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Anesth Analg 2004;99:1402-1407 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000135407.11545.36
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Abstract |
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We performed this study to assess the recovery period after neuromuscular blockade by electromyographic F-wave analysis, a method that supplies more information about more proximal parts of the motor system than conventionally used methods, e.g., mechanomyography (MMG). In 20 neurosurgical ASA physical status I or II patients anesthesia was induced and maintained with IV fentanyl and midazolam. Patients were randomly assigned to receive either 0.25 mg/kg mivacurium (MV group, n = 10) or 0.1 mg/kg pancuronium (PC group, n = 10) intraoperatively. MMG monitoring of the adductor pollicis muscle was performed continuously. F waves were recorded at the abductor pollicis muscle of the contralateral hand at train-of-four (TOF) ratios of 0.1, 0.25, 0.5, 0.7, 0.75, 0.8, 0.85, 0.9, and 0.95. Recovery of F-wave amplitudes after neuromuscular blockade with pancuronium was significantly slower compared with mivacurium (P = 0.004) during the clinically important recovery period defined by MMG TOF ratios from 0.7 to 0.95. This electrophysiologic finding suggests a differential recovery of the motor system after administration of pancuronium and mivacurium not detected by MMG.
IMPLICATIONS: Our findings using F-wave monitoring indicate a differential recovery of the whole motor system after administration of two different neuromuscular blocking drugs that was not detected by peripheral mechanomyography. This result may have been caused by different spinal effects of pancuronium compared with mivacurium.
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Introduction |
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Monitoring of neuromuscular function by evaluating the muscular response to electrical stimulation of a peripheral motor nerve is recommended when neuromuscular blocking drugs (NMBD) are administered during anesthesia. However, despite train-of-four (TOF) fade ratios of 0.8 or 0.9, residual neuromuscular blockade was reported (1,2). Conventionally used methods like mechanomyography (MMG) record the direct mechanical muscle response to a peripheral electrical stimulus. In contrast, monitoring of more proximal parts of the motor system may provide information about additional effects of NMBD on the motor system.
Peripheral stimulation of a motor nerve results in both orthodromic and antidromic impulse conduction. The antidromic excitation reaches the motor cell soma, where it initiates an orthodromical reexcitation which evokes a small muscle potential that is visible as a biphasic or polyphasic voltage signal called "F wave." Thus, the presence of a regular F wave requires the integrity of a motor axon from its axon hillock to the motor endplates (3). A decline of the F-wave amplitude may be attributable to spinal as well as peripheral effects. On the spinal level, the F-wave signal is modulated by the 
-motoneuron excitability, which depends on the balance of spinal excitatory versus inhibitory afferent input to that motoneuron (3). F-wave amplitude also depends on an unimpaired neuromuscular transmission in the periphery. F waves are always preceded by a direct muscle response (M wave) evoked by the orthodromic neural excitation. M-wave amplitude or M-wave area is usually monitored when electromyography (EMG) is used to assess neuromuscular transmission (4).
During neurosurgical operations of the cerebellopontine angle, F-wave monitoring is standard practice in our department (5). We observed a high sensitivity of the F-wave signal to the administration of various NMBD: F waves demonstrated decreased amplitudes up to 1 h after full recovery from neuromuscular blockade had been expected according to its reported duration of action. In a small pilot study we found drug-specific differences between NMBD with regard to the recovery of F-wave amplitudes, although TOF ratios as measured by MMG were identical. F-wave analysis appeared to combine the ability for monitoring the motor system from the spinal level (-motoneuron) to the peripheral neuromuscular junction with a high sensitivity towards neuromuscular blockade induced by NMBD.
We hypothesized that applying a TOF stimulation pattern by means of a peripheral nerve stimulator only incompletely monitors the state of the motor system during the recovery period after administration of NMBD and that F-wave monitoring may provide additional information. The aim of this investigation was to assess the recovery period after neuromuscular blockade by F-wave analysis because standard MMG monitoring only allows monitoring the neuromuscular junction and muscle contraction, whereas F-wave monitoring provides information about the entire -motoneuron. We recorded F-wave amplitudes to compare the recovery period after neuromuscular blockade with either pancuronium or mivacurium.
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Methods |
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After obtaining approval from our IRB (Ethics Committee of the University of Cologne) and written informed consent from each participant, we studied 20 neurosurgical patients who were classified as ASA physical status I or II, 19–66 yr of age, and scheduled for surgery of supratentorial tumors under general anesthesia. This study was performed in neurosurgical patients because maintenance of general anesthesia with fentanyl and midazolam allows unimpaired F-wave recording and therefore has been standard practice in our neurosurgical department for many years (5). Patients with a history of peripheral neurological disorders, neuromuscular diseases, or any dysfunction of the motor system were not included in this study. EMG as part of a routine preoperative diagnostic procedure before the surgery had to demonstrate normal variables. Further exclusion criteria were tumor localization in vicinity to the motor cortex and premedication with drugs that might interfere with neuromuscular transmission (e.g., anticonvulsant drugs). Patients were randomly assigned to receive either mivacurium (MV group,n = 10) or pancuronium (PC group,n= 10). Randomization was based on the results of computer-generated codes provided in sealed envelopes and opened on the day of surgery.
A pilot study of 10 patients confirmed the lack of impact of potentially confounding anesthetic co-factors (e.g., temperature, ventilation, and anesthetics) on the experimental variables MMG and F wave. Over a period of 2 h stable MMG and EMG signals (including F waves) were recorded. The side of intraarterial cannulation or IV line placement, which may impact on blood flow or temperature of the arms, did not interfere with MMG or EMG measurements.
In the current study anesthesia was induced with IV fentanyl (10 µg/kg) and midazolam (0.2 mg/kg). Tracheal intubation was performed without the aid of a muscle relaxant. Anesthesia was maintained with continuous administration of midazolam (0.15 mg · kg–1 · h–1) and fentanyl (7 µg · kg–1 · h–1). The lungs were ventilated with oxygen/air. Routine monitoring was used, and central venous pressure, urine output, and blood gas analysis were also monitored. Ventilation was adjusted to maintain a PaCO2 of 35–37 mm Hg. Body temperature was maintained between 36.0°C–37.0°C using a patient warming system, and the arms of the patients were wrapped.
F waves and M waves were obtained using a commercially available electrophysiologic stimulation and recording device (NeuroPack®, Nihon Kohden Inc., Tokyo, Japan). We applied the standard methodology used in our department for F-wave recording (5) that was previously described in detail (6). Briefly, the median nerve was stimulated at the right wrist transcutaneously with constant current square wave pulses (duration, 0.1 ms) at an interstimulus interval of 1 s. Responses were gathered on the abductor pollicis muscle of the right hand. Stimulation current was gradually increased to exceed that needed to evoke a maximum M wave (range, 10–25 mA). This current was used for all subsequent stimulations. Two series with different amplification for F-wave and M-wave analysis of eight consecutive stimuli were delivered at each time point and responses were hard copied by means of a thermoprinter for offline analysis. For MMG-monitoring the contralateral ulnar nerve was stimulated transcutaneously at the wrist with square-wave supramaximal stimuli of 0.2-ms duration, delivered in a TOF mode at 2 Hz every 15 s (NeuroStim T4®, Hugo Sachs Elektronik, March, Germany). The resulting twitches of the thumb were recorded using a force transducer and hard copied on a thermoprinter.
Electrophysiologic monitoring was started after hemodynamic variables were stable. A stabilization period of 15 min preceded EMG and MMG baseline measurements (4). A response variation 
2% for both MMG twitch height and M-wave amplitude had to be recorded. After baseline measurements were performed neuromuscular block was induced with bolus administration of 0.25 mg/kg of mivacurium (MV group) or 0.1 mg/kg of pancuronium (PC group), which are recommended doses for tracheal intubation (7). MMG recordings were performed continuously with TOF ratios calculated continuously (8). EMG M-wave and F-wave recordings were performed at the following TOF ratios, determined by MMG: 0.1, 0.25, 0.5, 0.7, 0.75, 0.8, 0.85, 0.9, and 0.95. Because of the obvious temporal differences of the recovery pattern between pancuronium and mivacurium, investigators could not be blinded.
Blood and effect-site concentrations of fentanyl and midazolam were simulated for each time point of data acquisition using a three-compartment model (IVA-SIM, Version 3.01; Zeneca; Planckstadt; Germany).
At each time point 2 series of 8 consecutive traces with different amplifications for M waves and F waves were recorded and maximal M- and F-wave peak-to-peak amplitudes were determined (Fig. 1). The resulting eight values for each wave form were averaged to provide single values for statistical analysis for each of the 10 time points of data acquisition.
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To compensate for interindividual variations attributable to the variable F-wave signal normalization of the raw data is standard practice (9). All F-wave amplitudes for each of the nine time points of experimental data acquisition were divided by baseline value, leading to dimensionless normalized F-wave amplitude values.
To compare the effect of pancuronium and mivacurium on the F wave and M wave during recovery from neuromuscular blockade the normalized mean F-wave and absolute M wave amplitudes were plotted against TOF ratios. F/M ratios, defined as absolute F-wave amplitude divided by absolute M-wave amplitude, were computed for each time point and each subject and plotted against TOF ratios. The F/M ratio allows differentiating between NMBD effects on both EMG variable (M and F wave) and F-wave-specific effects. The main focus of this study was the clinically important recovery period between TOF ratios of 0.7 to 0.95. For each patient we determined the area under the curve (AUC) of F-wave and M-wave amplitudes and F/M ratio from TOF ratios of 0.7 to 0.95 using the trapezoid algorithm (10). After testing for normality (Kolmogorov-Smirnov test) the mean AUC of each group were analyzed for differences by Student’s t-test.
Nominal data (gender, ASA physical status) were analyzed using Fisher’s exact test. After testing for normality (Kolmogorov-Smirnov test), ordinal data (age, height, weight, blood, and effect site concentrations) were analyzed using Student’s t-test.
Values are reported as mean ± SD unless otherwise stated. For all statistical procedures a P value < 0.05 was considered significant. The Statistical Package for the Social Sciences (SPSS, release 11.0; SPSS Inc., Chicago, IL) was used for all calculations.
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Results |
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One patient from the MV group did not complete the study period (i.e., reaching a TOF ratio of 0.95) because of a prolonged recovery after mivacurium. Hence, this patient was excluded from analysis as a result of incomplete data. Postoperative determination of pseudocholinesterase activity in this patient revealed a heterozygous atypical type of pseudocholinesterase. There were no differences in demographic data between groups (Table 1).
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Baseline administration of midazolam (0.15 mg · kg–1 · h–1) and fentanyl (7 µg · kg–1 · h–1) plus additional boluses resulted in mean hourly doses of 0.19 (± 0.043) mg · kg–1 · h–1 midazolam and 7.9 (± 1.0) µg · kg–1 · h–1 fentanyl for the MV group and 0.16 (± 0.071) mg · kg–1 · h–1 midazolam and 7.2 (± 2.8) µg · kg–1 · h–1 fentanyl for the PC group. The resulting simulated blood and effect site concentrations of midazolam and fentanyl showed no differences between both groups at all time points of data acquisition (data not shown).
The mean AUC of F-wave amplitudes at equal TOF ratios of 0.7 to 0.95 is significantly smaller (P = 0.004) after administration of pancuronium compared with mivacurium (Fig. 2). Mean AUC of M-wave amplitude did not differ significantly between groups (Fig. 3). The mean AUC of F/M ratios at TOF ratios of 0.7 to 0.95 is significantly smaller (P = 0.04) during recovery after application of pancuronium compared with mivacurium (Figure 4). Overall, F-wave amplitudes showed a different recovery pattern after administration of pancuronium compared to mivacurium, although assessment by MMG indicated an equal recovery.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We evaluated the recovery of neuromuscular blockade after administration of pancuronium or mivacurium by comparing amplitudes of the F-wave signal at equal TOF ratios of 0.7 to 0.95 determined by MMG. This is the first study investigating the recovery period after neuromuscular blockade by means of F-wave analysis. Our data showed a different recovery pattern of F-wave amplitudes after neuromuscular blockade with pancuronium compared with mivacurium, although MMG TOF ratios indicated an equal recovery. F-wave amplitude can be considered a variable reflecting the functional integrity of the motor system from the spinal portion of a motoneuron to the neuromuscular junction. Therefore, this finding suggests a different recovery of the motor system despite equal MMG TOF ratios confirming our hypothesis that F-wave monitoring can provide additional information on the state of the motor system.
The disparity between pancuronium and mivacurium in the recovery of F-wave amplitudes may be the result of confounding co-factors such as temperature and PaCO2, the application of different methods (EMG versus MMG) or a drug-related F-wave-specific effect. However, body temperature and ventilation were maintained stable during the study period and we could not detect any influence of these on F-wave monitoring over a 2-hour period during a pilot study conducted before the investigation.
If our result of a different recovery of F-wave amplitudes between the MV group and PC group was attributable to a fundamental method-specific difference between EMG and MMG rather than to a specific F-wave phenomenon, M-wave amplitudes should also demonstrate such a disparity, and any conclusion based on the particular nature of the F wave would be questionable. The pharmacodynamics of NMBD vary with evaluation by EMG or MMG (11,12). Moreover, evaluation of agreement or disagreement between the two methods for measuring neuromuscular blockade also must consider the site of measurement with respect to different sensitivities of NMBD for different muscles and the stimulation pattern. We did not want to change the established standards of F-wave monitoring in our department (abductor pollicis muscle; single stimulus, 1 Hz) (5). On the other hand, we performed MMG of the adductor pollicis muscle using a TOF stimulation pattern every 15 s (0.07 Hz) as recommended (4) to define measurement time points for recording the EMG. Despite these differences in site of measurement and stimulation pattern our data did not show a between-group difference of M-wave amplitudes at equal MMG TOF ratios. However, F/M ratios were significantly smaller in the PC group. Both results indicate that the EMG signal in general (represented by its first response, the M wave) is not affected differently after neuromuscular blockade with pancuronium or mivacurium. Thus, we suggest that the differential recovery of the F wave observed in the current study is the result of a drug-related F-wave specific phenomenon.
Because of its nature, the F-wave signal may be affected by various mechanisms influencing the spinal part of the -motoneuron as well as the neuromuscular transmission. Both sites have to be considered as potential effect sites of NMBD, which may differentially influence the F-wave signal.
The disparity of F-wave recovery in our study might be caused by an effect at the neuromuscular junction. In all patients F-wave latencies (time from stimulus application to F-wave onset) were found in a range between 20 and 40 ms (data not presented). A M wave-F wave couplet is therefore equivalent to a 40 Hz-paired pulse arriving at the neuromuscular junction. Because the total duration of the evoked EMG response is <15 ms, 2 distinct responses at a 40-ms interval can be detected with this technique. Increasing the frequency of stimulation produces a reduction of the resulting twitch responses and this reduction depends on the degree of residual neuromuscular blockade (13). Thus, the evoked F-wave may be accompanied by a short-acting phenomenon of "fading" causing a decreased F-wave amplitude. The TOF stimulation pattern used to elicit the MMG response delivered 4 stimuli every 500 ms (2 Hz). In contrast to the EMG response (<15 ms), the MMG response at the adductor pollicis muscle may last up to 300 ms. Thus, 2 stimuli at 40-ms intervals produce a weak tetanic response of the muscle. Consequently, a putative short "fading" of a 40 Hz-paired pulse cannot be detected by the MMG method because of a lack of temporal resolution. The "fade" phenomenon is supposedly caused by the blockade of prejunctional receptors, whereas blockade of the postjunctional receptors causes depression of twitch height (14). As a result of the fact that M-wave amplitudes (representing twitch height) do not differ between pancuronium and mivacurium at equal TOF ratios (representing "fading") in our study, different presynaptic effects at the neuromuscular junction of both NMBD are not plausible.
Consequently, the spinal cord level may be a potential site of NMBD influence on the recovery of F-wave amplitudes. IV administered NMBD are commonly believed to not cross the blood-brain barrier (BBB). However, Matteo et al. (15) have reported that d-tubocurarine passed into the cerebrospinal fluid (CSF) after IV administration. Broadwell and Sofroniew (16) showed that macromolecules such as albumin (and thus, presumably NMBD) may enter the central nervous system despite an intact BBB. Since the investigations of Eccles et al. (17) it is known that synaptic transmission between -motoneurons and interneurons (Renshaw cells) is mediated by acetylcholine (ACh). In vitro and animal studies revealed a differential effect of NMBD on neuronal nicotinic Ach receptors (18,19). It cannot be excluded that NMBD decrease spinal -motoneuron excitability because of a binding site located on the spinal cord level, which may contribute to peripheral muscle relaxation. However, such a central effect may be modulated by anesthetics. Recent articles using F-wave technique reported a decline of -motoneuron excitability for volatile anesthetics and propofol (6,9). The effect of fentanyl on F waves is minimal (20). Simulated blood and effect site levels of fentanyl and midazolam did not differ between groups in our study, and F-wave monitoring was not impaired under this anesthetic regimen in our pilot study or in the clinical setting (5). These findings suggest that a significant contribution of midazolam and fentanyl to the differences in F-wave amplitudes between groups is unlikely. Therefore, the disparity of F-wave recovery detected in the present study is potentially caused by a spinal effect of NMBD that seems to be stronger for pancuronium compared with mivacurium. Because of the study design, we can only speculate if clinical observations of residual impairment of motor functions after administration of NMBD (1,2,21) are related to the difference in F-wave recovery detected in our study.
In summary, we observed a different recovery pattern of F-wave amplitudes after administration of pancuronium compared with mivacurium at equal MMG TOF ratios. This indicates a differential recovery of the motor system potentially caused by a spinal effect. Further studies have to be designed to investigate the differential effects of other NMBD on the recovery of F-wave amplitudes.
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Acknowledgments |
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The authors thank Dr. G. Wassmer, Institute of Medical Statistics and Epidemiology, University of Cologne, for statistical advice. We also thank Mrs. K. Tamer and D. Wiegand, assistant medical technicians, Department of Neurosurgery, University of Cologne, for assistance with electrophysiologic recordings.
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Footnotes |
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Presented, in part, at the 9th ESA Annual Meeting in Gothenburg, Sweden, April 7–10, 2001.
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References |
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