IMPAIRED NEOSTIGMINE ANTAGONISM OF PANCURONIUM DURING ENFLURANE ANAESTHESIA IN MAN

Transcription

1 Br. J. Anaesth. (1982), 54,441 IMPAIRED NEOSTIGMINE ANTAGONISM OF PANCURONIUM DURING ENFLURANE ANAESTHESIA IN MAN S. DELISLE AND D. R. BEVAN r \, SUMMARY We have compared the rates of recovery of pancuronium-induced neuromuscular blockade after administration of neostigmine during anaesthesia maintained with nitrous oxide and mtermittent narcotics, halothane or enflurane. Thirty patients were studied m whom anaesthesia was maintained with 70% nitrous oxide in oxygen with: fentanyl or thiopentone, halothane ( % end-tidal), or enflurane ( % end-adal). Muscle twitch response was measured using train-of-four stimulation. Pancuronium 3mg/70kg wa» antagonized with neostigmine 2.5mg/70kg at 10% spontaneous recovery of the first twitch of the tram compared with control. There were no significant differences between the times to 10% spontaneous recovery of the first twitch or the rates of train-of-four recovery after neostigmine when the narcotic and halothane groups were compared. However, enflurane anaesthesia, in comparison with fentanyl, was associated with a significant increase m the time to 10% recovery (57.9 ±6.0 mm v ±7 0 mm) and with decreases in the train-of-four recoveries at 4, 5, 10, 20 and 30 min after neostigmine. We conclude that, under the conditions of this study, the antagonism of pancuronium-induced neuromuscular blockade with neostigmine was impaired during enflurane but not halothane anaesthesia. Several studies have demonstrated increases in the magnitude and duration of non-depolarizing neuromuscular blockade by inhalation anaesthetics in man (Katz and Gissen, 1967; Walts and Dillon, 1970; Katz, 1971b). Potentiation of paralysis by enflurane is greater than by equipotent concentrations of halothane (Fogdall and Miller, 1975) or narcotic-nitrous oxide anaesthesia (Lebowitz, Blitt and Walts, 1970). However, the influence of enflurane anaesthesia on the antagonism of nondepolarizing block by neostigmine has not been reported. We have studied the rates of recovery of neuromuscular activity following a standard dose of pancuronium which was antagonized by a standard dose of neostigmine at the same degree of spontaneous recovery in patients anaesthetized with equipotent concentrations of halothane or enflurane with 70% nitrous oxide. The rates of recovery have been compared with those in patients receiving nitrous oxide-narcotic anaesthesia. METHODS The study was approved by the hospital ethics committee. After informed consent 30 patients were S. DELISLE; D. R. BEVAN, M B, B CHIR,MRCP,FFARCS; Departments of Anaesthesia, Royal Victoria Hospital & McGill University, 687 Pine Avenue West, Montreal, Quebec, Canada H3A1A /82/ $01.00 studied during general surgical procedures. Their ages ranged from 27 to 77yr (mean 55.0) and their weights from 42 to 92 kg (mean 70.1). All received atropine 0.6 mg and an opiate, pethidine mgkg" 1 or morphine mg kg" 1, for premedication. All patients were free of hepatic, renal and neuromuscular disease. None had electrolyte abnormalities nor was any receiving drugs known to interfere with neuromuscular transmission. Anaesthesia was induced with thiopentone 3-5mgkg~', followed by suxamethonium 1 mgkg" 1 to facilitate intubation. The patients were divided randomly into three groups, with 10 patients in each group, for maintenance anaesthesia. There were no significant differences in weights, ages or sex ratios between the groups. All patients received 70% nitrous oxide in oxygen, ventilation of the lungs was controlled and the minute volume was adjusted to maintain end-tidal carbon dioxide at 4-5% (Beckman CO 2 analyser). This was supplemented in group 1 (control) with repeated small doses of fentanyl \x% kg" 1 or thiopentone 1-2 mg kg" 1 and in groups 2 and 3 with halothane or enflurane. Administration of the inhalation agents commenced immediately after tracheal intubation at an inspired concentration which maintained constant end-tidal concentrations of % halothane or % enflurane throughout the study, monitored with a Beckman analyser. The Macmillan Press Ltd 1982

2 442 BRITISH JOURNAL OF ANAESTHESIA After induction of anaesthesia, neuromuscular transmission was monitored continuously throughout the surgical procedure according to the method of Ali, Utting and Gray (1970). The ulnar nerve was stimulated supramaximally at the elbow using subcutaneous needle electrodes. Trains of four with square pulses of 0.2 ms duration at a frequency of 2 Hz and a train duration of 2 s were repeated every 10 s using a Grass S48 stimulator and a SIU 5 isolation unit. The hand and forearm were immobilized in a splint and the force of adduction of the adductor pollicis was measured with a force-displacement transducer (Grass F.T.10) and recorded using a pen-and-ink recorder (Grass Polygraph) at a paper speed of 50mmmin"'. Pancuronium bromide mg kg" 1 was administered as soon as full recovery from suxamethonium was demonstrated. Thus, in those patients receiving inhalation agents pancuronium was administered 12-15min after their commencement. After pancuronium the neuromuscular junction was allowed to recover spontaneously until the height of the first twitch of the train reached 10% of the height of the prepancuronium control value, when atropine 17 fig kg" 1 and neostigmine 36 ng kg" 1 were injected simultaneously. Controlled ventilation, neuromuscular transmission studies and anaesthesia with halothane or enflurane, if used, were continued for a further 30 min. The mean values are presented with the standard error of the mean as the index of dispersion. After one-way analysis of variance, probabilities for differences between the halothane and enflurane groups were compared with the control (fentanyl) group using Student's t test for unpaired data. The null hypothesis was rejected when P<0.05. RESULTS Before administration of pancuronium, muscle twitch activity had returned to normal and the train-of-four () the height of the fourth twitch as a percentage of the first in each train was , 97.5 ±0.9 and 96.4± 1.1 in the fentanyl, halothane and enflurane groups respectively. The time to 10% recovery in the control (fentanyl) group was 35.4±7.0min (mean±sem) (table I). The time was not altered significantly by halothane (29.4 ±4.4 min), but was prolonged by enflurane (57.9±6.0min; P<0.05). Following injection of neostigmine, all patients demonstrated a rapid increase in response to the first stimulus of each train, expressed as the percentage of the first twitch height compared with control () (table I). The rates of recovery of the fentanyl and halothane groups were similar. The mean values for the enflurane group were lower than for fentanyl but the differences were not statistically significant. Recovery of showed a similar general pattern. There were no differences between the recovery rates of fentanyl and halothane, but recovery of the enflurane group was less than the control group and the differences were significant at 4, 5, 10, 20 and 30 min after reversal with neostigmine. Thus the rate of recovery of neuromuscular transmission, when assessed using train-of-four stimulation, was significantly reduced during enflurane but not halothane anaesthesia. DISCUSSION In general, it is assumed that "the degree of neuromuscular blockade at the time when neostigmine is administered determines the speed and extent of antagonistic action by neostigmine" (Miller, 1976). The present study indicates that the rate of recovery is reduced when neostigmine is adminis- TABLE I. Times (mean±sem) to 10% spontaneous recovery and recovery of first stimulus of each tram, expressed as the percentage (± SEM) of the height of the first nuitch compared with control () and of recovery of tram-of-four () the height of the fourth twitch as a percentage of the first m each train after antagonism with neostigmine. *P <0 05 compared with control group (fentanyl), **P <0.01compared with control group (fentanyl) Tune after reversal (min) Fentanyl (35.4±7.0min to 10% ) 21.2 ± ± ± ± ± ± ± ± ± ± ± ±6.4 Halothane (29.4±4 4 min to 10% ) 17.5 ± ± ± ± ± ± ± : ±2.0 Enflurane (57 9*±6.0min to 10% ) 16 0 ± ± ± ± ± ± ± ± * ± * ± ** ± " 61 2** ±3 5

3 NEOSTIGMINE ANTAGONISM OF PANCURONIUM WITH ENFLURANE 443 tered during enflurane anaesthesia. Miller, Larson and Way (1972) demonstrated that the amount of neostigmine necessary to antagonize competitive neuromuscular blocking drugs was independent of the dose of relaxant administered. However, Katz (1971a) showed that, when the duration of paralysis was prolonged with a second dose of * pancuronium and antagonism was attempted with neostigmine at the same degree of spontaneous recovery, subsequent recovery after neostigmine was faster in those subjects who had received the larger cumulative dose of pancuronium. These studies suggest that the rate of recovery of neuromuscular, function is either unchanged or increased when the duration of the block is prolonged by increasing the dose of neuromuscular blocking drug. The present study indicates that, during enflurane anaesthesia, not only is the duration of pancuronium-induced neuromuscular blockade prolonged, but also the rate of recovery of neuromuscular activity after antagonism with neostigmine is decreased compared with patients anaesthetized with narcotics or equipotent concentrations of halothane. In vitro studies using isolated nerve-muscle preparations have demonstrated that the predominant action of inhalation anaesthetic agents on neuromuscular transmission is upon post-junctional structures (Kennedy and Galindo, 1975a, b; Waud and Waud, 1975a, b). They induce non-competitive depression of depolarization and at equivalent anaesthetic concentrations enflurane is more depressive than halothane (Waud and Waud, 1979). In man, although there are no reports using train-offour stimulation, the twitch response to single (Katz and Gissen, 1967) or tetanic stimuli at 30 (Lebowitz, Blitt and Walts, 1970) or 50 Hz (Fogdall and Miller, 1975) is not depressed during anaesthesia with nitrous oxide and halothane or enflurane at concentrations used in the present study. However, when the inhalation agents are combined with competitive neuromuscular blocking drugs the additive effects result in the potentiation of the relaxants (Waud, 1979). In the present study antagonism of the neuromuscular block with neostigmine was attempted at 90% block and this level was the result of the combined effects of the anaesthetic and relaxant. It has been shown that the enhanced depression of tetanic twitch response of tubocurarine by halothane is restored to normal by neostigmine (Hughes and Payne, 1979; Payne, Hughes and Al Azawi, 1980), but the depression of single twitch response by enflurane alone could not be antagonized by neostigmine (Lebowitz, Blitt and Walts, 1970). Thus, probably, only that block from the relaxant would be reversed with neostigmine and this, in part, explains the impaired reversal of the enflurane group. In addition, Stanski and colleagues (1980) have shown a time-dependent increase in sensitivity to tubocurarine during enflurane but not halothane anaesthesia. If the same phenomenon occurs with pancuronium it would also contribute to the impaired antagonism. During the course of the present study the concentration of anaesthetic agent in the muscles would have increased gradually and the effect on neuromuscular conduction would have been greater during enflurane than halothane anaesthesia for several reasons. Enflurane is a more potent depressant of neuromuscular conduction (Waud and Waud, 1979) and muscle equilibrium would have been greater as a result of its longer administration and lower muscle solubility (Eger, 1974). Simple calculations show that the muscle anaesthetic concentration at the end of the study would have reached approximately 80% of the end-tidal concentration in the enflurane group but only 50% in the halothane group. Patients anaesthetized with halothane showed no difference in duration or antagonism of neuromuscular blockade compared with those receiving fentanyl. This does not deny any action of halothane on neuromuscular transmission, because differences might have been seen if spontaneous recovery had been observed for longer. In addition preliminary studies in animals suggest that fentanyl may have a similar small potentiating effect (Krieg et al., 1980). Impaired neostigmine antagonism of a nondepolarizing neuromuscular blockade, as opposed to potentiation of its intensity and duration has only been proved in association with hypercapnia (Miller et al., 1975; Miller and Roderick, 1978; Tammisto, Wirtavouri and Salmenpera, 1981), metabolic alkalosis (Miller et al., 1975; Miller and Roderick, 1978) and antibiotic administration (Miller, 1976). Enflurane anaesthesia should be added to this list. However, the results of this study were obtained under standardized experimental conditions. In the clinical situation, reversal may be attempted at different, usually greater, degrees of spontaneous recovery of neuromuscular activity and the inhaled concentration of enflurane reduced before the end of surgery. Both of these would reduce the effects of the changes described.

4 444 BRITISH JOURNAL OF ANAESTHESIA REFERENCES All, H. H., Utting, J. E., and Gray, T. C. (1970). Stimulus frequency in the detection of neurorauscular block in human] Br.J. Anaesth., 42, 967. Eger, E.I (1974). Anesthetic Uptake and Action, p. 80. Baltimore Williams and Wilkins. Fogdall, R. P., and Miller, R. D (1975). Neuromuscular effects of enflurane, alone and with d-tubocuranne, pancuronium, and succinylcholine, in man. Anestheswlogy, 42, 173. Hughes, R, and Payne, J P. (1979) Interaction of halothane with non-depolarizing neuromuscular blocking drugs in man Br. J. Chn. Pharmacol., 7, 485. Katz, R. L. (1971a). Clinical neuromuscular pharmacology of pancuronium. Anestheswlogy, 34, 550. (1971b). Modifications of the action of pancuronium by succinylcholme and halothane. Anestheswlogy, 35, 602 Gissen, A. J (1967). Neuromuscular and electromyographic effects of halothane and its interaction with d-tubocurarine in man. Anestheswlogy, 28, 564. Kennedy, R. D, and Gahndo, A. D (1975a). Neuromuscular transmission in a mammalian preparation during exposure to enflurane. Anestheswlogy, 42,432 (1975b) Comparative site of action of various anaesthetic agents at the mammalian myoneural unction. Br. J. Anaesth., 47, 533. Kreig, N., Rutter, J M. J., Crul, J. F., and Booij, L. H. D J (1980). Preliminary refiew of the interactions of Org NC45 with anaesthetics and antibiotics in animals Br. J Anaesth, 52.33S Lebowitz, M. H., Bhtt, C. D., and Walts, L. F. (1970). Depression of twitch response to stimulation of the ulnar nerve during Ethrane anesthesia in man. Anestheswlogy, 33, 52. Miller, R D. (1976). Antagonism of neuromuscular blockade Anestheswlogy, 44, 318. Larson, C. P. r, and Way, W. L (1972). Comparative antagonism of d-tubocuranne, gallamine-, and pancuroniumlnduced neuromuscular blockades by neostigmine. Anestheswlogy, 37,503 Roderick, L. L. (1978). Acid-base balance and neostigmine antagonism of pancuronium neuromuscular blockade. Br.J Anaesth.,SO, 317 Van Nyhuis, L. S., Eger, E. I., and Way, W. L (1975). The effect of acid-base balance on neostigmine antagonism of d-rubocuranne-induced neuromuscular blockade. Anestheswlogy, 42, 377. Payne, J P., Hughes,R,and Al Azawi,S.(1980) Neuromuscular blockade by neostigmine in anaesthetized man Br. J Anaesth., 52, 69. Stanski, R. D., Ham, J., Miller, R. D., and Sheiner, L. B (1980). Time-dependent increase in sensitivity to d-tubocurarine during enflurane anesthesia in man. Anestheswlogy, 52,483. Tammisto, T., Wirtavo'uri, K., and Salmenperi, M. (1981). Effect of hypo- or hypercarbia on the neostigmine antagonism of pancuronium-induced neuromuscular blockade in man Br. J. Anaesth., 53, 116P. Walts, L F., and Dillon, J. B. (1970). The influence of the anesthetic agent on the action of curare in man. Anesth. Analg. (Cleve.),49,i7. Waud, B. E. (1979). Decrease in dose requirements of d-tubocurarine by volatile anesthetics Anestheswlogy, 52,298. Waud, D. R (1975a). The effects of diethyl ether, enflurane, and lioflursne at the neuromuscular junction. Anestheswlogy, 42, 275. (1975b). Comparison of the effects of general anesthetics on the end-plate of skeletal muscle Anestheswlogy, 43,540. (1979). Effects of volatile anesthetics on directly and indirectly stimulated skeletal muscle Anestheswlogy, 50,103 ALTERATION DE L'ANTAGONISME DU PANCURONIUM PAR LA NEOSTIGMINE AU COURS DE L'ANESTHESIE A L'ENFLURANE CHEZ L'HOMME RESUME Nous avons compare les vitesses de recuperanon d'un bloc neuromusculaire induit par le pancuronium apres administration de neostigmine au cours d'une anesthesie entretenue par le protoxyde d'azote et son des morphinomimetiques administres en disconnnu, soit de rhalothane, soit de 1'enflurane. Nous avons etudie 30 patients chez qui l'anesthesie generale etait entretenue soit avec du protoxyde d'azote (70%), du fentanyl et du thiopental, soit du protoxyde d'azote (70%) et de liialothane (0,55-0,65% en fin d'expiration), soit du protoxyde d'azote (70%) et de 1'enflurane (1,3-1,4% en fin d'expiration). La reponse musculaire du twitch etait mesuree en utjlisant la stimulation par le train de quatre On antagonisait l'action du pancuronium (3mg/70kg) par de la neostigmine (2,5 mg/70 kg), a 10% de recuperation spontanee du premier twitch du train par rapport a la valeur controle, lorsque Ton comparait les groupes avec morphinomimetiques et avec halothane. II n'y avait pas de difference significative entre les delais d'obtenaon d'une recuperation spontanee de 10% et les vitesses de recuperation du train de quatre apres neostigmine. Par contre, si on la compare a l'anesthesie entretenue au fentanyl, l'anesthesie a 1'enflurane s'accompagne d'un allongement significant du delai de recuperation de 10% (57,9 ± 6,0 mm contre 35,4 ± 7,0 mm) et d'une decroissance dans les recuperations du train de quatre a 4, 5, 10, 20 et 30 nun apres ncosngmine. Nous en concluons que, dans les conditions de cette etude, l'antagonisme, par la neostigmine, du bloc neuromusculaire induit par le pancuronium est altere par l'anesthesie a renflurane mais pas par l'anesthesie a l'halothane. ABGESCHWACHTE ANTAGONISIERENDE WIRKUNG VON NEOSTIGMIN AUF PANCURONIUM UNTER ENFLURANE-ANAESTHESIE BEIM MENSCHEN ZUSAMMENFASSUNG Wir haben die Erholungszeit emer durch Pancuronium hervorgerufenen neuromuskularen Blockade nach Gabe von Neostigmin bei Narkosen verglichen, die nut Lachgas/Sauerstoff entweder mit i v Narkotika oder mit Halothan bzw mit Enflurane unterhalten wurden. Wir untersuchten 30 Parienten, die erne Narkose mit N 2 O 70%-Fentanyl/Thiopental bzw. mit N 2 O 70%-Halothan (0,55 ±0,6%) oder nut N 2 O 70%-Enflurane (1,3 ±4%) erhielten. Die Muskelkontrakolitat wurde mit der "train-of-four"-methode gemmessen Pancuromum (3 mg/70 kg) wurde nut Neostigmin (2,5 mg/70 kg) antagonisiert, wenn eine 10% lge Spontanerholung der ersten Kontraktilitat un Vergleich zur Kontrollgruppe eingetreten war. Es gab kemen signifikanten Unterschied zwischen der Zen emer 10%igen Spontanerholung, der ersten Kontraktilitat und den Zeiten der

5 NEOSTIGMINE ANTAGONISM OF PANCURONIUM WITH ENFLURANE 445 "train-of-four"-erholung nach Neostigmin un Vergleich der l.v. Narkotika und der Halothan-Gruppe Unter Enfluran-Narkosc zeigte sich jedoch rm Vergleich zu Fentanyl ein deuthcher Anstieg der 10%-Erholungszeit (57,9± 6,0min ci 35,4 ± 7,0min) und Abnahme der "train-of-four"-zeiten 4, 5, 10, 20 und 30 mm nach Neosngmin-Gabe. Daraus schliefien wir, dai5 die antagonisierende Wirkung von Neostigmin auf die durch Pancuronium ausgeloste neuromuskulare Blockade bei Enflurane- Narkose abgeschwacht ist. Bei Halothan ist dies [edoch nichtder Fall. IMPOSIBILIDAD DE NEUTRALIZAR EL PANCURONIO CON NEOSTIGMINA DURANTE LA ANESTESIA EN EL HOMBRE MEDIANTE ENFLURANO SUMARIO Hemos comparado los regimenes de recuperaci6n del bloqueo neuromuscular inducido por pancuronio, despues de la administracion de neostigmma y durante la anestesia mantemda con oxido nitroso y narcoticos admimstrados intermitentemente, bien fuera halotano o enflurano. Se estudiaron treinta pacientes en los que la anestesia se mantuvo con oxido nitroso la 70% en fentanilo y tiopentona, con oxido nitroso al 70% en halotano (periodo final de 0,55-0,65%) o con oxido nitroso al 70% en enflurano (periodo final de 1,3-1,4%) Se midio la respuesta de crispamiento muscular usando estimulacion de cuatro impulsos. El pancuronio 3mg/70kg se neutralizo con neostigmina 2,5mg/70kg al acontecer una recuperacion espontinea del 10% correspondiente al primer impulso, en comparacion con el control. No hubo diferencias notables en los penodos de tiempo necesanos para obtener el 10% de recuperacion espontinea correspondientes a la primera crispacion, ru en los regimenes de recuperacion de los cuatro impulsos despues de administrar la neostigmina, cuando se compararon los grupos de narconcos y los de halotano Sin embargo, la anestesia con enflurano, en comparacon con la de fentanilo, vino asociado con un incremento significanvo del periodo necesano para obtener la recuperaci6n del 10% (57,9±6,0mm contra 35,4±7,0min) y con disminuciones de las recuperaciones de los cuatro impulsos, a los 4, 5, 10, 20, y 30 minutos despues de la neostigmina Concltumos que bajo las condiciones de este esrudio, la neutralizaci6n del bloqueo muscular inducido por pancuronio mediante la neostigmina se vio imposibilitada dutante la anestesia con enflurano pero no durante la de halotano