Br. J. Anaesth. (1983), 55, 955
PATTERN OF CHANGE OF BRONCHOMOTOR TONE FOLLOWING REVERSAL OF NEUROMUSCULAR BLOCKADE Comparison between atropine and glycopyrrolate J. HAMMOND, D. WRIGHT AND J. SALE
The method by which neuromuscular blockade is reversed has been a controversial issue for many years. There is now enough evidence to suggest that the concurrent administration of neostigmine with an anticholincrgic drug is less likely to give rise to dysrhythmia or bradycardia than if these drugs are given separately (Ovassapian, 1969). Furthermore, recent studies have shown the quaternary ammonium drug, glycopyrrolate, to be superior to atropine in respect of changes in the heart rate and antisialagogue activity (Cozanitis et al., 1980). Little is known about the changes in bronchomotor tone caused by neostigmine, or how effectively the anticholinergic drugs protect against the bronchoconstriction that could be anticipated from stimulation of muscarinic receptors in the bronchi. Conventionally, airways resistance is measured using whole body plethysmography with a conscious, co-operative volunteer. Although this technique is not suitable for measurements in the anaesthetized, artificially ventilated subject, the forced airflow oscillation method allows measurements to be made in this group of patients. Although clinically detectable narrowing of the airways is not usually a problem during reversal in the normal patient, it has been suggested that it may be of concern in the asthmatic subject (Gold, 1970). This trial was undertaken to investigate the changes in bronchomotor tone following reversal of J. HAMMOND, M.B., F.F.A.R.OS.; D.
WRIGHT, B.SC: J. SALE,
M.B., F.F-A-R.c.s.: Department of Anaesthetics, King's College Hospital Medical School, Denmark Hill, London SES 9RS.
neuromuscular blockade and to compare the degree of protection afforded by two commonly used anticholinergic drugs. PATIENTS AND METHODS
The study was approved by King's College Hospital Ethics Committee. Twenty patients, who had undergone elective surgery for which tracheal intubation and non-depolarizing neuromuscular blockade were required, were included in the study. Patients (A.S.A. groups I and II) were nonsmokers and gave no history of respiratory disease. Patients were excluded if receiving any drugs known to affect bronchomotor tone, such as 0 blockers. They were randomly allocated to receive either atropine 20ngkg -1 (10 patients) or glycopyrrolate 10 fig kg"1 (10 patients) with neostigmine SOngkg"1 for reversal of neuromuscular blockade at the end of surgery. Measurement of specific airways conductance
This was measured using the forced airflow oscillation method described by Jordan and colleagues (1981), following modifications to a Bain anaesthetic system (fig. 1). The reservoir bag of the Bain system was replaced by a purpose-built sinusoidal pump, producing an oscillating airflow of stroke volume 58 ml at 3 Hz. Airway pressure was measured at the tip of the tracheal tube, using a catheter connected to a Pioden UP2 pressure transducer. Flow was measured using a Fleisch no. 2 pneumotachograph © The Marmillan Press Ltd 1983
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Specific airways conductance (s. Gn) was measured using the forced airflow oscillation method, to study the effect of two regimens, commonly used for the reversal of neuromuscular blockade, on bronchomotor tone. Patients who had received neuromuscular blockers and had undergone elective surgery were randomly allocated to receive neosrigmine 5Ongkg~' given concurrently with either atropine 20ng kg"1 (10 patients) or glycopyrrolate 10 fig kg"1 (10 patients). Before administration, five baseline measurements of i.Gmw were obtained and measurements were then made at intervals of 1 min for the next 10 min At 3 min there was a significant difference in s.G,, between the two groups, higher values being found in the atropine group. At 10 min, no significant difference was seen between the groups, although both showed a significant decrease in s.Gn, compared with baseline values (P< 0.05).
BRITISH JOURNAL OF ANAESTHESIA
956
Electronic Computer
Processor
Suction
FIG. 1. Forced oscillation apparatus attached to the Bain system.
with a Validync MP45—1 differential pressure transducer. The pressure and flow signals were analysed electronically and processed on line using an Apple II computer programmed by J. R. Lehane. This produced resistance-volume curves from which the reciprocal, specific conductance, was derived directly. For further theoretical details, see Lehane, Jordan and Jones (1980), Jordan and others (1981) and Lehane (1982). Following premedication with papaveretum and hyoscine (in standard doses) anaesthesia was induced with Althesin and maintained with nitrous oxide in oxygen plus incremental doses of fentanyl, supplemented with cnflurane to eliminate the possibility of awareness. Neuromuscular blockade for trachea! intubation and the subsequent surgery was provided by pancuronium 80ngkg~'. Ventilation was maintained constant throughout the procedure and slight hyperventilation was induced. This, together with incremental doses of fentanyl, decreased the likelihood of the patient attempting to breathe immediately following reversal. The ECG was monitored in all patients. Five baseline measurements of s.Gn were made before reversal, the enflurane having been discontinued at least lOmin previously. Residual neuromuscular blockade was antagonized as skin closure was commenced and measurements of s. Gn
were made at 1-min intervals for the next lOmin. ECG and heart rate were monitored closely to detect any bradycardia since this can occur occasionally with these reversal regimens (Mirakhur et al., 1981). Attempts at spontaneous respiration were detected easily by inspection of the resistance-volume plot displayed on the visual display unit. Later, pharyngeal suction was carried out and on recommencement of spontaneous ventilation, the endotracheal tube was removed. RESULTS
None of the patients exhibited clinically detectable bronchoconstriction following reversal and no patient developed a heart rate of less than 60 beatmin"1. Specific conductance follows a positive skew distribution and, therefore, to perform any parametric statistical tests, it was necessary to transform all the data logarithmically. Figure 2 shows the mean changes in log s.G n compared with the baseline values for the two groups of patients. Figures 3 and 4 show the individual changes in the atropine and glycopyrrolate groups, respectively. Following administration of atropine and neostigmine, there appeared to be an initial increase in s.Gw during the first 3 min in all
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patients, whereas the glycopyrrolate-neostigmine tion of the drugs. The control values were also group showed no obvious trend. Thereafter, a compared. There was a significant difference steady decrease occurred in s. Gn in both groups. (-P< 0.05) in s.Gw between the two groups at 3 and The values of log s.Gn were compared using the 4min. There were no significant differences at any unpaired rtest at each sample time after administra- other times. Comparing the results at 10 min with
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baseline values (paired ttest), both groups showed a significant decrease in s.Gn ( P < 0.05), although no difference had been found between the two groups using the unpaired ttest. A comparison of the five control values, and the last four values of s. Gn for each patient, showed that six of 10 patients receiving atropine and neostigmine had a significant decrease in s. Gm ( P < 0.05). In the patients receiving glycopyrrolate and neostigmine, five out of 10 showed a significant decrease. DISCUSSION It was decided not to make this trial double-blind for two reasons. First, it became apparent very quickly from the change in heart rate which drug combination had been given and, second, the values of specific conductance were calculated by the computer without observer influence. It is known that both atropine and glycopyrrolate i.v. cause bronchodilatation and that, if administered in a dose ratio of 1:2, will have similar effects on s.G w . Furthermore, the effect of glycopyrrolate persists for at least 4 h, whereas the effect of atropine has ceased by this time (Gal and Suratt, 1981). Many anaesthetic agents may be expected to affect bronchomotor tone, although relatively little evidence exists as yet. For this reason the anaesthetic technique, including premedication, was kept constant. To our knowledge, no anaesthetic technique yet exists which has been shown to be complete-
ly free of autonomic or other bronchomotor effects. The results show that, following reversal with the two regimens, the changes in specific conductance against time followed a similar pattern to changes in heart rate demonstrated by Mirakhur and colleagues (1981). The initial increase in s.Gn in the atropine group was reflected by the initial tachycardia caused by the unopposed action of this drug. No such change was seen in the glycopyrrolate group because of the slower onset of action of this drug. The effect of neostigmine began after approximately 4min, following which time a steady decrease in s. Gn was observed. At lOmin both groups showed a small degree of bronchoconstriction compared with baseline values, although the values of s.Gn never decreased to that associated with detectable bronchospasm. In conclusion, it is shown that atropine and glycopyrrolate are equivalent in their degree of protection against neostigmine-induced bronchoconstriction in the normal subject. Further work is needed to evaluate the effects in asthmatic subjects, in whom difficulties might be anticipated. ACKNOWLEDGEMENTS
We would like to thank A. H. Robins Co. Ltd for finnnrinl assistance with this trial, and C. Jordan and J. Lehane for technical assistance and advice. Mrs V. Pcoley typed the manuscript.
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BRONCHOMOTOR TONE FOLLOWING REVERSAL REFERENCES
COURBE DE MODIFICATION DU TONUS BRONCHOMOTEUR APRES ANTAGONISME DU BLOC NEUROMUSCULAIRE Contparaison tntrt Atropint a CHycopyrrolats
La conductance specifique des voies aeriennes (Csva) a etc mesuree en utilisant la mcthode d'oscillation forcee du flux d'air, ceci pour etudier l'effet sur le tonus bronchomoteur de deux protocoles courants d'annulation du bloc neuromusculaire. Des patients qui avaient 6t6 curarises pour des actes de chirurgie reglee, ont requ de facpn aleatoire de la neostigmine 50 ng kg" 1 , associeesoitaderatropine20figkg~'(pour lOd'entreeux), soit a du glycopyrrolate 10/igkg" 1 (pour 10 autres). Avant l'injucrion, cinq mesures conlrole de la Csva ont iti faites, puis les mesures se sont succeciees toutes les minutes pendant 10 min. A la 3emin, il y avait une difference significative entre les deux groupes, le groupe atropine presentant des valeurs plus eJevees. A JO min, il n'y avait pas de difference significative entre lei groupes, bien que dans les deux, une diminution significative de Csva par rapport aux contrdles soit apparue (P< 0,05).
VERANDERUNGSMUSTER DES BRONCHOMUSKULAREN TONUS NACH ANTAGONISIERUNG VON MUSKELRELAXANTIEN Vergieich zwischen Atropm und Gtycopyrrolax ZUSAMMENFASSUNG
Um den Effekt von zwei verbreiteten Schemata zur Antagonisierung von Muskelrelaxantien auf den Tonus der Bronchialmuskulatur zu untersuchen, wurde die spezifische Lcitf&higkeit der Luftwege (s.G re ) mit Hilfe der Forced-airflowOizillationsmethode gemessen. Patienten, die zur Operation Muskelrelaxanticn bekommen hatten, wurden auf zwei Gruppen zufallsverteilt, von denen die eine mit Neosrigmin 50 ug kg und Atropin 20ugkg~' (10 Patienten), die andere mit Neostigmin 50ngkg~' und Qykopyrrplat lOfigkg"1 (10 Patienten) antagonisiert wurde. Vor der Antagonisierung wurden funf Ausgangsbestimmungen von s.Gn gemacht, nach Gabe der Antagonisten Mcssungen fur mehrere Minuten im Minutenabstand. Nach 3 Minuten ergab sic(i ein signifikanter Unterschied zwischen den beiden Gruppen; es fanden sich hShere Werte in der Atropingruppe. Nach 10 Minuten war dieser Unterschied aufgehoben, wobei jedoch beide Gruppen einen signifikanten Abfall von s.G,w gegenubef den Ausgangswerten aufweisen (P<0,05).
TIPO DE CAMBIO DEL TONO BRONCOMOTOR A RAIZ DE LA INVERSION DEL BLOQUEO NEUROMUSCULAR Comparacion entrt la atropina y el glicopirwlato SUMARIO
Se midio la conductibilidad electrica especifica de las vias respiratorias (s.Gn,) mediante el metodo de oscikdon de la corriente de aire forzado con el objeto de estudiar el efectp de los dos regimenes corrientemente utjlizados para la inversion del bloqueo neuromuscular en el tono broncomotor. Se distribuyeron al azar pacientes que habian recibido bloqueadorej neuromusculares y estuvieron sometidos a cirujia electiva para administrales 5Ongkg~' de neo-estigmina junto con ya sea 20/igkg" 1 dc atropina (10 pacientes) ya sea 10 fig kg"1 de glicopirrolato (10 pacientes). Antes dc la administracion, se obtuvieron cinco medicioncs de referenda del s.Gtw y despuei se tomaron mediciones a intervalos de 1 min. durante los proiimos 10 min. A los 3 mjn. hubo Una diferencia signiiicante del s.Gtw entre los dos grupos, los vajores mayorcs encontrandose en el grupo con atropina. A los 10 min., no habia ninguna diferencia signiiicante entre los grupos, aun'que ambos mostraron una reduccion significativa del s.Gn, e n comparacion con los valoret de referenda (P<0,05). ' ' '
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Cozantis, D. A., Dundee, J. W.,Merrctt, J. D., Jones, C.J., and Mirakhur, R. K. (1980). Evaluation of glycopyrrolate and atropine as adjuncts to reversal of non-depolarizing neuromuscular blocking agents in a "true-to-life" situation. Br. J. Anaesth., 52, 85. Gal, T. J., and Suratt, P. M. (1981). Atropine and glycopyrrolate effects on lung mechanics in normal man. Anetth. Analg., 60, 85. Gold, M. I. (1970). Anaesthesia for the asthmatic patient. Antsth. Analg., 49, 881. Jordan, C , Lehane, J. R., Jones, J. G., Altman, D. G., and Royston, J. P. (1981). Specific conductance using forced airflow oscillation in mechanically ventilated human subjects. / . Appl. Phytiol., 51, 715. Lehane, J. R. (1982). Assessment of pulmonary airway calibre. Br. J. Anaestk., S4,751. Jordan, C , and Jones, J. G. (1980). Influence of halothane and enflurane on respiratory airflow resistance and specific conductance in anaesthetized man. Br. J. Anaesth., 52, 773. Mirakhur, R. K., Dundee, J. W., Jones, C. J., Coppel, D. L., and Clarke, R. S. J. (1981). Reversal of neuromuscular blockade: dose determination studies with atropine and glycopyrrolate given before or in a mixture with neostigmine. Antsth. Analg., 60, 557. Ovassapian, A. (1969). Effects of administration of atropine and neostigmine in man. Anath. Analg., 48, 219.
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