POTENTIATION OF THE NEUROMUSCULAR BLOCKADE PRODUCED BY ALCURONIUM WITH HALOTHANE, ENFLURANE AND ISOFLURANE

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1 Br.J. Anaesth. (987), 9, 0-06 POTENTIATION OF THE NEUROMUSCULAR BLOCKADE PRODUCED BY ALCURONIUM WITH HALOTHANE, ENFLURANE AND ISOFLURANE S. J. KEENS, J. M. HUNTER, S. L. SNOWDON AND J. E. UTTING Volatile anaesthetic agents are already known to potentiate many competitive neuromuscular blockers. Thus neuromuscular blockade produced by tubocurarine has been shown to be potentiated by halothane (Katz and Gissen, 967) and, to a greater extent, by enflurane (Lebowitz, Blitt and Walts, 970) and isoflurane (Miller et al., 97). Similarly, pancuronium has been shown to be potentiated by halothane (Katz, 97), enflurane (Schuh, 98) and isoflurane (Miller et al., 97). The requirement for alcuronium is also known to be decreased when volatile anaesthetic agents are used (Grimmeisen, 96), but there is no information available as to the quantitative effect of volatile agents on the block produced by this agent, despite its widespread use in the U.K. It was decided, therefore, to study the effect of three commonly-used volatile anaesthetic agents, halothane, enflurane and isoflurane, on the neuromuscular blockade produced by alcuronium, monitoring neuromuscular function by electromyography (EMG). Two approaches were used: in the first, conventional cumulative doseresponse curves were constructed; in the second, a more clinical approach was used and an attempt was made to determine the effect of the volatile agents on the degree and duration of blockade following a single dose of neuromuscular blocker. PATIENTS AND METHODS Ethical committee approval was obtained and a total of 60 patients, scheduled for general surgical S. J. KEENS,* M.B., F.F.A.R.CLS.; JENNIFER M. HUNTER, M.B., F.F-A.R.CS. ; S. L. SNOWDON, M.B., F.F.A.R.OS.; J. E. UTTING, M.B., F.F.A.R.C.S.; University Department of Anaesthesia, Royal Liverpool Hospital, Prescot Street, P.O. Box 7, Liverpool L69 BX. Accepted for Publication: July, 986. Present address, for correspondence: Anaesthetic Department, Royal Preston Hospital, Sharoe Green Lane, Preston, Lancashire PR HT. SUMMARY The potentiation of alcuronium by halothane, enflurane and isoflurane was investigated using e/ectromyography. In the first study, cumulative dose-response curves were constructed in four groups of 0 patients anaesthetized with one of the inhalation agents and nitrous oxide, or with fentanyl and droperidol {control). All three agents reduced the ED^ of alcuronium; the effect was marked with isoflurane (P < 0.00) but less so with halothane (P < 0.0) and enflurane (ns). In the second part of the investigation, designed primarily to test the duration of action of alcuronium with each agent, a single bolus dose of alcuronium 0. mg kg' was given to four similar groups (n = ). The duration of action was significantly prolonged by enflurane (P < 0.0) and isoflurane (P < 0.0), but not by halothane. The possible reasons for this are discussed. or gynaecological operations, gave consent to their inclusion in the study. Each patient was premedicated with promethazine 0 mg orally the night before operation, with or without morphine 0 mg and cyclizine 0 mg i.m. h before the expected start of surgery. In both parts of the study, the concentrations of the volatile agent(s) were measured using a "Normac" anaesthetic agent monitor (Datex Ltd), the calibration of which had been verified using a flame ionization detector and calibrated gas mixtures. End-tidal carbon dioxide concentrations were measured using a capnometer (Datex Ltd) which had been calibrated against cylinders of known composition. Sampling for both volatile agents and carbon dioxide concentrations was via a cannula inserted through the face mask angle-

2 0 BRITISH JOURNAL OF ANAESTHESIA piece and later through the catheter mount. The ECG was monitored continuously and arterial pressure was measured regularly with an oscillotonometer. Dose-response curves Four groups each of 0 patients were studied. In the first group (group ), anaesthesia was induced with fentanyl, droperidol and thiopentone; the patient then breathed nitrous oxide and oxygen (0%) via an anaesthetic face mask, ventilation being assisted if necessary to maintain the end-tidal carbon dioxide concentration between and 6%. At this stage, control EMG traces were obtained. After this had been achieved, alcuronium was given in divided doses of 0 ng kg" at intervals of min until the evoked action potential had decreased to less than 0% of control and at least four increments of alcuronium had been given. The study was then terminated, and a tracheal tube was passed. In the other three groups, induction of anaesthesia was with thiopentone alone. The patient then breathed nitrous oxide in oxygen while control EMG measurements were obtained. Immediately these had been achieved, halothane (group ), enflurane (group ) or isoflurane (group ) was added and, after an induction period of 0 min, end-tidal concentrations were kept constant (to within 0.%) at 0.7% halothane,.7% enflurane and.% isoflurane for a further 0 min, making 0 min in all. Alcuronium was then given in divided doses as described for group. Single bolus dose study In the second part of the study, 0 patients were given a single bolus dose of alcuronium 0. mg kg", after control EMG traces had been recorded in the manner described above. Tracheal intubation was performed and anaesthesia supplemented by either fentanyl and droperidol (group ), halothane (0.% end-tidal concentration; group 6), enflurane ( % end-tidal concentration; group 7) or isoflurane (0.7% end-tidal concentration; group 8). Artificial ventilation was established and the end-tidal carbon dioxide concentration was maintained throughout anaesthesia between 6%, the ventilatory rate being b.p.m. Monitoring by electromyography was continued until the first incremental dose of alcuronium was given. Neuromuscular monitoring The method of monitoring neuromuscular function by electromyography has been described previously (Calvey, 98). The skin was cleaned with acetone and the hand immobilized in a splint. ECG electrodes were placed over the ulnar nerve in the forearm for stimulation, and recording electrodes (Conn Med Stress ECG electrodes) placed over the adductor pollicis brevis and the base of the index finger on the palm of the hand. A copper earth electrode was placed between the stimulating and recording electrodes. Stimulation voltage was increased until the evoked compound muscle action potential (CMAP) reached its maximum height, after which the voltage was increased by a further % to ensure supramaximal stimulation. The positions of the recording electrodes were adjusted, if necessary, to give a biphasic CMAP trace. The stimulator was set to deliver single pulses with a width of 0. ms duration every s (0.08 Hz) in the first part of the study (groups ) as this mode of stimulation was similar to that used in other work on cumulative dose responses (Donlon, Ali and Savarese, 97). A train-of-four ( Hz) every min was used in the second part of the study, as this was more practicable for use over a prolonged period. EMG signals were amplified with an isolated biological amplifier having frequency filters set at -. KHz and recorded on u.v. light-sensitive paper from the trace displayed on the oscilloscope of a Medelec MS6 EMG machine. Method of analysis In every patient, the height of each action potential was measured and expressed as a percentage of the height of the control. These values were then plotted on a graph against time. In the first part of the study, the degree of depression of the action potential caused by each increment of neuromuscular blocker was calculated and plotted on log-probit axes (fig. ). The ED 0 values were read from these individual dose-response plots. Before comparing these ED M it was necessary to ensure that the lines were parallel. A straightforward mathematical slope could not be determined, since the axes were not linear, one being logarithmic, the other a probit scale. A measure of the slope of each line was, therefore, obtained from a slope function determined by a graphical method (Litchfield and

3 NEUROMUSCULAR BLOCKADE WITH ALCURONIUM 0 TABLE I. The ED W (pg kg *)for alcuronium is given for each of the four groups studied, together with the SEM. The significance level, obtained using Wilcoxon Rank Sum Test, of a comparison between group I and each of the other three groups is also noted. No significant difference (ns) was found between enflurane and fentanyl using this method Group ED., SEM Significance level. Fentanyl. Halothane. Enflurane. Isoflurane <0.0 ns < Alcuronium (pg kg' ) 00 FIG.. Log-dose-response curve. Graph drawn from the data obtained from one patient with % decrease in height of compound muscle action potential (CMAP) plotted on a probit scale against the cumulative dose of alcuronium on a logarithmic scale. Point A = ED,,; Point B = ED M ; Point C = ED M. Wilcoxon, 99). The slope function was given by the formula ED 8 /ED 60 + ED 60 /ED 6 The mean slope function of the groups did not differ significantly. The mean ED 60 values of the groups were then compared using a nonparametric test of significance: the Wilcoxon Rank Sum Test (Wilcoxon, 9). In the second part of the study, the rate of recovery from the neuromuscular blockade produced by a standard dose of alcuronium was studied. The time from the maximum depression of the height of the first of the train-of-four action potentials to the point at which the height of the action potential had recovered by one-tenth of that maximum depression was measured in a manner similar to that used by Miller and co-workers (97). For example, if the height of the control CMAP was 0 mm and this was depressed to mm (90 % depression), the time taken to recover by a height of 0 /0 =.6 mm (i.e. to 7.6 mm) was taken as an indication of the duration of the effect of alcuronium on the CMAP. RESULTS Cumulative dose-response curves The results of the cumulative dose-response study are shown in table I. The apparent ED M of alcuronium with each of the volatile agents was less than it was in the control group. This reduction was greatest with isoflurane (P < 0.00). A smaller, although still significant, decrease was found in the halothane group (P < 0.0). The mean ED 60 in the enflurane group (9.6 ug kg" ) was not statistically different from the mean ED 60 in the fentanyl group (06.8 ug kg" ), even though this difference was greater than that for the halothane group (mean EDJO 96. ug kg" ). This apparent anomaly is explained by greater variability within the enflurane group. Single bolus dose study The minimum height of the CMAP after a standard 00-ug kg" bolus dose of alcuronium was very variable in those patients given an inhalation agent (table II), and ranged from a maximum depression of % of control (patient of the enflurane group) to a minimum depression of % (patient of the isoflurane group). In contrast, there was much less variation between patients in the fentanyl group (range from 6 % to 7 % of control). The time from injection of the neuromuscular blocker to the maximum depression also varied greatly and this variation was especially marked in the enflurane group where it ranged from 8 to min. As can be seen (table II), the variability in the fentanyl group was much less (from 8 to 6 min). The mean time taken for recovery to one-tenth of the maximum degree of depression was greatest in the isoflurane group (mean.6 min) compared with the fentanyl group (mean of.6 min); this difference reached a significance level of 0.0. The increase in mean recovery time in the enflurane group (mean of 0.8 min) was less than that in the isoflurane group but, because of less

4 0 BRITISH JOURNAL OF ANAESTHESIA TABLE II. The smallest height of the CMAP as a percentage of control in each of the patients who received a tingle bolus of alcuronium 0. mg kg' is given, together with the mean value obtained in each group. Also recorded is the time from injection of the alcuronium to the maximum depression of the CMAP in each patient and the time to recovery to /0 of the maximum depression. Statistical significance using the Wilcoxon Rank Sum Test between the mean value for each group and the mean value for the fentanyl group is also given : *0.0S;**0.0;ns>0.0 Group Patient No. Minimum height of CMAP (% of control) Time from injection of relaxant to maximum depression ofcmap(min) Time to recovery to /0 of the maximum depression (min) : Fentanyl : Halothane (ns) (ns) (ns) 7: Enflurane (ns) (ns) ** 8: Isoflurane (ns) 9.8 (ns).6* variability within the group, reached a significance level of 0.0. There was no prolongation of the recovery time in the group of patients anaesthetized with halothane (.8 min) compared with the fentanyl group (.6 min). DISCUSSION The results of the cumulative dose response study show a greater effect on the compound muscle action potential by incremental doses of alcuronium when anaesthesia is supplemented by volatile anaesthetic agents. Surprisingly, the smallest effect was in the group anaesthetized with enflurane, which is usually considered to be the most potent agent for potentiating the competitive neuromuscular blockers (Schuh, 98). There is a spectrum of potentiation of the competitive neuromuscular blockers, with less potentiation of the shorter-acting drugs such as atracurium (Rupp, McChristian and Miller, 98) and vecuronium (Rupp, Miller and Gencarelli, 98) than the longer acting neuromuscular blockers such as pancuronium and tubocurarine. Alcuronium is a synthetic derivative of tubocurarine, which itself is markedly potentiated by enflurane (Schuh, 98), and it might be expected that alcuronium would be similarly potentiated. The most obvious possibility for failing to find a marked potentiation by this agent in the dose-response study whilst at the same time finding that the volatile agent markedly prolonged the duration of action of the neuromuscular blocker is that ethical constraints imposed on the investigators meant that time for full equilibration might not have been allowed and, in particular, equilibration at the neuromuscular junction may not have been complete. This factor may well have been more important with enflurane than with the

5 NEUROMUSCULAR BLOCKADE WITH ALCURONIUM 0 other volatile agents, although it must be said that it is surprising, if this be the case, that the dose-response curves of the enflurane group were closely parallel to the others. It has been found that potentiation of neuromuscular blockade by enfiurane increases linearly with duration of exposure for at least - h (Stanski et al., 980). A slow linear increase might not greatly affect the slope of the dose response curve as the time taken to perform this study was relatively short, but it might be expected that the rate of recovery would be substantially affected by a progressive increase in potentiation of alcuronium if this were measured over a relatively long period of time (the time from injection of neuromuscular blocker until recovery to one-tenth of the maximum depression in the enflurane group was 7. min). In fact, there was marked prolongation of the effect of alcuronium by both isoflurane and enflurane, despite only moderate reduction in the ED S0. This illustrates a crucial limitation of the value of dose-response curves in determining the potentiation of neuromuscular blockers by volatile agents; with enflurane, at least, different dose-response curves might be obtained for up to h, depending on the duration of exposure to the agent. There are, however, other problems. The onset time of block by competitive neuromuscular blockers is longer under enflurane anaesthesia than under halothane (Rupp, Miller and Gencarelli, 98) and, as the increments in the present study were given at regular -min intervals, the maximum depression of the CMAP may not have been reached in the enflurane group before the next increment of alcuronium was given although inspection of the traces suggested that this was not so. The cumulative dose technique is a satisfactory way of comparing different neuromuscular blockers only if their duration of action is long compared with the time taken to perform the cumulative dose-response procedure (Donlon, Ali and Savarese, 97; Donlon et al., 980). It is less satisfactory with shorter acting agents of which the duration of action is short relative to the time for the cumulative dose procedure (Ording et al., 98). In the latter case, erroneous results may be produced because the first dose of the relaxant has worn off appreciably before the last dose has its maximum effect. Alcuronium, however, is sufficiently long-acting to justify the use of the cumulative dose technique. Most studies of potentiation by volatile agents have used mechanical twitch response, although electromyography of the adductor pollicis has been used to show that halothane increased both the degree and duration of neuromuscular blockade caused by atracurium (Stirt et al., 98). By using electromyography, any direct depressant effect of enflurane on muscular contractility might not be manifest. If the potentiation caused by enfiurane was, therefore, largely the result of a direct depressant effect on muscular contraction, studies measuring the effects on muscle cell depolarization (i.e. electromyography) might demonstrate less effect with enflurane. The fundamental finding of this study is that the action of alcuronium is prolonged markedly both by isoflurane and enflurane. Thus, although the "intubating" dose of alcuronium when using enflurane or isoflurane will be approximately the same as when using a neurolept technique or halothane, the duration of effect of alcuronium will be very much longer in those receiving these agents. Thus problems could arise if incremental doses are given "by the clock" when using these anaesthetic supplements although the difficulty might be less with halothane or with a neurolept technique. Relative overdose may lead to difficulty in antagonism of blockade at the end of prolonged surgery, as has been shown when enflurane is used in conjunction with pancuronium (Delisle and Bevan, 98), and it is suggested that some form of monitoring of neuromuscular function should be undertaken when using myoneural blocking drugs in conjunction with enflurane or isoflurane for anything other than short procedures. ACKNOWLEDGEMENTS This study was funded in part by a grant from the Mersey Regional Health Authority. REFERENCES Calvey, T. N. (98). Assessment of neuromuscular blockade by electromyography, A review. J. R. Soc. Mtd., 77, 6. Delisle, S., and Bevan, D. R. (98). Impaired neostigmine antagonism of pancuronium during enflurane anaesthesia in man. Br. J. Aruusth.,,. Donlon, J. V., Ali, H. H., and Savarese, J. J. (97). A new approach to the study of four non-depolarising muscle relaxants in man. Aneith. Analg.,, 9. Savarese, J. J., Ah, H. H., and Teplik, R. S. (980). Human dose-response curves for neuromuscular blocking drugs a comparison of two methods of construction and analysis. Anetthesiology,, 6. Grimmeisen, H. (96). Diallyl-nor-toxiferin. Erfahrungen mit einem neuartigen Muskelrelaxans. Anaesihtsisi,, 8.

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