Concentration-dependent suppression of F-waves by sevoflurane does not predict immobility to painful stimuli in humans{dagger}

J. H. Baars*, D. Kalisch, K. F. Herold, D. A. Hadzidiakos and B. Rehberg

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.


    Abstract
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Background. Decreased spinal excitability contributes to the immobilizing effects of halogenated ethers during general anaesthesia. Recurrent spinal responses such as F-waves reflect spinal excitability and are suppressed by volatile anaesthetics. To evaluate whether F-waves are suitable for monitoring immobility, the concentration-dependent effects of sevoflurane on F-waves were compared with effects on the Bispectral IndexTM (BISTM). The predictive power of all parameters for movement responses to noxious stimuli was tested. In addition, the effect of the noxious stimulus itself on F-waves was investigated.

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 pharmacokinetic–pharmacodynamic 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


    Introduction
 Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Evidence from animal studies suggests that volatile anaesthetics mediate immobility during surgical stimulus by affecting the spinal cord rather than the forebrain1 and consequently evoked spinal responses, such as the H-reflex and F-waves, have been suggested as monitors of immobility in humans.2 3 The amplitude of the monosynaptic H-reflex correlates with the suppression of movement in response to noxious stimuli during anaesthesia with volatile anaesthetics.3 4 The circuitry of the H-reflex corresponds to the monosynaptic stretch reflex except that the muscle spindle sense organs are bypassed by direct electrical stimulation.

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 pharmacokinetic–pharmacodynamic (PK–PD) 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.


    Material and methods
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
The protocol for this study was approved by the local ethics committee (Charité, Berlin, Germany), and written informed consent was obtained from all patients. The study was performed prior to elective gynaecological surgery on 28 female patients who were classified as ASA I or II. Patient exclusion criteria were pregnancy, any neuromuscular diseases, use of medication acting on the central nervous system, abuse of alcohol or illicit drugs and contraindications to inhalational induction of anaesthesia.

Study design
Patients fasted for at least 6 h before the study. Eighteen patients received oral midazolam 0.1 mg kg–1 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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Fig 1 Original tracings of M-wave and F-wave (A) before anaesthesia and (B) under 1.0% end-tidal sevoflurane concentration (stimulus intensity 24 mA).

 
Anaesthesia was induced with sevoflurane via a tight-fitting facemask. Neither opioids nor nitrous oxide were used during the entire study period. The sevoflurane concentration was initially increased until patients tolerated the insertion of a laryngeal mask airway. End-tidal partial pressure of carbon dioxide () was monitored continuously to ensure normocapnia (=35–40 mm/Hg) by manual support of ventilation. The mean arterial blood pressure was maintained within 15% of the pre-anaesthetic value with crystalloid or colloid infusions. End-tidal sevoflurane concentrations were measured using the infrared spectrophotometric analyser of an anaesthesia workstation (either Dräger Julian, Lübeck, Germany, or Modulus, Ohmeda, Madison, WI, USA) and recorded at 20-s intervals on a computer disk. The fresh gas flow was set to 4–6 litre min–1 pure oxygen during the study period. The sevoflurane vaporizer setting was set at 8% for 4 min until end-tidal concentration reached approximately 4%, which led to almost complete suppression of the F-waves. The end-tidal sevoflurane concentration was then decreased to 0.4–1.5% (minimum–maximum) until the F-wave amplitude increased again. A complete recovery of the F-wave was limited because sevoflurane concentration had to be increased when patients moved or began to cough. When time permitted, sevoflurane concentration was increased and then decreased again. Otherwise, the study period ended, and patients received fentanyl 0.1 mg and cis-atracurium 0.1 mg kg–1 (if intubation was necessary).

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{Omega}. 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.

Pharmacodynamic–pharmacokinetic analysis
Individual concentration–response functions were fitted to the data and the calculated plasma concentrations using a spreadsheet program (Excel, Microsoft, Redmond, WA, USA) and a simple sigmoidal PK–PD model:

In this model, E0 is the baseline effect, ceff is the apparent effect site concentration, EC50 is the concentration that causes 50% of the maximum effect and {lambda} (Hill coefficient) describes the slope of the concentration–response relation. The hysteresis between changes in calculated plasma concentration and observed effect was modelled by an effect compartment and a first-order rate constant ke0 determining the efflux from the effect compartment:

where Cet is the end-tidal concentration of sevoflurane and Ceff is the effect compartment concentration of sevoflurane. The effect-site equilibration half-life t1/2ke0 was calculated as (ln 2)/ke0.

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 Kruskal–Wallis 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 concentration–response 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.


    Results
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
F-waves were reliably elicited in all 28 patients included in the study. In one patient, the F-wave amplitude did not recover after reducing the sevoflurane concentration. This patient was excluded from further analysis. In four other patients the EEG data could not be evaluated because of either a high level of background noise (three patients) or extended periods of burst suppression pattern (one patient). The characteristics of the 28 patients (all female) were an age of 40 (28–64) yr, a body weight of 62 (SD 8) kg and a height of 165 (6) cm.

Pharmacodynamic–pharmacokinetic analysis
The average F-wave amplitude before induction of anaesthesia was 358 (149) µV (range 98–578 µV). These values correspond to the E0 values in the PK–PD 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 (0.66–0.83) and 0.81 (0.76–0.89), respectively. For comparison, the median r2 value of the BIS was 0.88 (0.75–0.93).

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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Fig 2 Individual hysteresis loops (effect vs end-tidal sevoflurane concentration) and collapsed loops (effect vs effect compartment concentrations) of the different drug effect measures. Original data from all patients. The collapsed curves were generated from the individual equilibration time constants. To estimate the goodness of the fit the grey line shows the mean concentration–response curve of all patients (see Fig. 4). Loops for F-wave amplitude are shown in (A) and (B), for F-wave persistence in (C) and (D) and for the BIS in (E) and (F). BIS values were recorded only every 20 s; therefore the BIS loops have fewer data points. Because of the high interindividual variability the F-wave amplitude was normalized to individual control values.

 
The individual fitted parameters derived from the PK–PD modelling of all patients are presented in Figure 3. The EC50 values of the F-wave amplitude (0.79 (0.33)%) differed significantly (ANOVA and Tukey multicomparison test, P<0.001) from both the F-wave persistence (1.40 (0.64)%) and BIS (1.55 (0.59)%). The equilibration half-times of both F-wave amplitude (6.8 (3.8) min) and F-wave persistence (7.7 (4.5)) were significantly larger (Tukey multicomparison test, P<0.05) than those of the BIS (3.9 (2.6)). Similarly, the Hill coefficient {lambda}, which yielded values of 3.6 (IQR 2.7–5.4), 5.2 (4.0–6.9) and 1.1 (0.9–1.5) for F-wave amplitude, F-wave persistence and BIS, respectively, was significantly different (Kruskal–Wallis test with Dunn's post hoc test, P<0.001) between the F-wave variables and the BIS. Premedication with midazolam did not significantly influence the fitted parameters (Student t-test).



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Fig 3 (A) EC50, (B) equilibration half-time and (C) Hill coefficient ({lambda}) time derived from the individual sigmoidal PK–PD modelling of the drug effects examined. Horizontal bar, mean value for EC50 and equilibration half-time; median for Hill coefficient. (F-wave amplitude and persistence, n=27; BIS, n=23.)

 
Movement response to noxious stimuli
F-wave amplitude, F-wave persistence, BIS and end-tidal sevoflurane concentration all predicted movement better than chance alone. However, they did not differ significantly from each other. The predictive value for predicting the movement response to peripheral electrical stimulation was assessed using the prediction probability (see Material and methods). The values are presented in Table 1. To compare the results obtained from the PK–PD analysis with those of the movement responses the different sigmoidal concentration–response curves constructed using the mean values of EC50 and slope parameters together with the logistic regression curve for the movement response to noxious electrical stimulation are displayed in Figure 4.


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Table 1 Prediction probability Pk for movement to noxious electrical stimulation for different predictors.

 


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Fig 4 Comparison of the sigmoidal concentration–response curves for suppression of F-wave amplitude, F-wave persistence, and bispectral index. These curves were generated from the mean values of the computer fits of all individual concentration–response curves at each concentration. The broken line shows the logistic regression curves for the suppression of the motor response to noxious electrical stimulation. Horizontal error bars, standard errors of the EC50 values; circles, individual movement response (filled circles, response; open circles, no response). For the BIS, F-wave amplitude and persistence the x-axis displays the effect site concentrations, whereas the logistic regression curve is based on end-tidal concentrations.

 
The logistic regression curve calculated by the method of Waud10 and based on a total of 28 tetanic electrical stimuli (11 positive and 17 negative responses), has an EC50 of 1.5% (SE 0.15) and a slope coefficient of 4.3 (SE 2.2). The population pharmacodynamic analysis suggested by Bailey and Gregg11 yielded similar results: 1.5% and 2.8 for the EC50 and the slope coefficient, respectively. Therefore suppression of movement and suppression of F-wave persistence occur in the same concentration range, whereas the F-wave amplitude is suppressed at lower sevoflurane concentrations. Since the data for the movement response were not obtained at steady state, but during slowly decreasing (<0.5% in 5 min) concentrations of sevoflurane, the EC50 for the movement response may have been underestimated.

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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Fig 5 Response of F-wave amplitude to noxious electrical stimulation (t=0 s; stimulus intensity: 50 Hz, 60 mA, 5 s, 0.2 ms square wave) for (A) patients who did not move after stimulation (non-movers) and (B) patients who did move (movers). Data are expressed as mean (SD).

 


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Fig 6 Consecutive EMG tracings around noxious stimulation in one patient. The noxious stimulation was performed during end-tidal sevoflurane concentrations of 2%. The patient did not move after stimulation. Background noise remained stable during the tetanic stimulation at the wrist which did not cause any recordable artifacts.

 

    Discussion
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
This study investigated the relationship between end-tidal sevoflurane concentration and the amplitude or persistence of the spinal F-wave compared with BIS. The results demonstrate that the sigmoidal model used for the BIS can also adequately describe the suppression of the F-wave amplitude by sevoflurane. The reason for the better modelling of the BIS compared with the F-wave is the large interstimulus variability. The F-wave amplitude and persistence correlate with the number of excited motor units. Since only a small number of motor units are excited (say three to eight), an increase or decrease of only two or three motor units results in a drastic change of F-wave amplitude. Averaging of the data would have improved the fitted parameters but would have adversely affected the ke0 modelling. The equilibration half-time found for suppression of the F-wave amplitude was significantly longer than that of the BIS. This difference points to separate underlying mechanisms, or at least separate effect sites for anaesthetic effects on F-waves and the EEG. The equilibration half-time for the suppression of the H-reflex, another measure of spinal excitability, is in the same range as the equilibration half-time of the suppression of spinal F-waves observed in this study.13 The delay of the spinal effects of volatile anaesthetics could explain our clinical observation that reflex movements can occur shortly after mask induction (e.g. when inserting an intravenous cannula) even though low BIS values indicate deep sedation. The mechanism underlying the differences in equilibration half-times for the spinal cord and forebrain has not been addressed in the study. Such differences may originate either from differences in the anaesthetic wash-in and wash-out of the effect compartment (depending on blood flow, partition coefficients and compartment volume) or from neuronal dynamics.

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 PK–PD-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 20–50 mA, Zhou and colleagues applied a stimulus of 40–80 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 1.7–2.7% are reported for the abductor pollicis muscle16 in healthy human subjects. Normal values in other muscles in humans are 5–10%.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 PK–PD 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.


    Acknowledgments
 
This work was supported by DFG-grant Re1534/2.


    Footnotes
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
{dagger} This work was presented in part at the Meeting of the German Society of Anaesthesiologists, Munich, 2003. Back


    References
 Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
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