GLYCOPYRROLATE-NEOSTIGMINE MIXTURE FOR ANTAGONISM OF NEUROMUSCULAR BLOCK: COMPARISON WITH ATROPINE- NEOSTIGMINE MIXTURE

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1 Br.J. Anaesth. (1977), 49, 82 GLYCOPYRROLATE-NEOSTIGMINE MIXTURE FOR ANTAGONISM OF NEUROMUSCULAR BLOCK: COMPARISON WITH ATROPINE- NEOSTIGMINE MIXTURE R. K. MIRAKHUR, J. W. DUNDEE AND R. S. J. CLARKE SUMMARY Glycopyrrolate, a new anticholinergic agent, was evaluated and compared with atropine. Glycopyrrolate 0.2 mg to neostigmine 1.0 mg was found to be safe and effective. The heart rates remained more stable with glycopyrrolate, and the frequency of arrhythmia, which was both transient and of no consequence, was similar in the two s. The antisialogogue action of glycopyrrolate was superior to that of atropine. When antagonism of neuromuscular block is required, atropine is the usual anticholinergic drug employed to counteract the muscarinic actions of neostigmine. The timing of its administration with regard to that of neostigmine has been controversial; it has been administered both before and together with' neostigmine in an attempt to offset the extreme bradycardia that may follow the administration of the anticholinesterase drug. Cardiac arrest and even death have been reported in anaesthetized patients following the i.v. administration of atropine and neostigmine (Clutton-Brock, 1949; Hill, 1949; Macintosh, 1949; Lawson, 196). In most instances the drugs were administered together and the cause of the arrest was attributed to the summation of the cholinergic action of neostigmine and the initial central vagal stimulation of atropine. Sudden sympathetic predominance also could be responsible for such cardiac arrest (Jones, Deutsch and Turndorf, 1961). More recent reports have implicated atropine (when given before neostigmine) as the cause of serious tachycardia and arrhythmia (Jones, Deutsch and Turndorf, 1961; Eger, 1962) and Ovassapian (1969) observed that the degree and duration of the tachycardia were more marked when atropine preceded neostigmine. Although the studies of Kemp and Morton (1962) and Rosner, Kepes and Foldes (1971) popularized the use of a mixture of atropine and neostigmine, Baraka (1968a, b) found that both the previous administration of atropine and its mixture with neostigmine were safe provided oxygenation was maintained. R. K. MIRAKHUR, M.D., F.F.A.R.C.S. ; J. W. DUNDEE, M.D., PH.D., F.F.A.R.C.S., M.R.C.P.J R. S. J. CLARKE, M D., PH.D., F.F.A.R.C.S.J Department of Anaesthetics, The Queen's University of Belfast. Belfast, Northern Ireland. 6 A main disadvantage of atropine is its short duration of action (Wangeman and Hawk, 1942). L-Hyoscine (Scopolamine), another commonly used anticholinergic agent, has not only a short duration of action but has also a weak action on the cardiac vagus (Orkin, Bergman and Nathanson, 196). Both atropine and hyoscine, being tertiary amines, cross the blood-brain barrier and thus have some central effects. Franko and Lunsford (1960) found glycopyrrolate (Robinul) (- [(cyclopentylhydroxyphenylacetyl)oxy] - 1,1-dimethylpyrrolidinium) (fig. 1) to be a potent, Br- FIG. 1.Glycopyrrolate (-[(cyclopentylhydroxyphenylacetyl) oxy]-l,l-dimethylpyrrolidinium). long-acting anticholinergic agent and more recently it has been recommended as a suitable alternative to atropine (Klingenmaier et al., 1972; Ramamurthy, Shaker and Winnie, 1972; Oduro, 197). Its main advantages are that it has an onset of action similar to that of neostigmine and, being a quaternary compound, it does not cross the blood-brain barrier. It has been shown also to be a more effective antisialogogue than is atropine (Wyant and Kao, 1974). In view of these desirable properties it was decided

2 826 BRITISH JOURNAL OF ANAESTHESIA to evaluate this drug, in a mixture with neostigmine, during the antagonism of non-depolarizing myoneural block and to compare this combination with an atropine-neostigmine mixture. PATIENTS AND METHODS Forty fit adult patients of both sexes were studied. All were free from serious systemic disease (ASA grades I and II) and were undergoing various intra-abdominal operations. Premedication consisted of morphine or pethidine in conventional dosage and atropine 0.6 mg, given by i.m. injection 90 min before operation. Anaesthesia was induced with 2.% thiopentone 4- mg. kg- 1 and tracheal intubation was facilitated by using the non-depolarizing muscle relaxants pancuronium or tubocurarine. Anaesthesia was maintained with 70% nitrous oxide in oxygen supplemented by either halothane 0.% or incremental doses of fentanyl. Additional doses of muscle relaxant were administered as required. Ventilation was controlled during the operation and its adequacy was assessed by arterial blood-gas analysis. If necessary, ventilation was adjusted to maintain blood-gas concentrations at their baseline value. Halothane was discontinued at least 1 min before the end of the operation was anticipated and the last dose of muscle relaxant or narcotic analgesic was given at least 0 min before the end of the operation. The oropharynx was sucked free of secretions before antagonism and anaesthesia was continued with the same mixture of nitrous oxide in oxygen until extubation had been performed. The adequacy of ventilation was assessed again during the process of reversal. Any stimulation such as pharyngeal suction was avoided during the reversal process. The electrocardiogram (lead II) was monitored continuously throughout the operation and recordings were commenced about 2 min before the antagonism mixture was injected and continued until the 10th min after injection, or earlier if the patient was rejecting the endotracheal tube. The e.c.g. was analysed in detail for changes in cardiac rate and rhythm. All patients were awake 10 min after the end of the operation. In order to assess the amount of secretion, oropharyngeal suction was performed just before extubation. This was carried out by the attending anaesthetist who was not participating in the trial and did not know which anticholinergic drug (atropine or glycopyrrolate) had been given to the patient. This anaesthetist classified the secretions as excessive, moderate or minimal based on his clinical experience. Systolic arterial pressure was monitored at 1-min intervals during the course of antagonism. The patients were divided into two equal s of patients each. One received neostigmine 2. mg and atropine 1.2 mg while the other received neostigmine 2. mg and glycopyrrolate 0. mg. Each combination was given to alternate patients and injected over a period of 1 s. RESULTS The two s of patients were similar in their physical characteristics (table I). TABLE I. Physical characteristics of patients No. of patients Age (yr + SEM) Weight (kg ± SEM) Physical status ASA I ASA II Female Male Atropineneostigmine ± ± The mean heart rates in the two s are shown in table II and the percentage differences from the control values are shown in figure 2. It was apparent that, in the atropine, mean heart rate increased and that this increase was maximal at 1 min following injection. The increase in rate differed significantly (P<0.0) from baseline at 1 and 2 min. The rate decreased to less than the control value after the 4th min and remained so throughout the remaining period of study. This decrease was, however, significant (P<0.0) only at 6 min after injection. In the TABLE II. Mean heart rate ( ± SEAT) after injection of antagonizing mixture. (n = ) Time after injection (min) Before injection Atropine-neostigmine ± ± ±.9

3 GLYCOPYRROLATE-NEOSTIGMINE MIXTURE 827 w O I S - ^ - extubation. During antagonism arterial blood-gas tensions were adequate in both s (table III). TABLE III. Blood-gas analyses (kpa±sem) during antagonism Pco 2 Po a Atropine-neostigmine 4.64 ± ± ± TIME (M1N) FIG. 2. Percentage changes in mean heart rate after the injection of the antagonizing mixtures: neostigmine and glycopyrrolate, neostigmine and atropine. of patients who received glycopyrrolate there was no increase in mean heart rate which remained near the value before injection for the first 2 min. The rate decreased thereafter but differed significantly from baseline only at 6 min following injection. Significant differences were found between the atropine and glycopyrrolate s at 1 and 2 min after injection, corresponding to the period of maximum tachycardia in the atropine. One hour after antagonism the heart rates were similar in the two s although they were significantly less than the control values in both s (glycopyrrolate : P<0.02; atropine : P<0.00). In the atropine sinus arrhythmia occured in one patient and nodal rhythm, of brief duration, in two patients. In addition, one patient had a continuous inverted T-wave and another had marked sinus bradycardia which required additional i.v. atropine 6 min after the injection of the antagonizing mixture. In the receiving glycopyrrolate three patients exhibited nodal rhythm at 2, 4 and 7 min after the antagonism. Two other patients had single atrial ectopic beats at 4 and 6 min respectively. The remaining patients in both the s remained in sinus rhythm throughout. The changes in systolic arterial pressure were insignificant in both s. The arterial pressure tended to increase by 10- mm Hg towards the end of the procedure when the patients were waking. However, this returned to baseline values soon after 60 There was no difference between the two s in the incidence of excessive secretion (table IV). However, the quality of dryness was significantly better (P < 0.0) in the receiving glycopyrrolate. Minimal Moderate Excessive Total TABLE IV. Secretions during antagonism Number 12 of patients Atropineneostigmine DISCUSSION This study demonstrates the safety and effectiveness of both glycopyrrolate and atropine in antagonizing the muscarinic actions of neostigmine when the latter was given for the reversal of neuromuscular block. It was found that a safe and effective ratio of the two drugs was glycopyrrolate 0.2 mg : neostigmine 1 mg. This conclusion had been reached previously by Ramamurthy, Shaker and Winnie (1972) while examining the time sequence and dosage of glycopyrrolate with respect to neostigmine. Previous studies (Baraka, 1968b; Ovassapian, 1969; Rosner, Kepes and Foldes, 1971) have shown that atropine and neostigmine are better administered together. In these studies it was found that tachycardia as a result of atropine occured always before bradycardia as a result of neostigmine. Baraka (1968b) suggested that the atropine molecules attached themselves directly to the cardiac cholinergic receptors, whereas neostigmine acted indirectly by inhibiting the hydrolysis of acetylcholine and promoting its accumulation and subsequent competition with the atropine molecules already present

4 828 BRITISH JOURNAL OF ANAESTHESIA One of the aims in giving an anticholinergic drug together with neostigmine is to prevent the bradycardia which invariably follows the injection of neostigmine. Usually atropine causes an initial tachycardia which, while the antagonism is still incomplete, gives way to bradycardia which can be alarming on occasions. Similar changes in heart rate were observed in the present study. In comparison, the heart rate changed little with glycopyrrolate. We did not observe an initial tachycardia with the use of the glycopyrrolate-neostigmine mixture although the heart rate did decrease slightly over the period of antagonism. However, a slight initial tachycardia has been reported by others (Klingenmaier et al., 1972; Ramamurthy, Shaker and Winnie, 1972) and Wong and others (1974) reported significant increases in heart rate in children undergoing cardiac surgery following the use of glycopyrrolate-neostigmine mixtures. The increases were less than those noted with the atropine-neostigmine mixture but the greatest tachycardia following glycopyrrolate (in the mixture) occured at 2 min after injection as compared with the peak at 1 min following atropine. An explanation for the lesser degree of tachycardia with the use of glycopyrrolate in the mixture could be that both glycopyrrolate and neostigmine are quaternary compounds and thus have a similar onset of action. In contrast atropine, being a tertiary amine, reaches the receptor sites faster than neostigmine (Rosner, Kepes and Foldes, 1971). In unpublished studies on volunteers, we found that glycopyrrolate does not cause tachycardia even in the absence of neostigmine. This was true for doses of up to 0.2 mg given i.v., doses which, however, caused a marked and significant reduction in salivary secretion. On the basis of the study in volunteers one could have postulated the presence of two types of cholinergic receptors; one in the heart and the other in the salivary glands. However, the protection which glycopyrrolate affords against neostigmine-induced bradycardia casts doubt on this hypothesis. A weak negative correlation was observed between the initial heart rates and the maximal increase in rate in the of patients receiving glycopyrrolate. In contrast, a significant negative correlation was observed by Wong and others (1974). However, they were studying children undergoing cardiac surgery who were receiving various types of drugs and who had possible malfunction of the autonomic nervous systems. The absence of a significant correlation may be because glycopyrrolate has little effect on heart rate. The myoneural block was antagonized even in the patients with slow heart rates without any incident or recourse to more glycopyrrolate or other anticholinergic agent. The arrhythmias observed in both s were transient and insignificant and did not require any therapy. The commonest arrhythmia was transient nodal rhythm and non-specific T-wave changes. Klingenmaier and colleagues (1972) reported a very low frequency (4.1%) of arrhythmia in patients receiving a glycopyrrolate-neostigmine mixture. Wong and others(1974) foundahigher frequency of arrhythmia in patients receiving glycopyrrolate when they compared their findings with those of Salem and others (1970) who had administered atropine to similar patients. They found also that more patients in their atropine converted from abnormal to normal rhythms. Thus, they suggested that adequate vagal blockade was required before the onset of the action of neostigmine and that vagal blockade was better achieved with atropine. However, we cannot substantiate their claims as the types of patients studied by us were different. Secretions can be copious and, at times, a problem associated with the use of atropine-neostigmine mixtures. However, it has been shown that glycopyrrolate is a more effective antisialogogue than atropine (Wyant and Kao, 1974). In the present study, it was found that more patients had "minimal" secretions in the receiving glycopyrrolate compared with the atropine. Thus it would appear that both atropine and glycopyrrolate are effective anticholinergic agents and will counteract the muscarinic actions of neostigmine. There was no difference in the frequency of arrhythmia, which was transient in both s. However, glycopyrrolate was associated with more stable heart rates and this could be useful when tachycardia is present already or is undesirable. ACKNOWLEDGEMENTS During the course of this study, Dr Mirakhur was in receipt of a Royal Victoria Hospital Research Fellowship. The supplies of glycopyrrolate (Robinul) were kindly provided by A. H. Robins Company Ltd. Thanks are due to the surgical colleagues and nursing staff of theatres of the Royal Victoria Hospital, Belfast. Dr J. Elliott, Consultant Anaesthetist, was helpful in the conduct of cases and Dr D. L. Coppel, Consultant Anaesthetist, criticized the manuscript. Dr I. W. Carson helped in the analysis of e.c.g. REFERENCES Baraka, A. (1968a). Safe reversal (1): atropine followed by neostigmine: an electrocardiographic study. Br. J. Anaesth., 40, 27.

5 GLYCOPYRROLATE-NEOSTIGMINE MIXTURE 829 Baraka, A. (1968b). Safe reversal (2): atropine-neostigmine mixture: an electrocardiographic study. Br. J. Anaesth., 40, 0. Clutton-Brock, J. (1949). Death following neostigmine. Br. Med. J., 1, Eger, E. I., u (1962). Atropine, scopolamine and related compounds. Anesthesiology, 2, 6. Franko, B. V.. and Lunsford, C. D. (1960). Derivatives of -pyrrolidinols. Ill: The chemistry, pharmacology and toxicology of some N-substituted--pyrrolidyl a-substituted phenylacetates. J. Med. Pharmaceut. Chem., 2, 2. Hill, M. (1949). Death after neostigmine injection. Br. Med. J... 2, 601. Jones, R. E., Deutsch, S., and Turndorf, H. (1961. Effects of atropine on cardiac rhythm in conscious and anesthetised man. Anesthesiology, 22, 67. Kemp, S. W., and Morton, H. J. V. (1962). The effect of atropine and neostigmine on the pulse rates of anaesthetised patients. Anaesthesia, 17, 170. Klingenmaier, C. H., Bullard, R., Thompson, D., and Watson, R. (1972). Reversal of neuromuscular blockade with a mixture of neostigmine and glycopyrrolate. Anesth. Analg. (Cleve.), 1, 468. Lawson, J. J. (196). Cardiac arrest following the administration of neostigmine. Br. J. Anaesth., 28, 6. Macintosh, R. R. (1949). Death following injection of neostigmine. Br. Med. J. 1, 82. Oduro, K. A. (197). Glycopyrrolate methobromide. II: Comparison with atropine sulphate in anaesthesia. Can. Anaesth. Soc.J., 22, 466. Orkin, L. R., Bergman, P. S., and Nathanson, M. (196). Effect of atropine, scopolamine and meperidine on man. Anesthesiology, 7, 0. Ovassapian, A. (1969). Effects of administration of atropine and neostigmine in man. Anesth. Analg. {Cleve.), 48, 219. Ramamurthy, S., Shaker, M. H., and Winnie, A. P. (1972). Glycopyrrolate as a substitute for atropine in neostigmine reversal of muscle relaxant drugs. Can. Anaesth. Soc. J., 19, 99. Rosner, V., Kepes, E. R., and Foldes, F. F. (1971). The effects of atropine and neostigmime on heart rate and rhythm. Br.J. Anaesth., 4, Salem, M. R., Ylagan, L. B., Angel, J. J., Vedam, V. S., and Collins, V. J. (1970). Reversal of curarization with atropine-neostigmine mixture in patients with congenital cardiac disease. Br.J. Anaesth., 42, 991. Wangeman, R. P., and Hawk, M. H. (1942). The effects of neostigmine, atropine and scopolamine on human subjects. Anesthesiology,, 24. Wong, A. Y., Salem, M. R., Mani, M., Padillo, E.. and Mehta, A. B., (1974). Glycopyrrolate as a substitute for atropine in reversal of curarization in paediatric cardiac patients. Anesth. Analg. (Cleve.),, 412. Wyant, G. M., and Kao, E. (1974). Glycopyrrolate methobromide. I: Effect on salivary secretion. Can. Anaesth. Soc.J., 21, 20. MELANGE DE GLYCOPYRROLATE ET DE NEOSTIGMINE POUR L'ANTOGONISME DU BLOC NEUROMUSCULAIRE: COMPARAISON AVEC LE MELANGE D'ATROPINE ET DE NEOSTIGMINE RESUME L'auteur a evalue le glycopyrrolate, nouvel agent antocholinergique, et l'a compare a l'atropine. II a trouve que 0,2 mg de glycopyrrolate pour chaque 1 mg de nsostigmine etait efficace et sans danger. La frequence cardiaque est restee plus stable avec le glycopyrrolate tandis que la frequence d'arythmie, qui etait transitoire et sans importance, a ete similaire dans les deux es. La reaction antisialogogue a ete plus prononcee avec le glycopyrrolate qu'avec l'atropine. GLYCOPYRROLAT-NEOSTIGMINMISCHUNG ALS GEGENWIRKUNG FUR EINEN NEURO- MUSKULAREN BLOCK: VERGLEICH MIT EINER ATROPIN-NEOSTIGMINMISCHUNG ZUSAMMENFASSUNG Ein neuer anticholinergischer Wirkstoff, Glycopyrrolat, wurde untersucht und mit Atropin verglichen. Glycopyrrolat, 0,2 mg, auf Neostigmin, 1,0 mg, envies sich als sicher und wirksam. Die Herztatigkeit blieb auf Glycopyrrolat stabiler, und die Haufigkeit von Arrhytmie, die nur fiuchtig und unwesentlich auftrat, war in beiden Gruppen ahnlich. Die anti-speicheltreibende Wirkung von Glycopyrrolat war der von Atropin uberlegen. MEZCLA DE GLICOPIRROLATO-NEOESTIGMINA EN ANTAGONISMO DEL BLOQUEO NEUROMUSCULAR: COMPARACION CON MEZCLA DE ATROPINA-NEOESTIGMINA SUMARIO Glicopirrolato, un nuevo anticolinergico, fue evaluado y comparado con atropina. Glicopirrolato 0,2 mg a 1,0 mg de neoestigmina se hall6 que era innocuo y eficaz. Los rimos cardiacos permanecieron mas estables con glicopirrolato, y la frecuencia de arritmia, que fue pasajera y sin consecuencias, fue similar en los dos grupos. La acci6n antisialogoga del glicopirrolato fue superior a la de atropina.