 0.2 ms square-wave tetanic stimulus) from a peripheral nerve stimulator (Fischer and Paykel, Auckland, New Zealand) was applied to surface electrodes placed on the volar surface of the forearm during the period of decreasing end-tidal sevoflurane concentrations. The stimulation was performed at 3-min intervals until a gross purposeful movement of the head or extremities (excluding the stimulated arm) was observed.
Neurophysiological data acquisition
The F-wave was evoked and recorded using a Neuropack 4 Mini machine (Nihon Kohden, Tokyo, Japan). Stimulation electrodes were placed 2 cm apart over the posterior tibial nerve at the ankle and recording electrodes were positioned 3 cm apart over the abductor pollicis muscle. All electrodes (including EEG) were adhesive Ag/AgCl electrodes (Medicotest blue point, Istykke, Denmark). Stimuli were applied continuously throughout the study with a frequency of 0.2 Hz and duration of 0.1 ms. The stimulus intensity (mean electric current 26.1 (SD 5.9) mA) was adjusted prior to anaesthesia to achieve maximal F-wave amplitude within the limits of comfort for the patient. It was then kept constant over the entire study period. It is known that, despite constant stimuli, the amplitude of the resulting F-waves varies by >70% from stimulus to stimulus (Fig 1A). Electromyography (EMG) data of 100-ms duration recorded over the abductor pollicis after each stimulus were filtered (filter settings: 3 kHz low-pass filter, 20 Hz high-pass filter) and then digitized at a sampling rate of 5 kHz (DAQ-Card 516, National Instruments, Austin, TX, USA). The digitized waveform of the F-wave was analysed and stored on a computer. Data acquisition and analysis were performed automatically by a DasyLabprogram (DATALOG GmbH, Mönchengladbach, Germany). F-wave persistence, i.e. the number of measurable F-waves divided by the number of stimuli, was determined offline from a series of nine successive stimuli (45 s), yielding 10 discrete steps. F-wave persistence is also a measure of excitability in the neuronal pool examined. Although it also varies between different muscles, nerves and subjects, F-wave persistence remains more stable over time than the F-wave amplitude. The F-wave persistence in the upper limb varies from 60% to 100%, but nearly 100% persistence is found in the tibial nerve, which was stimulated in this study. To distinguish F-waves from background noise the recorded EMG signal was reviewed visually; only appropriately timed deflections, which clearly contrasted with the baseline noise, were accepted as F-waves. Depending on the individual background noise level, the smallest accepted F-wave amplitude varied between 30 and 50 µV.
The EEG was recorded in a bifrontal montage (Fpz-A1 and Fpz-A2) using an A-1000 EEG monitor (Aspect Medical Systems, Natick, MA, USA). Filter settings were 0.25 and 70 Hz, and both Bispectral IndexTM (BISTM) and spectral edge smoothing rates were set to 30 s. Electrode impedances were checked and kept below 5 k. Processed EEG data were recorded via a serial communication protocol. BIS (version B31v02) was used for further analysis. Data from time periods where burst suppression occurred (burst suppression index >0) were discarded.
Pharmacodynamicpharmacokinetic analysis
Individual concentrationresponse functions were fitted to the data and the calculated plasma concentrations using a spreadsheet program (Excel, Microsoft, Redmond, WA, USA) and a simple sigmoidal PKPD model:
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The fitted parameters of the different electrophysiological measures were compared using one-way analysis of variance (ANOVA) with Tukey's multiple comparison post hoc test or KruskalWallis statistics with Dunn's multicomparison test (Prism 3.0, GraphPad Software, San Diego, CA, USA). Statistical significance was assumed if P<0.05. Results in the text are presented as mean (SD) unless stated otherwise. To estimate the influence of premedication on the different fitted parameters (E0, EC50, t1/2ke0), the values of the two groups (premedication vs no premedication) were compared using Student's t-test (Excel, Microsoft).
Movement response to noxious stimuli
The relation between end-tidal concentration and the movement response to noxious electrical stimulation was described by the logistic regression model developed by Waud.10 This method allows a direct comparison with other concentrationresponse functions. In addition, the population pharmacodynamic analysis published by Bailey and Gregg11 was used. To estimate and compare the predictive value of the different variables, we calculated the prediction probability Pk) introduced by Smith and colleagues.12 Pk is a non-parametric correlation measure which indicates the probability that a variable correctly predicts anaesthetic depth, in this case a movement response. A Pk value of 1.0 indicates perfect prediction, whereas a value of 0.5 indicates that the predictive value of the variable is no better than chance alone. The calculation of Pk was based on values of each variable that were averaged over 1 min prior to the noxious electrical stimulation.
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Results |
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Pharmacodynamicpharmacokinetic analysis
The average F-wave amplitude before induction of anaesthesia was 358 (149) µV (range 98578 µV). These values correspond to the E0 values in the PKPD analysis. The increase in sevoflurane concentration during induction of anaesthesia caused a clear reduction of the F-wave amplitude and persistence (Fig. 1). When the sevoflurane concentration was decreased, the F-waves recovered. The chosen sigmoidal model could adequately describe this concentration-dependent suppression of the F-wave amplitude and persistence with median (IQR) r2 values of 0.73 (0.660.83) and 0.81 (0.760.89), respectively. For comparison, the median r2 value of the BIS was 0.88 (0.750.93).
The individual hysteresis loops derived from the raw data of the different variables for all patients are presented in Figure 2. The hysteresis loops also demonstrate the high stimulus-to-stimulus variability of the F-wave amplitude and to a lesser extent of the F-wave persistence, which is inherent in the data.
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Effects of tetanic stimulation on the F-wave
The noxious electrical stimulation at the wrist led to an increase in F-wave amplitude in the abductor pollicis muscle. After <1 min, the F-wave amplitude reached pretetanic levels. The time course of the F-wave amplitude around the tetanic stimulation is presented in Figure 5. Nine consecutive tracings around the tetanic stimulation are shown in Figure 6. Tetanic stimulation did not cause artifacts in the EMG recordings for any of the patients.
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Discussion |
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In our arguments, we equate changes in processed EEG variables to effects on the forebrain. Although the EEG does reflect certain forebrain effects of anaesthetics, there may be other effects which cannot be detected in the EEG, especially not with global indices such as the BIS. Therefore we cannot exclude the possibility that anaesthetic effects on spinal cord excitability are secondary to forebrain effects not reflected in the EEG.
The observed differences of both the equilibration half-time and the EC50 values are based on a comparison of individual fits of a simple PKPD-model. We did not employ a population approach (Bayesian approach) since the primary aim of our study was not to build a best population model for the F-waves and BIS but to compare equilibration half-times and EC50 values of spinal and EEG variables that were generated simultaneously in the same patients.
The F-wave amplitude is already strongly suppressed at sevoflurane concentrations far below the minimal alveolar concentration (MAC), which makes the F-wave amplitude a rather unsuitable candidate for monitoring immobility. The low probability of predicting movements to noxious electrical stimulation confirms the unsuitability of the F-wave amplitude for monitoring immobility. These findings appear to be only partly in accordance with the results of Zhou and colleagues3 who reported that F-wave suppression correlates with surgical immobility. One possible explanation for this difference might be the different stimulation currents used in each study. While the posterior tibial nerve in this study was stimulated with 2050 mA, Zhou and colleagues applied a stimulus of 4080 mA. Nevertheless, the average pre-anaesthetic F-wave amplitude of 0.60 mV reported by Zhou and colleagues was similar to the value of 0.49 mV obtained in this study. However, higher stimulation currents might have resulted in higher F-wave amplitudes under sevoflurane. On the other hand, Zhou and colleagues did not use the prediction probability and could only demonstrate that the individual F-wave persistence, but not F-wave amplitude, differed between patients responding with movement to an electrical noxious stimulus and patients who did not respond. This is in line with our finding that the EC50 value for persistence is much closer to the MAC value of sevoflurane than the EC50 for F-wave amplitude. However, in our analysis for sevoflurane, F-wave persistence did not predict movement in response to painful electrical stimulation better than the BIS. In addition, monitoring F-wave persistence as an index of immobility may not be suitable during clinical practice because of the profound suppression of F-wave amplitude at clinical concentrations of sevoflurane. Determining the exact F-wave persistence under sevoflurane concentrations of 1 MAC is prone to interference because of the low signal-to-noise ratio.
Animal studies in rats14 15 have also shown dose-dependent suppression but only moderate suppression of F-waves with various volatile anaesthetics. During 1.2 MAC sevoflurane the F-wave amplitude remained >50% of the baseline value.14 One reason for this discrepancy could be species differences. The ratio of the F-wave amplitude to the corresponding direct muscle response (F/M ratio) is an estimate of the amount of the motoneurone pool that produces F-waves.6 Rampil and King14 reported a mean F/M ratio of 31% in rats even under 0.6 MAC sevoflurane, whereas mean F/M ratios of 1.72.7% are reported for the abductor pollicis muscle16 in healthy human subjects. Normal values in other muscles in humans are 510%.6 This large difference demonstrates that the size of the motoneurone pool involved in the production of F-waves is much smaller in humans than in rats.
In small animals, the antidromic stimulus, which is responsible for the formation of F-waves, arrives at the spinal motoneurone before the monosynaptic excitation, which is transmitted by Ia afferents, while the reverse is true in humans.17 The longer the distance between the stimulating electrode and the spinal cord, the more important is the higher conduction velocity of the Ia afferents compared with the synaptic delay between the Ia afferent and the motoneurone. Therefore in larger animals or humans the afferent-induced action potential cancels the antidromic invasion, inhibiting the formation of F-waves. F-waves in humans are preferentially generated by recurrent responses of larger and faster conducting motoneurones, a fact which may relate to a greater chance of collision and mutual extinction of orthodromic (reflex) and antidromic impulses in smaller axons.18 This selection of faster motoneurones contributes to a smaller motoneurone pool involved in F-waves in humans compared with small animals. It is possible that the faster and larger motoneurones involved in F-wave generation in humans are particularly sensitive to sevoflurane. This may also explain the high sensitivity of F-waves to isoflurane found in goats.8 In this study, the suppression of the F-waves could be partially reversed by noxious electrical stimulation. Rampil and King14 hypothesized that the reduction of motoneurone excitability by inhaled anaesthetics might be caused by hyperpolarization of the motoneurone. Noxious stimulation could overcome this hyperpolarization through mechanisms such as temporal or spatial summation by activating spinal circuits to a higher level of alertness. This might explain why Zhou and colleagues19 could still record F-wave amplitudes reduced to 42% of the pre-anaesthetic values under anaesthesia with 1 MAC of isoflurane during surgical stimulation.
Spinal F-wave amplitude is already suppressed at lower sevoflurane concentrations than the H-reflex, another index of spinal excitability. Both responses are produced by electrical activation of different parts of the central and peripheral nervous system. The H-reflex is evoked by electrical stimulation of Ia afferents that project to the homonymous motoneurones. In this way small motoneurones innervating slow motor units are first recruited.20 However, F-waves are generated by antidromic activation of motoneurones and are predominantly produced by larger motoneurones as discussed above.5 This difference between the motoneurone size for F-waves and H-reflexes may help to explain why the change of the H-reflex amplitude correlates better than the change of the F-wave amplitude with the suppression of movement. Voluntary movement, transcranial magnetic stimulation21 and the H-reflex20 all follow the size principle of recruitment order from smaller to larger motoneurones, which is violated by F-waves. It seems sensible to assume that movement in response to noxious stimulation also follows the size principle of recruitment. This implies that movement after noxious stimulation originates from smaller motoneurones whose excitability can probably not be assessed by F-waves but only by H-reflexes.
In summary, we have shown that F-wave persistence and amplitude are suppressed at lower sevoflurane concentrations than the H-reflex and the MAC value, possibly because of differences in the motor neurone pool involved in the respective responses. The PKPD analysis of our data yields further evidence to support the hypothesis that sevoflurane depresses motoneurone excitability via a site of action different from the forebrain.
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Acknowledgments |
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Footnotes |
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References |
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