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CLINICAL COMPARISON OF ATRACURIUM AND VECURONIUM (ORG NC 45)
Br. J. Anaesth. (1983), 55,125
CLINICAL COMPARISON OF ATRACURIUM AND VECURONIUM (ORG NC 45) E. N. ROBERTSON, L. H. D. J. BOOIJ, R. J. FRAGEN AND J. F. CRUL SUMMARY
Two new, potent, short-acting, non-depolarizing neuromuscular blocking drugs have been introduced recently. Vecuronium, the monoquaternary homologue of pancuronium, has been shown to be free from cardiovascular side-effects (Booij et al., 1980; Krieg, Crul and Booij, 1980), and histamine releasing properties (Booij, Krieg and Crul, 1980). Atracurium, a bisquaternary tetrahydropapaverum derivative, has also been shown to be free from cardiovascular side-effects (Payne and Hughes, 1981) and to cause histaminff release only in doses 8-16 times the neuromuscular blocking dose (Hughes and Chappie, 1981). Vecuronium was found to be about five times more potent than atracurium and to result in comparable intubating conditions (Gramstad and Lilleaasen, 1982). In this study, the pharmacodynamics of these two drugs, their cardiovascular effects, and any evidence of histamine release were compared at various doses following i.v. administration. PATIENTS AND METHODS Studies were performed in 64 healthy (ASA I and II) patients aged between 18 and 65 yr. Informed consent to participate in the study was obtained at the time of the preoperative visit. The study was apE.N. ROBERTSON, F.F^JLC.S.JL.H. D. J.BOOIJ,M.D.,PH.D.; J. F. CRUL, M.D., PH.D., F.F.A.R.C.S.; Department of Anesthesiology, Catholic University, Nijmegen, The Netherlands. R. J. FRAGEN, M.D., Department of Anesthesiology, Northwestern University, Chicago, U.S.A. 0OO7-O912/83/020125-O5 $01.00
proved by the hospital Ethics committee. Each patient was premedicated with diazepam 10 mg by mouth 2 h before induction of anaesthesia, plus droperidol 2.5-5 mg with piritramide 7.5-15mg i.m., 30-60min before induction of anaesthesia. Anaesthesia was induced with fentanyl 4f\igkg~I and thiopentone 5mgkg~' i.v. Intubation of the trachea was achieved 3-5 min after spraying the pharynx, larynx and trachea with 4% lignocaine spray. Maintenance of anaesthesia was with 67% nitrous oxide in oxygen. Mechanical ventilation was instituted and FEco2 maintained between 4.5 and 5vol%. Incremental doses of fentanyl 0.05 mg, thiopentone 50 mg, or droperidol 2.5 mg were given as required. The ulnar nerve was stimulated through surface electrodes at the wrist. Supramaximal pulses were delivered using a nerve stimulator at a rate of 0.1 Hz with a duration of 0.2 ms. The isometric twitch tension produced by this stimulation, as quantified by a force displacement transducer, was continuously recorded on a polygraph. The electrocardiogram (ECG), finger plethysmogram and end-expiratory carbon dioxide concentration (FE'cCh) were measured continuously in each patient. Evidence of rmtaminp release, for example, urticaria, skin rash, bronchospasm (Bowman, 1982), was sought following each administration of either neuromuscular blocking drug. The study was divided into three main sections in © The Macmillan Press Ltd 1983
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The potency, histamine releasing ability, cardiovascular effects, and pharmacodynamics of vecuronium and atracurium were investigated in 64 healthy patients following administration i.v. Cumulative dose-response curves showed vecuronium to be 4.4 times as potent as atracurium. Using the calculated EQ90 of each drug (43 fig kg' 1 for vecuronium and 188 fig kg' 1 for atracurium), vecuronium had a significantly more rapid onset time and shorter duration of action than atracurium. When three times the ED90 doses were used (129jigkg" 1 for vecuronium and 564 fig kg"1 for atracurium), no statistically significant differences in the pharmacodynamics were seen between the two drugs, although vecuronium tended to be shorter-acting. There was no clinical evidence of histaminr release during the study. No clinically significant changes in arterial pressure or heart rate were seen after the injection of either drug, although vecuronium caused a statistically significant decrease in heart rate (—5%) at 5 arid 10 min after administration. Both drugs would appear to have certain advantages over existing non-depolarizing neuromuscular blocking drugs.
126
which atracurium and vecuronium were compared with each other. Patients were assigned randomly to either drug group. Preparations of drugs used were in the form supplied by the manufactures. Atracurium was kept at 4 °C until the time of administration.
BRITISH JOURNAL OF ANAESTHESIA was calculated as: diastolic pressure + (pulse pressure/3). Pharmacodynamic results were analysed statistically using Student's unpaired ttest and cardiovascular results using Student's paired rtest. P<0.05 was considered to be significant.
PartB Bolus injections of the calculated ED90 of vecuronium and atracurium were given i.v. to 20 patients (10 in each group). The onset time (time from end of injection to maximum effect)', duration 25 (time from end of injection to 25% twitch recovery), duration 90 (time from end of injection to 90% twitch recovery), recovery rate (time from 25 to 75% twitch recovery) and degree of blockade were all measured, recorded and calculated in each patient. The pharmacodynamic results were analysed statistically using Student's unpaired rtest. P < 0 . 0 5 was considered to be significant. PartC Three times the calculated EDM of vecuronium and atracurium were given i.v. to 20 patients (10 in each group) and the indices mentioned in Part B measured, recorded and calculated. Arterial pressure (using oscillotonometry) and heart rate (HR) (from ECG) were recorded immediately before and 2, 5, and 10 min after the injection of the drug. Mean arterial pressure (MAP)
15
Time (min) FIG. 1. Actual tracings of cumulative dose-response studies using vecuronium (upper) and atracurium (lower). Incremental doses (in ng kg"') given at arrows.
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RESULTS Part A When the twitch height was stable, cumulative Within-group analysis of the ages and weights of the small doses of atracurium 0.01-0.1 mgkg"1 or vec- patients showed no significant differences (table I). uronium 0.005-0.025 mg kg"1 were given to 24 patients i.v. (14 patients in the vecuronium group and 10 in the atracurium group). Each patient received TABLE I. Characttristia of patients (agt and weight valuts art mean 1 SEAf) three to six incremental doses of drug i.v. The time between each dose was 2.5-3 min. No. of After the injection of each dose, the twitch reDrug group patients Age (yr) Weight (kg) sponse was observed until the maximum effect was 36.714.4 69.013.6 Vecuronium 14 obtained, as judged by three consecutive twitches of PartA 41.014.8 71.514.1 10 Atracurium equal height (Donlon, Ali and Savarese, 1974). The next incremental dose was then given. PartB Vecuronium 10 31.511.4 59.016.3 Atracurium 32.512.7 61.014.3 10 From these results, dose-response curves were constructed for each patient and each drug using 68.513.1 Vecuronium 10 41.815.5 non-linear least square fitting of the model where PartC Atracurium 10 44.314.2 67.513.5 the block was described as a distribution function (integrated Gaussian). From these dose-response Vecuronium curves, ED», ED90, and slopes were calculated for each patient. The ED50, ED90 and slopes of each drug group were compared using Student's t test. P < 0.05 was considered to be significant.
COMPARISON OF VECURONIUM AND ATRACURIUM Part A Two examples (one of vecuronium and one of atracurium) of actual tracings of cumulative doseresponse studies are given in figure 1. The calculated EDJO and ED90 values for atracurium were 131.1 ^gkg"1 and 188.7ngkg"1, respectively, and for vecuronium 31.1 fig kg"1 and 43.2 ng kg"1, respectively (table II). Using the calculated ED90 values, vecuronium appeared to be 4.4 times more potent than atracurium (fig. 2). The slopes of the lines were not significantly different.
PartC One hundred percent blockade was produced in every patient. There were no significant differences between the pharmacodynamic values for each drug, although vecuronium tended to be shorteracting than atracurium (table III). The recovery rate of atracurium was the same in both parts B and C. In the vecuronium groups, the recovery rate was significantly prolonged (P<0.01) with increased dosage.
The control values of MAP and HR were not significantly different. There was a significant decrease (4 - 5%) in heart rate in the vecuronium group at 5 and 10 min after injection ( P < 0.05) (figs 3 and 4).
8 L o"
75
* •/ * ^S
% 50 x
N(
25-
-4 ^
8°' / 8 / 8/'° 8V °
* Atracurium
0-1 20
40
60 80100
150 200 3O0
Dose (ugkg' 1 )
FIG. 2. Dose-response curves for atracurium (n = 10) and vecuronium (n = 14).
—•OrgNC45 0.13mgkg-1 - - ° Atracurium 0.56 mg kg' 1
I
TABLE II. EDx and EDm (mean±SEM) for atracurium and vecuronium calculafd from cumulative dost—response curves. n = no. patients
10 Time (mm)
Drug Vecuronium (« = 14) Atracurium (n = 10)
31.1 ±1.6 131.1 ±6.5
43.2±2.0 188.7±8.4
FIG. 3. Changes in heart rate (HR) immediately before, and 2, 5, and 10 min after injection of three times the ED90 dose of vecuronium (Org NC 45) and atracurium (n = 10 in each group).
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Part B The degree of blockade produced by the calculated ED90 of vecuronium (43 fig kg"1) was 90.9% and for atracurium (USiigkg-1) 85.3% (table III). The degrees of blockade were not significantly different, and there was no difference between the blockades produced and the expected blockade (90%). All other pharmacodynamic indices were significantly less for vecuronium (P<0.01).
127
TABLE III. Comparison ofthepharmacodynamics of vecuronium and atracurium afuroneand thne times tht calculated ED90 dost. Values art mtan ± SEM. ** Significant difference between eauipotent doses (P < 0.01); n = 10 patients at each dost Dose Drug
Onset (min)
Duration 25 (min)
Duration 90 (min)
Recovery rate (min)
% Block
Part B (1 x EDJIO)
Vecuronium Atracurium
43 188
**4.7±0.3 6.7±0.4
**10.9±0.8 17.1 ±1.4
**20.3±1.0 32.0 ±1.6
**6.8±0.6 12.0±0.5
PanC(3xEDoo) Vecuronium Atracurium
129 564
2.6±0.2 2.6±0.3
39.0 ±3.2 45.3±3.3
52.6±7.6 58.3±4.0
13.8±1.9 11.0±0.7
90.9±2.5 85.3±4.0 100 100
BRITISH JOURNAL OF ANAESTHESIA
128 • Org NC 45 0.13 mg kg"1 — o Atracurium 0.56 mg kg' 1 c •
a. <
70
-65 10
Time (min)
In no patient in any of the three groups (A, B, or C) was there clinical evidence of histaminf; release after either neuromuscukr blocking drug. DISCUSSION The ED» (31.1 Mgkg"1) and ED*, (43.2/ig kg"1) of vecuronium, obtained in this study, are comparable to previously reported results (Krieg, Crul and Booij, 1980; Agoston et al., 1980). The ED» and EDJIO of atracurium (131.1 ngkg" 1 and 1 188.7 ngkg" , respectively) seem to be lower than the values found by other investigators (Payne and Hughes, 1981). Nevertheless, the relative potency of vecuronium to atracurium noted in this study (4.4) was almost identical to that found by other investigators (Gramstad and Lilleaasen, 1982). Differences in anaesthetic technique (especially premedication) may partly explain the lower values obtained for atracurium in this study. When the calculated ED90 of atracurium and vecuronium were given i.v., they produced blocks of 85.3 ±4.0 and 90.9 ± 2.5percent, respectively. This suggests that cumulative dose-response curves correlate well with single injections. This was shown to be true for tubocurarine and pancuronium (Donlon etal., 1980) and vecuronium (Krieg, Crul and Booij, 1980). The pharmacodynamics of atracurium and vecuronium are comparable to previously reported studies (Payne and Hughes, 1981; Crul and Booij, 1980). Vecuronium was significantly shorter-acting than atracurium when the smaller dose was used in this study. When the larger doses were used (part C), vecuronium tended to be shorter-acting than atracurium, although this difference was not statisti-
Vecuronium has been shown to produce little histamine release after intradermal injection (Booij, Krieg and Crul, 1980). Atracurium caused histamine release only when 8-16 times the neuromuscular blocking dose was used i.v. (Hughes and Chappie, 1981). In this study there was no clinical evidence of histamine release after the injection of either drug i.v. Both drugs appear, therefore, to be without significant histamine releasing ability in normal clinical doses in normal patients. No clinically significant changes in heart rate or arterial pressure were seen with either drug. There was a statistically significant decrease in heart rate after vecuronium, but this was small (4—5%), and was not considered clinically significant. Similar alterations in heart rate have been noted by other investigators (Barnes et al., 1982). Both the drugs studied would seem to have some advantages over listing neuromuscular blocking drugs since neither seems to release histamine or produce significant cardiovascular changes when administered in clinical doses. ACKNOWLEDGEMENTS
The authors thank Dr P. Ponsioen (Chef de Clinique) for arranging Hiniml sessions, Dr J. van Egmond for help with statistical analysis, Organon for supplies of vecuronium, and the Wellcome Foundation Ltd for supplies of atracurium.
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FIG. 4. Changes in mean arterial pressure (MAP) immediately before, and 2, S, and 10min after injection of three times the EDgo dose of vecuronium (Org NC 45) and atracurium (n = 10 in each group).
cally significant. Since these doses are in the range that might normally be used in clinical anaesthesia (43-129 ng kg"1 for vecuronium and 188-564 Hgkg"1 for atracurium), vecuronium would appear to have some advantage over atracurium. The reproducible recovery rate of atracurium, found in this study, has been commented on before (Payne and Hughes, 1981; Hughes and Chappie, 1981). The prolongation of the recovery rate of vecuronium has also been noted in other studies (Agoston et al., 1980) but has not been considered to be significant. If vecuronium terminates its effects by redistribution, as suggested by several pharmacokinetic studies (Agoston et al., 1977; Booij et al., 1981), the prolonged recovery rate might suggest that the distribution volume is becoming saturated at these doses. If even greater doses of vecuronium were used, the increase in the duration of recovery may lead, possibly, to a prolongation of the total duration of action. In contrast, the steady recovery rate of atracurium might suggest that the metabolic pathways thought to terminate its effects (Hofmann elimination and ester hydrolysis) are not saturated at the doses used in this'study. At what dose these pathways could be saturated has yet to be determined in man.
COMPARISON OF VECURONIUM AND ATRACURIUM REFERENCES
COMPARAISON CLINIQUE DE L'ATRACURIUM ET DU VECURONIUM (ORG NC 45) RESUME
Nous avons ctiidic chez 64 patients en bonne sante la puissance, le potentkl histaminoliberateur, les effets cardiovasculaires et la pharmacodynamie du vecuronium et de l'atracurium administres par vote intraveineuse. Les courbes doses cumlatives-reponses ont montre que le vecuronium etait 4,4 fois plus puissant que l'atracurium. En utilisant I'EDCJQ calculee de chaque agent (43 ng kg"1 pour le vecuronium et 188 fig kg"1 pour Tatracurium), le vecuronium a eu un debut d'action significauvcmcnt plus rapide et une duree d'action plus breve que l'atracurium. En utilisant trois fois l'ED^ (129ngkg"' pour le vecuronium et 564ngkg~' pour ratracurium), il n'y a pas eu de differences statistiquement significative* entre les pharmacodynamiques des deux agents, bien que la duree d'action du vecuronium ait etc
plutdt breve. II n'y a pas eu d'arguments (-Uniques en faveur d'une histaminoliberation au cours de l'etude. II n'y a pas eu de modifications cliniquement significatives de prenion arterielle ou de frequence cardiaque apres l'injection de l'un ou l'autre agent, bien que le vecuronium ait entrain^ une diminution statistiquement significative de la frequence cardiaque ( === 5%) a 5 et 10 min apres administration. Ces deux agents semblent presenter des avantages certains sur les agents myorelaxants non depolarisants existants.
EIN KLINISCHER VERGLEICH VON ATRACURIUM UND VECURONIUM (ORG NC 45) ZUSAMMENFASSUNG
Potenz, HintaminfrnKi^ningafahigkffit, kardiovaskulare Wirkungen und pharmakokinetische Eigenschaften von Atracurium und Vecuronium wurden nach intravenoser Verabreichung bei 64 gesunden Patienten untersucht. Kumulative Dosisreaktionskurven erwiesen Vecuronium um 4.4 mal starker als Atracurium. Unter Verwcndung des fur jede Droge errechneten ED90 (43 fig kg"1 fur vecuronium und 188 ug kg"1 fur Atracurium) zeigte vecuronium cine wesentlich raschere Wirkung und cine kurzere Wirkungsdauer als Atracurium. Bei Verwendung der dreifachen ED^o-Dosen (129 fig kg"1, Vecuronium, 564 f»8 kg"1. Atracurium) gab es keine sutistisch bedeutsamen pharmakokinetischen Unterschiede zwischen den beiden Drogen, wenn auch Vecuronium im allgemeinen kurzer wirksam war. Wahrend der Studie gab es keine klinischen Beweise fur das Freiwerden von Histamin. Klinisch signifikante Veranderungen von arteriellem Druck oder Herztltigkeit wurden nach der Injektion der Drogen nicht beobachtet, obwohl Vecuronium ein statistisch bedeutsames Absinken der HerztStigkeit (===5%) bewirkte - 5 und 10 Minuten nach Verabreichung. Beide Drogen durften gegenuber vbrhandenen, nichtdepolarisierenden neuromuskuliir blockierenden Drogen gewisse Vorteile haben.
COMPARACION CLINICA DEL ATRACURIUM Y DEL VECURONIUM (ORG NC 45) SUMARIO
Se investjgaron en 64 pacientes sanos, a raiz de una administraci6n intravenosa, la potenda, la habilidad de liberacidn de bistamina, los cfectos cardiovasculares y las farm&codin£micas del vecuronium y del atracurium. Las curves acumulativas de dosis— respuesta mostraron que el vecuronium ere 4,4 veces mas potente que el atracurium. Haciendo uso del ED90 calculado de cada droga (43figkg"' para el vecuronium y 188(igkg"' para el atracurium), el vecuronium presento un tiempo de iniciacion significativamente mas rapido y una actividad de duration mas corta que el atracurium. Al triplicar las dosis de ED90 (129ngkg"' para el vecuronium y 564ngkg~' para el atracurium), no se observaron diferencias estadisticas significativas entre las farmacodinamicas de las dos drogas, aunque el vecuronium tendio a tener una actividad mis corta. No se obtuvo evidencia clinica significativa de liberacion de hittamina dutante el estudio. No se observaron cambios clinicos significativos en la presion arterial ni en el ritmo cardiaco despues de la inyeccion de cualquiera de las drogas, aunque el vecuronium ocasiono una disminucidn del ritmo cardiaco (aprox. 5%) estadisticamente significative a los 5 y 10 minutos de la administracion. Ambas drogas parecen presentar ciertas ventajas sobre las drogas de bloqueo neuromuscular no despolarizantes.
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Agoston, S., Crul, J. F., Kerstcn, V. W., Houwertjes, M. C , and Scaf, A. H. J. (1977). The relationship between disposition and duration of action of a congeneric series of steroidal neurmuscular blocking agents. Acta Anaetthesiol. Scand., 21, 24. Salt, P., Newton, D., Bencini, A., Boomsma, P., and Erdmann, W. (1980). Neuromuscular blocking action of OrgNC45, a new pancuronium derivative, in anaesthetized patients. Br. J. Anaath., 52, 53S. Barnes, P. K., Brindle-Smith, G., White, W. D., and Tennant, R. (1982). Comparison of the effects of OrgNC45 and pancuronium bromide on heart rate and arterial pressure in anaesthetized man. Br. J. Anaath., 54,435. Bocdj, L. H. D. J., Edwards, R. P., Sohn, Y. S., and Miller, R. D. (1980). Cardiovascular and neuromuscular effects of Org NC 45, pancuronium, metocurine and d-tubocurarine in dogs. Anttth. Analg., 59,26. Krieg, N., and Crul, J. F. (1980). Intradermal histamine releasing effect caused by OrgNC45. Ada Anaathaiol. Scand., 24, 393. Vree, T. B., Hurkmans, F., Reekers-Ketting, J. F., and Crul, J. F. (1981). Pharmacokinetics and pharmacodynamics of the muscle relaxant OrgNC45 and each of its hydroxy metabolites in dogs. Anaathaist, 30, 329. Bowman, W. C. (1982). Non-relaxant properties of neuromuscular blocking drugs. Br. J. Anatsth., 54,147. Crul, J. F., and Booij, L. H. D. J. (1980). First clinical experiences with Org NC 45. Br.J. Anatsth., 52, 49S. Donlon, J. V., Ali, H. H., and Savarese, J. J. (1974). A new approach to the study of four non-depolarizing relaxants in man. Anath. Analg., 53,934. Savarese, J. J., Ali, H.H.,andTeplik.R. S. (1980). Human dose-response curves for neuromuscular blocking drugs. Anathtswlogy, 53,161. Grams tad, L., and T illraasen, P. (1982). Dose-response relation for atracurium, Org NC 45 and pancuronium. Br. J. Anaath., 54,647. Hughes, R., and Chappie, D. J. (1981). The pharmacology of atracurium: A new competitive neuromuscular blocking agent. Br.J. Anatsth., 53, 31. Krieg, N . , Crul, J. F., and Booij, L. H. D. J. (1980). Relative potency of OrgNC45, pancuronium, alcuronium and tubocurarine in anaesthetized man. Br. J. Anaath., 52,783. Payne, J. P., and Hughes, R. (1981). Evaluation of atracurium in anaesthetized man. Br. J. Anaath., 53,45.
129
CLINICAL COMPARISON OF ATRACURIUM AND VECURONIUM (ORG NC 45) E. N. ROBERTSON, L. H. D. J. BOOIJ, R. J. FRAGEN AND J. F. CRUL SUMMARY
Two new, potent, short-acting, non-depolarizing neuromuscular blocking drugs have been introduced recently. Vecuronium, the monoquaternary homologue of pancuronium, has been shown to be free from cardiovascular side-effects (Booij et al., 1980; Krieg, Crul and Booij, 1980), and histamine releasing properties (Booij, Krieg and Crul, 1980). Atracurium, a bisquaternary tetrahydropapaverum derivative, has also been shown to be free from cardiovascular side-effects (Payne and Hughes, 1981) and to cause histaminff release only in doses 8-16 times the neuromuscular blocking dose (Hughes and Chappie, 1981). Vecuronium was found to be about five times more potent than atracurium and to result in comparable intubating conditions (Gramstad and Lilleaasen, 1982). In this study, the pharmacodynamics of these two drugs, their cardiovascular effects, and any evidence of histamine release were compared at various doses following i.v. administration. PATIENTS AND METHODS Studies were performed in 64 healthy (ASA I and II) patients aged between 18 and 65 yr. Informed consent to participate in the study was obtained at the time of the preoperative visit. The study was apE.N. ROBERTSON, F.F^JLC.S.JL.H. D. J.BOOIJ,M.D.,PH.D.; J. F. CRUL, M.D., PH.D., F.F.A.R.C.S.; Department of Anesthesiology, Catholic University, Nijmegen, The Netherlands. R. J. FRAGEN, M.D., Department of Anesthesiology, Northwestern University, Chicago, U.S.A. 0OO7-O912/83/020125-O5 $01.00
proved by the hospital Ethics committee. Each patient was premedicated with diazepam 10 mg by mouth 2 h before induction of anaesthesia, plus droperidol 2.5-5 mg with piritramide 7.5-15mg i.m., 30-60min before induction of anaesthesia. Anaesthesia was induced with fentanyl 4f\igkg~I and thiopentone 5mgkg~' i.v. Intubation of the trachea was achieved 3-5 min after spraying the pharynx, larynx and trachea with 4% lignocaine spray. Maintenance of anaesthesia was with 67% nitrous oxide in oxygen. Mechanical ventilation was instituted and FEco2 maintained between 4.5 and 5vol%. Incremental doses of fentanyl 0.05 mg, thiopentone 50 mg, or droperidol 2.5 mg were given as required. The ulnar nerve was stimulated through surface electrodes at the wrist. Supramaximal pulses were delivered using a nerve stimulator at a rate of 0.1 Hz with a duration of 0.2 ms. The isometric twitch tension produced by this stimulation, as quantified by a force displacement transducer, was continuously recorded on a polygraph. The electrocardiogram (ECG), finger plethysmogram and end-expiratory carbon dioxide concentration (FE'cCh) were measured continuously in each patient. Evidence of rmtaminp release, for example, urticaria, skin rash, bronchospasm (Bowman, 1982), was sought following each administration of either neuromuscular blocking drug. The study was divided into three main sections in © The Macmillan Press Ltd 1983
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The potency, histamine releasing ability, cardiovascular effects, and pharmacodynamics of vecuronium and atracurium were investigated in 64 healthy patients following administration i.v. Cumulative dose-response curves showed vecuronium to be 4.4 times as potent as atracurium. Using the calculated EQ90 of each drug (43 fig kg' 1 for vecuronium and 188 fig kg' 1 for atracurium), vecuronium had a significantly more rapid onset time and shorter duration of action than atracurium. When three times the ED90 doses were used (129jigkg" 1 for vecuronium and 564 fig kg"1 for atracurium), no statistically significant differences in the pharmacodynamics were seen between the two drugs, although vecuronium tended to be shorter-acting. There was no clinical evidence of histaminr release during the study. No clinically significant changes in arterial pressure or heart rate were seen after the injection of either drug, although vecuronium caused a statistically significant decrease in heart rate (—5%) at 5 arid 10 min after administration. Both drugs would appear to have certain advantages over existing non-depolarizing neuromuscular blocking drugs.
126
which atracurium and vecuronium were compared with each other. Patients were assigned randomly to either drug group. Preparations of drugs used were in the form supplied by the manufactures. Atracurium was kept at 4 °C until the time of administration.
BRITISH JOURNAL OF ANAESTHESIA was calculated as: diastolic pressure + (pulse pressure/3). Pharmacodynamic results were analysed statistically using Student's unpaired ttest and cardiovascular results using Student's paired rtest. P<0.05 was considered to be significant.
PartB Bolus injections of the calculated ED90 of vecuronium and atracurium were given i.v. to 20 patients (10 in each group). The onset time (time from end of injection to maximum effect)', duration 25 (time from end of injection to 25% twitch recovery), duration 90 (time from end of injection to 90% twitch recovery), recovery rate (time from 25 to 75% twitch recovery) and degree of blockade were all measured, recorded and calculated in each patient. The pharmacodynamic results were analysed statistically using Student's unpaired rtest. P < 0 . 0 5 was considered to be significant. PartC Three times the calculated EDM of vecuronium and atracurium were given i.v. to 20 patients (10 in each group) and the indices mentioned in Part B measured, recorded and calculated. Arterial pressure (using oscillotonometry) and heart rate (HR) (from ECG) were recorded immediately before and 2, 5, and 10 min after the injection of the drug. Mean arterial pressure (MAP)
15
Time (min) FIG. 1. Actual tracings of cumulative dose-response studies using vecuronium (upper) and atracurium (lower). Incremental doses (in ng kg"') given at arrows.
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RESULTS Part A When the twitch height was stable, cumulative Within-group analysis of the ages and weights of the small doses of atracurium 0.01-0.1 mgkg"1 or vec- patients showed no significant differences (table I). uronium 0.005-0.025 mg kg"1 were given to 24 patients i.v. (14 patients in the vecuronium group and 10 in the atracurium group). Each patient received TABLE I. Characttristia of patients (agt and weight valuts art mean 1 SEAf) three to six incremental doses of drug i.v. The time between each dose was 2.5-3 min. No. of After the injection of each dose, the twitch reDrug group patients Age (yr) Weight (kg) sponse was observed until the maximum effect was 36.714.4 69.013.6 Vecuronium 14 obtained, as judged by three consecutive twitches of PartA 41.014.8 71.514.1 10 Atracurium equal height (Donlon, Ali and Savarese, 1974). The next incremental dose was then given. PartB Vecuronium 10 31.511.4 59.016.3 Atracurium 32.512.7 61.014.3 10 From these results, dose-response curves were constructed for each patient and each drug using 68.513.1 Vecuronium 10 41.815.5 non-linear least square fitting of the model where PartC Atracurium 10 44.314.2 67.513.5 the block was described as a distribution function (integrated Gaussian). From these dose-response Vecuronium curves, ED», ED90, and slopes were calculated for each patient. The ED50, ED90 and slopes of each drug group were compared using Student's t test. P < 0.05 was considered to be significant.
COMPARISON OF VECURONIUM AND ATRACURIUM Part A Two examples (one of vecuronium and one of atracurium) of actual tracings of cumulative doseresponse studies are given in figure 1. The calculated EDJO and ED90 values for atracurium were 131.1 ^gkg"1 and 188.7ngkg"1, respectively, and for vecuronium 31.1 fig kg"1 and 43.2 ng kg"1, respectively (table II). Using the calculated ED90 values, vecuronium appeared to be 4.4 times more potent than atracurium (fig. 2). The slopes of the lines were not significantly different.
PartC One hundred percent blockade was produced in every patient. There were no significant differences between the pharmacodynamic values for each drug, although vecuronium tended to be shorteracting than atracurium (table III). The recovery rate of atracurium was the same in both parts B and C. In the vecuronium groups, the recovery rate was significantly prolonged (P<0.01) with increased dosage.
The control values of MAP and HR were not significantly different. There was a significant decrease (4 - 5%) in heart rate in the vecuronium group at 5 and 10 min after injection ( P < 0.05) (figs 3 and 4).
8 L o"
75
* •/ * ^S
% 50 x
N(
25-
-4 ^
8°' / 8 / 8/'° 8V °
* Atracurium
0-1 20
40
60 80100
150 200 3O0
Dose (ugkg' 1 )
FIG. 2. Dose-response curves for atracurium (n = 10) and vecuronium (n = 14).
—•OrgNC45 0.13mgkg-1 - - ° Atracurium 0.56 mg kg' 1
I
TABLE II. EDx and EDm (mean±SEM) for atracurium and vecuronium calculafd from cumulative dost—response curves. n = no. patients
10 Time (mm)
Drug Vecuronium (« = 14) Atracurium (n = 10)
31.1 ±1.6 131.1 ±6.5
43.2±2.0 188.7±8.4
FIG. 3. Changes in heart rate (HR) immediately before, and 2, 5, and 10 min after injection of three times the ED90 dose of vecuronium (Org NC 45) and atracurium (n = 10 in each group).
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Part B The degree of blockade produced by the calculated ED90 of vecuronium (43 fig kg"1) was 90.9% and for atracurium (USiigkg-1) 85.3% (table III). The degrees of blockade were not significantly different, and there was no difference between the blockades produced and the expected blockade (90%). All other pharmacodynamic indices were significantly less for vecuronium (P<0.01).
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TABLE III. Comparison ofthepharmacodynamics of vecuronium and atracurium afuroneand thne times tht calculated ED90 dost. Values art mtan ± SEM. ** Significant difference between eauipotent doses (P < 0.01); n = 10 patients at each dost Dose Drug
Onset (min)
Duration 25 (min)
Duration 90 (min)
Recovery rate (min)
% Block
Part B (1 x EDJIO)
Vecuronium Atracurium
43 188
**4.7±0.3 6.7±0.4
**10.9±0.8 17.1 ±1.4
**20.3±1.0 32.0 ±1.6
**6.8±0.6 12.0±0.5
PanC(3xEDoo) Vecuronium Atracurium
129 564
2.6±0.2 2.6±0.3
39.0 ±3.2 45.3±3.3
52.6±7.6 58.3±4.0
13.8±1.9 11.0±0.7
90.9±2.5 85.3±4.0 100 100
BRITISH JOURNAL OF ANAESTHESIA
128 • Org NC 45 0.13 mg kg"1 — o Atracurium 0.56 mg kg' 1 c •
a. <
70
-65 10
Time (min)
In no patient in any of the three groups (A, B, or C) was there clinical evidence of histaminf; release after either neuromuscukr blocking drug. DISCUSSION The ED» (31.1 Mgkg"1) and ED*, (43.2/ig kg"1) of vecuronium, obtained in this study, are comparable to previously reported results (Krieg, Crul and Booij, 1980; Agoston et al., 1980). The ED» and EDJIO of atracurium (131.1 ngkg" 1 and 1 188.7 ngkg" , respectively) seem to be lower than the values found by other investigators (Payne and Hughes, 1981). Nevertheless, the relative potency of vecuronium to atracurium noted in this study (4.4) was almost identical to that found by other investigators (Gramstad and Lilleaasen, 1982). Differences in anaesthetic technique (especially premedication) may partly explain the lower values obtained for atracurium in this study. When the calculated ED90 of atracurium and vecuronium were given i.v., they produced blocks of 85.3 ±4.0 and 90.9 ± 2.5percent, respectively. This suggests that cumulative dose-response curves correlate well with single injections. This was shown to be true for tubocurarine and pancuronium (Donlon etal., 1980) and vecuronium (Krieg, Crul and Booij, 1980). The pharmacodynamics of atracurium and vecuronium are comparable to previously reported studies (Payne and Hughes, 1981; Crul and Booij, 1980). Vecuronium was significantly shorter-acting than atracurium when the smaller dose was used in this study. When the larger doses were used (part C), vecuronium tended to be shorter-acting than atracurium, although this difference was not statisti-
Vecuronium has been shown to produce little histamine release after intradermal injection (Booij, Krieg and Crul, 1980). Atracurium caused histamine release only when 8-16 times the neuromuscular blocking dose was used i.v. (Hughes and Chappie, 1981). In this study there was no clinical evidence of histamine release after the injection of either drug i.v. Both drugs appear, therefore, to be without significant histamine releasing ability in normal clinical doses in normal patients. No clinically significant changes in heart rate or arterial pressure were seen with either drug. There was a statistically significant decrease in heart rate after vecuronium, but this was small (4—5%), and was not considered clinically significant. Similar alterations in heart rate have been noted by other investigators (Barnes et al., 1982). Both the drugs studied would seem to have some advantages over listing neuromuscular blocking drugs since neither seems to release histamine or produce significant cardiovascular changes when administered in clinical doses. ACKNOWLEDGEMENTS
The authors thank Dr P. Ponsioen (Chef de Clinique) for arranging Hiniml sessions, Dr J. van Egmond for help with statistical analysis, Organon for supplies of vecuronium, and the Wellcome Foundation Ltd for supplies of atracurium.
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FIG. 4. Changes in mean arterial pressure (MAP) immediately before, and 2, S, and 10min after injection of three times the EDgo dose of vecuronium (Org NC 45) and atracurium (n = 10 in each group).
cally significant. Since these doses are in the range that might normally be used in clinical anaesthesia (43-129 ng kg"1 for vecuronium and 188-564 Hgkg"1 for atracurium), vecuronium would appear to have some advantage over atracurium. The reproducible recovery rate of atracurium, found in this study, has been commented on before (Payne and Hughes, 1981; Hughes and Chappie, 1981). The prolongation of the recovery rate of vecuronium has also been noted in other studies (Agoston et al., 1980) but has not been considered to be significant. If vecuronium terminates its effects by redistribution, as suggested by several pharmacokinetic studies (Agoston et al., 1977; Booij et al., 1981), the prolonged recovery rate might suggest that the distribution volume is becoming saturated at these doses. If even greater doses of vecuronium were used, the increase in the duration of recovery may lead, possibly, to a prolongation of the total duration of action. In contrast, the steady recovery rate of atracurium might suggest that the metabolic pathways thought to terminate its effects (Hofmann elimination and ester hydrolysis) are not saturated at the doses used in this'study. At what dose these pathways could be saturated has yet to be determined in man.
COMPARISON OF VECURONIUM AND ATRACURIUM REFERENCES
COMPARAISON CLINIQUE DE L'ATRACURIUM ET DU VECURONIUM (ORG NC 45) RESUME
Nous avons ctiidic chez 64 patients en bonne sante la puissance, le potentkl histaminoliberateur, les effets cardiovasculaires et la pharmacodynamie du vecuronium et de l'atracurium administres par vote intraveineuse. Les courbes doses cumlatives-reponses ont montre que le vecuronium etait 4,4 fois plus puissant que l'atracurium. En utilisant I'EDCJQ calculee de chaque agent (43 ng kg"1 pour le vecuronium et 188 fig kg"1 pour Tatracurium), le vecuronium a eu un debut d'action significauvcmcnt plus rapide et une duree d'action plus breve que l'atracurium. En utilisant trois fois l'ED^ (129ngkg"' pour le vecuronium et 564ngkg~' pour ratracurium), il n'y a pas eu de differences statistiquement significative* entre les pharmacodynamiques des deux agents, bien que la duree d'action du vecuronium ait etc
plutdt breve. II n'y a pas eu d'arguments (-Uniques en faveur d'une histaminoliberation au cours de l'etude. II n'y a pas eu de modifications cliniquement significatives de prenion arterielle ou de frequence cardiaque apres l'injection de l'un ou l'autre agent, bien que le vecuronium ait entrain^ une diminution statistiquement significative de la frequence cardiaque ( === 5%) a 5 et 10 min apres administration. Ces deux agents semblent presenter des avantages certains sur les agents myorelaxants non depolarisants existants.
EIN KLINISCHER VERGLEICH VON ATRACURIUM UND VECURONIUM (ORG NC 45) ZUSAMMENFASSUNG
Potenz, HintaminfrnKi^ningafahigkffit, kardiovaskulare Wirkungen und pharmakokinetische Eigenschaften von Atracurium und Vecuronium wurden nach intravenoser Verabreichung bei 64 gesunden Patienten untersucht. Kumulative Dosisreaktionskurven erwiesen Vecuronium um 4.4 mal starker als Atracurium. Unter Verwcndung des fur jede Droge errechneten ED90 (43 fig kg"1 fur vecuronium und 188 ug kg"1 fur Atracurium) zeigte vecuronium cine wesentlich raschere Wirkung und cine kurzere Wirkungsdauer als Atracurium. Bei Verwendung der dreifachen ED^o-Dosen (129 fig kg"1, Vecuronium, 564 f»8 kg"1. Atracurium) gab es keine sutistisch bedeutsamen pharmakokinetischen Unterschiede zwischen den beiden Drogen, wenn auch Vecuronium im allgemeinen kurzer wirksam war. Wahrend der Studie gab es keine klinischen Beweise fur das Freiwerden von Histamin. Klinisch signifikante Veranderungen von arteriellem Druck oder Herztltigkeit wurden nach der Injektion der Drogen nicht beobachtet, obwohl Vecuronium ein statistisch bedeutsames Absinken der HerztStigkeit (===5%) bewirkte - 5 und 10 Minuten nach Verabreichung. Beide Drogen durften gegenuber vbrhandenen, nichtdepolarisierenden neuromuskuliir blockierenden Drogen gewisse Vorteile haben.
COMPARACION CLINICA DEL ATRACURIUM Y DEL VECURONIUM (ORG NC 45) SUMARIO
Se investjgaron en 64 pacientes sanos, a raiz de una administraci6n intravenosa, la potenda, la habilidad de liberacidn de bistamina, los cfectos cardiovasculares y las farm&codin£micas del vecuronium y del atracurium. Las curves acumulativas de dosis— respuesta mostraron que el vecuronium ere 4,4 veces mas potente que el atracurium. Haciendo uso del ED90 calculado de cada droga (43figkg"' para el vecuronium y 188(igkg"' para el atracurium), el vecuronium presento un tiempo de iniciacion significativamente mas rapido y una actividad de duration mas corta que el atracurium. Al triplicar las dosis de ED90 (129ngkg"' para el vecuronium y 564ngkg~' para el atracurium), no se observaron diferencias estadisticas significativas entre las farmacodinamicas de las dos drogas, aunque el vecuronium tendio a tener una actividad mis corta. No se obtuvo evidencia clinica significativa de liberacion de hittamina dutante el estudio. No se observaron cambios clinicos significativos en la presion arterial ni en el ritmo cardiaco despues de la inyeccion de cualquiera de las drogas, aunque el vecuronium ocasiono una disminucidn del ritmo cardiaco (aprox. 5%) estadisticamente significative a los 5 y 10 minutos de la administracion. Ambas drogas parecen presentar ciertas ventajas sobre las drogas de bloqueo neuromuscular no despolarizantes.
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Agoston, S., Crul, J. F., Kerstcn, V. W., Houwertjes, M. C , and Scaf, A. H. J. (1977). The relationship between disposition and duration of action of a congeneric series of steroidal neurmuscular blocking agents. Acta Anaetthesiol. Scand., 21, 24. Salt, P., Newton, D., Bencini, A., Boomsma, P., and Erdmann, W. (1980). Neuromuscular blocking action of OrgNC45, a new pancuronium derivative, in anaesthetized patients. Br. J. Anaath., 52, 53S. Barnes, P. K., Brindle-Smith, G., White, W. D., and Tennant, R. (1982). Comparison of the effects of OrgNC45 and pancuronium bromide on heart rate and arterial pressure in anaesthetized man. Br. J. Anaath., 54,435. Bocdj, L. H. D. J., Edwards, R. P., Sohn, Y. S., and Miller, R. D. (1980). Cardiovascular and neuromuscular effects of Org NC 45, pancuronium, metocurine and d-tubocurarine in dogs. Anttth. Analg., 59,26. Krieg, N., and Crul, J. F. (1980). Intradermal histamine releasing effect caused by OrgNC45. Ada Anaathaiol. Scand., 24, 393. Vree, T. B., Hurkmans, F., Reekers-Ketting, J. F., and Crul, J. F. (1981). Pharmacokinetics and pharmacodynamics of the muscle relaxant OrgNC45 and each of its hydroxy metabolites in dogs. Anaathaist, 30, 329. Bowman, W. C. (1982). Non-relaxant properties of neuromuscular blocking drugs. Br. J. Anatsth., 54,147. Crul, J. F., and Booij, L. H. D. J. (1980). First clinical experiences with Org NC 45. Br.J. Anatsth., 52, 49S. Donlon, J. V., Ali, H. H., and Savarese, J. J. (1974). A new approach to the study of four non-depolarizing relaxants in man. Anath. Analg., 53,934. Savarese, J. J., Ali, H.H.,andTeplik.R. S. (1980). Human dose-response curves for neuromuscular blocking drugs. Anathtswlogy, 53,161. Grams tad, L., and T illraasen, P. (1982). Dose-response relation for atracurium, Org NC 45 and pancuronium. Br. J. Anaath., 54,647. Hughes, R., and Chappie, D. J. (1981). The pharmacology of atracurium: A new competitive neuromuscular blocking agent. Br.J. Anatsth., 53, 31. Krieg, N . , Crul, J. F., and Booij, L. H. D. J. (1980). Relative potency of OrgNC45, pancuronium, alcuronium and tubocurarine in anaesthetized man. Br. J. Anaath., 52,783. Payne, J. P., and Hughes, R. (1981). Evaluation of atracurium in anaesthetized man. Br. J. Anaath., 53,45.
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