HAEMODYNAMIC RESPONSES TO ANTAGONISM OF TUBOCURARINE BLOCK WITH ATROPINE-NEOSTIGMINE MIXTURE IN CHILDREN

Br.J. Anaesth. (1977), 49, 901

HAEMODYNAMIC RESPONSES TO ANTAGONISM OF TUBOCURARINE BLOCK WITH ATROPINE-NEOSTIGMINE MIXTURE IN CHILDREN M. R. SALEM, T. TOYAMA, A. Y. WONG, H. K. JACOBS AND E. J. BENNETT SUMMARY

Since the early reports of cardiac arrest and death following the administration of neostigmine (CluttonBrock, 1949; Hill, 1949; Macintosh, 1949; Lawson, 1956; Pooler, 1957), various methods have been introduced to provide safe antagonism of myoneural block. These include hyperventilation to ensure adequate removal of carbon dioxide (Riding and Robinson, 1961), oxygenation (Baraka, 1968a), injection of atropine followed by neostigmine (Wylie and Churchill-Davidson, 1972), simultaneous injection of both drugs (Kemp and Morton, 1962; Baraka, 1968b), titration of the required dose using a nerve stimulator (Wylie and Churchill-Davidson, 1972) and substituting glycopyrrolateforatropine (Ramamurthy, Shaker and Winnie, 1972; Wong et al., 1974). Simultaneous injection of atropine and neostigmine has been adopted in preference to atropine followed by neostigmine (Baraka, 1968b; Salem et al., 1970). In spite of the wide use of the mixture, the haemodynamic responses to these drugs when given simultaneously have not been studied previously, perhaps because there was no simple method that would permit beat-to-beat measurements of the stroke volume. It has been proposed that cardiac output could be estimated accurately from variations in transthoracic electrical impedance (Kubicek et al., 1966). By producing a signal whose wave form is related to M. R. SALEM, M.D.; T. TOYAMA, M.D.; A. Y. WONG, M.D.; H. K. JACOBS, PH.D.; Department of Anesthesiology, Cook

County Hospital and The Hektoen Institute for Medical Research of Cook County Hospital, Chicago, Illinois, U.S.A. E. J. BENNETT, M.D., Abraham Lincoln School of Medicine, University of Illinois Hospitals.

events in the cardiac cycle, the stroke volume, and cardiac output, could be measured (Kubicek et al., 1966; Baker et al., 1971; Denniston et al., 1976). Recently, haemodynamic measurements obtained by variations in transthoracic electrical impedance have been evaluated in children (Labadidi et al., 1971). We have used the impedance cardiograph to study the haemodynamic changes following the injection of a mixture of atropine 20 f^g/kg and neostigmine 50 [xg/kg in children. METHODS

The investigation was approved by our hospital's ethical committee. Twenty healthy children of average weight undergoing elective non-cardiac operations were investigated. Ten were aged between 2 and 4 yr, five between 4 and 8 and five between 8 and 12 yr. All had fasted for a minimum of 5 h before surgery. They were visited the day before operation and the older children were reassured about their forthcoming anaesthetic experience. Premedication consisted of hyoscine 0.15-0.4 mg and morphine sulphate 0.18mg/kg given i.m. l h before the anticipated anaesthesia induction time. Anaesthesia was induced with either thiopentone or halothane. Suxamethonium 1.5mg/kg was given i.v. to facilitate tracheal intubation. Anaesthesia was then maintained with nitrous oxide 70% in oxygen. An initial dose of tubocurarine 0.3-0.5 mg/kg was given and intermittent doses were given thereafter as required. Ventilation was controlled at constant volume, appropriate to the patient, and a constant rate (between 12 and 22/min), throughout the

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Following antagonsim of tubocurarine block with a mixture of atropine 20 ng/kg and neostigmine 50 (ig/kg in 20 children, heart rate decreased from a control value of 110.4 beat/min to 90.1 at 5 min and 89.2 at 6 min (P < 0.02). Stroke volume index did not change during the first 5 min from a control value of 36.3 ml. beat" 1 . m~2 but a significant increase to 48 ml.beat"'.m" 2 was observed at the 6th and 7th mins following the injection of the mixture (P < 0.05). Cardiac index and mean arterial pressure remained unaltered throughout the period of observation. Normal sinus rhythm was maintained in all patients. It was concluded that antagonism of tubocurarine with an atropineneostigmine mixture does not produce any important haemodynamic change in children.

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BRITISH JOURNAL OF ANAESTHESIA tracheal tube was removed after it was established that neuromuscular function had recovered adequately. The data were subjected to statistical analysis using the t test for paired data. RESULTS

The haemodynamic variables during antagonism with the atropine-neostigmine mixture are shown in table I. Mean arterial pressure did not change significantly during antagonism (control value 80.2 mm Hg). Heart rate increased from a control mean value of 110.4 beat/min to 123.1 beat/min 1 min after injection of the mixture. This increase was not statistically significant. This was followed by a gradual decrease to 90.1 at 5 min and 89.2 at 6 min. Both values were significantly different from control (7><0.02). Stroke volume index did not change significantly from the control value of 36.3 ml .beat" 1 .m~2 during the first 5 min following the injection of the mixture. A significant increase to 48 ml. beat" 1 . m~2 was observed at the 6th and 7th minutes (/><0.05). Cardiac index remained essentially unaltered throughout the period of observation. Figures 1, 2 and 3 represent percentage changes in heart rate, stroke volume index and cardiac index respectively. All patients maintained normal sinus rhythm during and after injection of the mixture. No e.c.g. changes were noted. The block was antagonized as indicated by maintenance of the twitch height following tetanic stimulation and absence of posttetanic facilitation. When nitrous oxide was discontinued, the patients wakened promptly. Since muscular movements were encountered in some patients after the 7th minute following administration of the mixture, we discarded impedance measurements after the 7th minute.

TABLE I. Haemodynamic measurements during antagonism of curarization with a mixture of atropine 20 y-g/kg and neostigmine 50 v-glkg in children. Values are means ± SEM

Control Heart rate (beat/min)

110.47 + 7.1 Mean arterial pressure (mm Hg) 80.20 + 2.94 Stroke volume index 36.3 (ml. beat- 1 , m- 2 ) + 3.2 2 Cardiac index (litre.m- .min-') 3.88 + 0.37

30 s

1 min

2 min

3 min

4 min

5 min

120.42

123.19 + 6.7 84.23 + 3.02 31.3 + 3.3 3.87 ±0.39

113.33 + 6.27 83.42 + 3.14 37.3 + 4.0 3.88 + 0.35

101.6 + 6.89 82.75 + 3.24 38.2 + 3.5 3.65 + 0.35

94.7 + 6.15 80.54 + 3.38 41.8 + 3.6 3.71 + 0.34

90.15** + 5.77 79.30 + 3.46 42.9 + 3.7 3.78 + 0.38

±6.7

81.22 + 3.15 35.9 + 4.4 4.21 + 0.48

* /><0.01; ** P<0.02—compared with control measurements.

6 min

7min

89 29**

93.80 + 11.7 84.62 + 7.13 48.5*

±6.44

79.01 + 3.74 48.7* + 4.8 3.98 + 0.37

±4.2

4.37 + 0.94

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procedure and during antagonism of the myoneural block, using an Air Shields Ventimeter Ventilator with a paediatric attachment for small children. Before the injection of the antagonizing mixture arterial blood was sampled to check that Pa C02 and PzOt were in the range 4-5.2 kPa and greater than 13.2 kPa respectively. Four aluminium electrodes with mylar adhesive backing were placed circumferentially around the patient's neck and abdomen after induction of anaesthesia to allow haemodynamic measurements using the impedance cardiograph as described by Labadidi and others (1971). Systolic and diastolic arterial pressure were measured during the operation by auscultation using a sphygmomanometer, and the e.c.g. was displayed continuously. Rectal temperature was maintained between 36.5 and 37.5 °C, a heating blanket being used when necessary. The following haemodynamic variables were obtained or derived: heart rate (HR), from e.c.g., stroke volume index (SVI) and cardiac index (CI). In addition, mean arterial pressure was calculated as: (systolic pressure + 2 diastolic pressure)/3. All measurements were taken in duplicates and the average was calculated. After the operation was completed, surgical stimulation was avoided and control measurements were obtained. The mixture of atropine 20 |xg/kg and neostigmine 50 fxg/kg was then injected into an arm vein, via an i.v. line, the period of injection lasting 5-10 s. The measurements were repeated at 30 s, 1 min and at each subsequent minute up to 7 min. Lead II e.c.g. was recorded continuously before and after injection of the mixture. Controlled ventilation with nitrous oxide and oxygen was continued during the period of observation. After the measurements at the 7th min, nitrous oxide was discontinued and 100% oxygen was given. The

HAEMODYNAMIC RESPONSE TO ANTAGONISM OF TUBOCURARINE

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FIG. 1. Mean change in heart rate from control (%) following injection of the atropine-neostigmine mixture. Bars represent 2 SD.

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FIG. 2. Mean change in stroke volume index (%). Bars represent 2 SD. DISCUSSION

Because of the reports of cardiac arrest and arrhythmia following administration of neostigmine, anaesthetists have been reluctant to antagonize non-depolarizing neuromuscular blockade, especially in critically ill patients and patients with cardiac disease. Although

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FIG. 3. Mean change in cardiac index (%). Bars represent 2SD.

most previous reports incriminated neostigmine as the cause of cardiac arrhythmia, recent investigations suggest that pretreatment with atropine might be responsible (Jones, Deutsch and Turndorf, 1961). To minimize the cardiac effects of atropine, the use of the mixture has been advocated (Kemp and Morton, 1962; Baraka, 1968b). It has been shown that the effect of atropine in the mixture precedes that of neostigmine, resulting in an initial increase in heart rate before neostigmine produces its slowing effect. An inverse relationship between the initial heart rate and the maximum increase in rate after the injection of the mixture has been demonstrated in adults (Baraka, 1968b) and in children (Salem et al., 1970). Although previous studies were limited to observations of heart rate and e.c.g., they suggested that the mixture does not carry any serious hazards, even in children with cyanotic congenital heart disease (Salem et al., 1970; Wong et al., 1974). The accuracy of cardiac output measurements by transthoracic electrical impedance has been established (Baker et al., 1971; Labadidi et al., 1971; Denniston et al., 1976). Values determined simultaneously by dye dilution and electrical impedance at rest and during graded exercise in adults were found to be linearly related and significantly correlated (r = 0.90; P< 0.001) (Denniston et al., 1976). In children without intracardiac shunts or valvular insufficiency, the absolute mean difference between

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160%-

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BRITISH JOURNAL OF ANAESTHESIA Labadidi, Z., Ehmke, D. A., Durnin, R. E., Leaverton, P. E., and Lauer, R. M. (1971). Evaluation of impedance cardiac output in children. Pediatrics, 47, 870. Lawson, J. J. (1956). Cardiac arrest following the administration of neostigmine. Br. J. Anaesth., 28, 336. Macintosh, R. R. (1949). Death following neostigmine. Br. Med.J., 1, 852. Pooler, H. E. (1957). Atropine, neostigmine and sudden death. Anaesthesia, 12, 198. 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, 399. Riding, J. E., and Robinson, J. S. (1961). The safety of neostigmine. Anaesthesia, 16, 346. Salem, M. R., Ylagan, L. B., Angel, J. F., 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. 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 pediatric cardiac patients. Anesth. Analg. (Cleve.), 53, 412. Wylie, W. D., and Churchill-Davidson, H. C. (1972). A Practice of Anesthesia, 3rd edn. Chicago: Year Book Medical Publishers, Inc. REACTIONS HEMODYNAMIQUES DES ENFANTS A L'ANTAGONISME DU BLOCAGE PAR LA TUBOCURARINE A L'AIDE D'UN MELANGE D'ATROPINE-NEOSTIGMINE

ACKNOWLEDGEMENT

We wish to express our thanks to Mr Frank Hurley for his technical assistance with the impedance cardiograph.

RESUME

Par suite de Pantagonisme du blocage par la tubocurarine a l'aide d'un melange d'atropine 20 ng/kg et de neostigmine REFERENCES 50 |ig/kg sur 20 enfants, la frequence cardiaque a baisse Baker, L. E., Judy, W. V., Geddes, L. E., Langley, F. M., d'une valeur temoins de 110,4 battements/min a 90,1 apres and Hill, D. W. (1971). The measurement of cardiac 5 min et a 89,2 apres 6 min (P < 0,02). L'indice du debit output by means of electrical impedance. Cardiovasc. Res. systolique n'a pas change pendant les 5 premieres min par rapport a la valeur temoin de 36,3 ml.battement^.nv 2 ; Cent. Bull., 9, 135. mais on a observe aux sixieme et septieme minutes qui ont Baraka, A. (1968a). Safe reversal: atropine followed by une augmentation significative neostigmine: an electrocardiographic study. Br. J. suivi l'injection du melange a 48ml.battement- l .m- 2 (P<0,05). L'indice cardiaque et Anaesth., 40, 27. (1968b). Safe reversal: atropine-neostigmine mixture: la pression arterielle moyenne sont restes inchanges pendant toute la periode d'observation. On a maintenu le rythme an electrocardiographic study. Br. J. Anaesth., 40, 30. Clutton-Brock, J. (1949). Death following neostigmine. sinusal sur tous les malades. II en a ete conclu que l'antagonisme de la tubocurarine a l'aide d'un melange d'atropineBr. Med.J., 1, 1007. Denniston, J. C , Maher, J. T., Reeves, J. T., Cruz, J. C , neostigmine ne produit pas de variations hemodynamiques Cymerman, A., and Grover, R. F. (1976). Measurement importantes chez les enfants. of cardiac output by electrical impedance at rest and HAMODYNAMISCHE REAKTIONEN AUF during exercise. J. Appl. Physiol, 22, 67. Hill, M. (1949). Death after neostigmine injection. Br. ANTAGONISMUS ZU Med.J., 2, 601. TUBOCURARINBLOCKIERUNG MITTELS Jones, R. E., Deutsch, S., and Turndorf, H. (1961). EINER ATROPIN-NEOSTIGMINMISCHUNG BEI KINDERN Effects of atropine on cardiac rhythm in conscious and anesthetized man. Atiesthesiology, 22, 67. ZUSAMMENFASSUNG Kemp, S. W., and Morton, H. J. V. (1962). The effect of atropine-neostigmine on the pulse rate of anaesthetized Nach einem Antagonismus zu einer Tubocurarinblockierung mittels einer Mischung von 20 (ig/kg Atropin und 50 fig/kg patients. Anaesthesia, 17, 170. Kubicek, W. G., Karnegis, J. N., Patterson, R. P., Witsoe, Neostigmin sank die Herztatigkeit von einem Kontrollwert D. A., and Mattson, R. H. (1966). Development and von 110,4 Schlagen/min nach 5 Minuten auf 90,1 und evaluation of an impedance cardiac output system. nach 6 Minuten auf 89,2 (P < 0,02). Der Schlagvolumenindex blieb wahrend der ersten 5 Minuten unverandert auf Aerosp. Med., 37, 1208.

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the two methods was found to be 5.5% (Labadidi et al., 1971). The anaesthetized patient provides ideal conditions for comparative measurements by transthoracic electrical impedance, since movement artefacts which may distort the wave form are eliminated. In the present study the initial increase and delayed decrease in heart rate were associated with opposite changes in stroke volume index. Consequently, the cardiac output remained essentially unchanged throughout the period of observation. The mechanism of these paradoxical changes in heart rate and stroke volume index is not clear. However, it is possible that delayed slowing of the heart initiated by neostigmine might have resulted in an increase in ventricular filling pressure and a subsequent increase in stroke volume. The present investigation indicates that antagonism of tubocurarine block with a mixture of atropine 20 (xg/kg and neostigmine 50 fj-g/kg does not produce any undesirable haemodynamic changes. The doses given in this study are used commonly. Although our observations were limited to 7 minutes after injection of the mixture, it is unlikely that there were any further significant effects of these drugs.

HAEMODYNAMIC RESPONSE TO ANTAGONISM OF TUBOCURARINE dem Kontrollwert von 36,3 ml.Schlag-'.m-', aber ein wesentlicher Anstieg auf 48 ml. Schlag-'.m" 2 wurde nach 6 und 7 Minuten nach Injektion der Mischung beobachtet (P<0,05). Herzindex und mittlerer arterieller Druck blieben wahrend der gesamten Beobachtungszeit unverandert. Der normale Sinusrhytmus wurde bei alien Patienten bewahrt. Zusammenfassend wird geschlossen, dass ein Antagonismus zu einer Tubocurarinblockierung mittels einer Atropin-Neostigminmischung keine bedeutenden hamodynamischen Veranderungen bei Kindern hervorruft. RESPUESTAS HEMODINAMICAS AL ANTAGONISMO DEL BLOQUEO CON TUBOCURARINA CON UNA MEZCLA DE ATROPINA Y NEOSTIGMINA EN LOS NINOS

20 ninos, el ritmo cardiaco disminuyo desde un valortestigo de 110,4 pulsaciones/min hasta 90,1 a los 5 min y 89,2 a los 6 min (P < 0,02). El indice de volumen sistolico no cambio durante los primeros 5 min desde un valor-testigo de 36,3 ml. latido~l. m~! pero se observo un aumento significativo hasta 48 ml. latido"1. m~2 en el sexto minuto y el septimo minuto consecutivos a la inyeccion de la mezcla (P<0,05). El Indice cardiaco y la tension arterial media no experimentaron cambio durante todo el periodo de observacion. El ritmo sinusal normal fue mantenido en todos los pacientes. Se concluye que el antagonismo de tubocurarina con una mezcla de atropina y neostigmina no produce ningun cambio hemodinamico importante en los ninos. Downloaded from http://bja.oxfordjournals.org/ at Cornell University Library on July 13, 2015

SUMARIO

Tras el antagonismo del bloqueo con tubocurarina con una mezcla de atropina 20 ng/kg y neostigmina 50 (ig/kg en

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