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COMPARISON BETWEEN THE CONTINUOUS INFUSION OF VECURONIUM AND THE INTERMITTENT ADMINISTRATION OF PANCURONIUM AND VECURONIUM
Br. J. Anaath. (1984), 56,473
COMPARISON BETWEEN THE CONTINUOUS INFUSION OF VECURONIUM AND THE INTERMITTENT ADMINISTRATION OF PANCURONIUM AND VECURONIUM G. NOELDGE, H. HINSKEN AND W. BUZELLO SUMMARY
III received a 0.075-mg kg ' trading Hiw ntCTfiimniirinpl"« a mnriniinm infiirirm ( m i t i m w y ^ irimiih^ni-.
ously) delivering 0.075 mg kg" 1 h . With repeated injections of pancuronium (group I) or vecuronium (group II), the durations of blockade to 25% recovery were 64 and 25 min, respectively. Maintenance doses had to be injected every 42 min with pancuronium and every 12 min with vecuronium. The recovery rmvn from 25% to 75% of control twitch tension were 44 v. 12 min. The continuous infusion of vecuronium (group HI) produced -consistent neuromuscular blockade at an average level of 87% twitch depression. The times from the end of infusion to 25%, and from 25% to 75%, recovery averaged 20 and 26 min, respectively. These values did not correlate with the total dose of vecuronium infused. For clinical practice, the suggested loading dose is 1.5 rime* the F.D^ ( ° (1.07 mgkg" 1 ) followed by an infimirm of the Bmt dr«e per hniir. Thf infmrinn should be started within 10 min of the injection of the InaHing dose.
Having demonstrated previously that, during prolonged surgical procedures, bolus injections of vecuronium were required as frequently as every 10 min, Buzello and Noeldge (1982) suggested that the continuous infusion of this drug would be a more appropriate technique with which to maintain a consistent degree of neuromuscular blockade. This mode of administration' has been studied in the present paper. PATIENTS AND METHODS Thirty-six patients (ASA I and II) undergoing gynaecological surgery were studied after informed consent had been obtained. Individuals younger than 20 and older than 60 years of age, and those with conditions or medications known to affect the pharmacodynamics of neuromuscular blocking drugs were excluded from the study. All patients were premedicated with atropine 0.01 mg kg"1, pethidine 0.7mgkg~' and triflupromazine O.lSmgkg"1 i.m. 45min before the induction of anaesthesia which was accomplished with thiopentone 250-350mg and fentanyl 0.3-0.5mg. The G. NOELDGE, M.D.; H. HINSKEN, M.D.; W. BUZELLO,* M.D.;
Department of Anaesthe: anlogy, University Hospital, Hugstetter Str. 55, D-7800 Freiburg, Federal Republic of Germany. •Present address: Department of Anesthesiology, Texas Tech University School of Medicine, 4800 Alberta Ave., El Paso, Texas 79905, U.S.A.
trachea was intubated following neuromuscular blockade with a loading dose of pancuronium or vecuronium (see below) and anaesthesia was maintained with increments of fentanyl and nitrous oxide in oxygen (2:1). No halogenated inhalation anaesthetics were used. Ventilation was controlled, and neostigmine 0.015 mg kg"1 and atropine 0.01 mgkg"1 injected i.v. if residual neuromuscular blockade was present at the end of the procedure. Neuromuscular transmission was monitored by recording the evoked twitch tension of the adductor pollicis muscle with the aid of a boomerang force displacement transducer (Walts, 1973), further details of which have been described previously (Buzello and Noeldge, 1982). Neuromuscular blockade was achieved with pancuronium, or vecuronium, depending on the random assignment of the patient to three different experimental programmes (fig. 1): all patients received equal loading doses (0.075mgkg"1) of pancuronium (group I) or vecuronium (groups II, III). In groups I and II, onefifth of the loading dose (0.015mgkg"1) of pancuronium or vecuronium was repeated whenever neuromuscular transmission had recovered to 25% of control. In group III an i.v. infusion of vecuronium 0.075 mg kg"1 h"1 was started at the time of injection of the loading dose (0.075mgkg~ 1 ). The rate of infusion was kept constant during the operation © The Macmillan Press Ltd 1984
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 29, 2015
The neuromuscular blocking effects of repeated bolus injections of pancuronium, or vecuronium, and of the continuous infim'nn of vecuTonhim have been compared in 36 patients by means of evoked twitch rirwinn Groups I and II received a loading dose (0.075 mg kg"1) of pancuronium or vecuronium, respectively, ch followed by 0.015-mgkg do l hid recovered to 25% of control. Group
474
BRITISH JOURNAL OF ANAESTHESIA TABLE I. Patitnt data (mean ± SD) Group I: Group II: Group III: repetitive repetitive continuous pancuronium vecuromum vecuromum (II-12) (n = 12) (»= 12)
Age(yr) Weight (kg) Duration of anaestfa. (min) Duration of infusion (min)
50±ll 75± 11 185 ±70
42± 8 69±11 127±31
TABLE III. Indicts of nturomuscular transmission after a 0.075mgkg~l loading dost and O.OlS-mgkg'1 maintenance doses of pancuronium and vecuronium. Dur2s and DUT^ 25™ duration from end of injection of loading dose and maintenance dost, respectively, to recovery of 25% of control twitch tension (overall values); recovery time *> time from 25% to 75% of control twitch tension. Numbers art means± SD; n.s. ~ not significant; ***P < 0.005
46±10 67± 6 159±51
Group I: repetitive pancuronium
Group II: repetitive vecuronium
5.6±3.6 (n-12)
3.4±2.4 (n=12) 25±7 (n=12) 12±4 (n = 75) 5±1.7 (n- 12)
86±37 Time of onset (min)
Number of maint. doses per hour Average total of maint. doses (mgkg-'h- 1 ) Recovery time 25%-75% (min)
64±34 (n-12) 42 ±16 (n = 23) 1.7±0.7
0.075 (n=12) 15±7
0.025 (»-12) 44±22 (n-7)
RESULTS
Patients in the three groups were comparable with respect to age, weight and duration of anaesthesia (table I). The numbers of maintenance doses required in groups I and II are indicated in table II. The indices of neuromuscular blockade appropriate to the three different modes of administration are presented in tables III and IV. Figure 1 presents one individual tracing from each group. Within 1.5 to 6 min of the loading dose of either neuromuscular blocking drug, total neuromuscular blockade had been achieved in all patients, and there were no significant differences between the three groups. The duration of action of the loading dose of pancuronium (to 25% recovery of twitch tension (Dur25)) was of the order of 1 h (group I), being on average 2.6 times longer than that for vecuronium (group II). The maintenance doses of pancuronium acted for 3.5 times as long as those of vecuronium (DurItP25)- Correspondingly, the total requirement for neuromuscular blocker to maintain neuromuscular transmission below 25% of control was three TABLE II. Number of patitna requiring difftrtnl numbers ofmainunance doses with pancuronium and vecuronium (group land II) Number of r
Pancurunium Vecuronium
1
2
3
5
3
4 1 2
4
• l t n lane•r doses
5 6
7
2 3
1
8
9
10 11
2
1
Total 12 12
times greater with vecuronium. In group III (continuous infusion of vecuronium) the initial period of total blockade lasted for almost 1 h until an equilibrium was established at an average of 13% of control twitch tension. The degree of steady state blockade was subject to considerable individual variation, and in one patient the twitch tension stabilized at 60% of control. At the end of surgery, seven out of 12 patients in group I had recovered spontaneously to 75% of the control twitch tension. In groups II and III, nine of 12 patients receiving vecuronium had recovered spontaneously to 75% of the control twitch tension. Among these patients, the shortest recovery times
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irrespective of the resultant degree of blockade. The speed of onset, duration and reversal of neuromuscular blockade were taken from the individual tracings and calculated as means and standard deviations. Their definitions are given in tables III and IV. Students's t test was used to assess statistical significance. Linear regressions were calculated by the least squares method.
TABLE IV. Indices of neuromuscular transmission after a 0.075mgkg'1 loading dose and 0.075-mg kg~' h~l infusion of vecuronium (meant SD) Group III: continuous vecuronium Time of onset (min) Duration of infusion (min) Constant block % (% of control) Time from start of infusion to constant block (min) Recovery time 25%-75% (min) Time from end of infusion to 2 5% recovery (min) to 7 5% recovery (min)
2±0.5 86±37 13±23
n-12 n-12 n-12
57 ±21
n-12
26±6
n- 9
20 ±10 42 ±16
n-12 n= 9
INFUSION OF VECURONIUM
475
GROUP I 0.075 mg k g ' 1
PC
I
bolus I • increm.1
0.015 mg kg -1
•m.r
• AiL-
recovery time • 33 min GROUPII 0075 mgkg- 1 0015 mg kg-'
58 kg 49 yr
bolus • Infus.
70 kg 5 0 yr
30
60
120
90
150
min
FIG. 1. Individual tracings of neuromuscular blockade caused by repetitive i.v. infection of pancuronium (PC) and vecuronium (NC), and continuous i.v. infmrinn of vecuronhim.
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 29, 2015
recovsry tim*i21mln
were seen with the repeated doses of vecuronium (table III, group II), while after the infusion of vecuronium and the incremental doses of pancuronium the recovery times were 1.7 and 2.9 times as long, respectively (tables HI and IV). In groups I and II the recovery times did not correlate with the number of maintenance doses administered. In group III, when the infusion was discontinued, about 20 min elapsed until twitch tension returned to 25% of control, and it took another 20 min to obtain 75% of control twitch tension (recovery time). There was a significant negative correlation between residual neuromuscular transmission at the end of infusion and the time from the end of the infusion to recovery of 25% of control twitch height (fig. 2). No correlation existed between residual neuromuscular transmission and recovery time (25-75%), nor did the recovery time (range 13-32 min) correlate with the duration of infusion (range 16-160min; r=0.3). Neostigmine 0.015mgkg~' i.v. was effective inreversingresidual neuromuscular blockade in all patients within 5-10 min.
injections was inconvenient from a practical point of view. The most satisfactory results were obtained with a continuous infusion of vecuronium, which provided adequate surgical relaxation for any desired period of time without evidence of cumulation. However, after the infusion of vecurOnium, recovery of neuromuscular transmission was slower than
DISCUSSION In operations of more than 1 h duration the administration of pancuronium by repeated i.v. injection provided adequate neuromuscular blockade: the disadvantages were related to an extremely variable duration of action and slow recovery. In contrast, the duration of action of equieffective doses of vecuronium was more predictable, and the final recovery of neuromuscular transmission occurred much more rapidly. However, the need for frequent
30 30 % t ransm tssion •t*ndof Infusion
bolus
- Infusion
time from and of infusion to M X recovery
at and of Infusion
FIG. 2. Correlation between residual neuromuscular transmission at end of infusion and recovery of twitch tension. Upper panel: tracing of evoked twitch tension. Diamond line •• duration of infusion; broken lint* —timefrom end of infusion to iccoveiy of 25% of control twitch tension; solid line«»recovery time (25-75%). Left panel: wgnifiram negative correlation between the level of neuromuscular transmission at end of infusion and time from end of infusion to 25% recovery. Right panel: no correlation between level of neuromuscular transmission at end of infusion and recovery time (25-75%).
476
study and our present study. They all represent about 1.6 times the 90% blocking dose of either drug (Robertson et al., 1983). The results with the infusion of atracurium are similar to the findings with the continuous administration of vecuronium except for the recovery time which was 7 min shorter with atracurium than with vecuronium. This difference may be a result of their different metabolic disposition. Hofmann elimination is the major metabolic pathway controlling the duration of action of atracurium (Hughes and Chappie, 1981). In contrast, vecuronium undergoes redistribution and excretion with very little metabolic degradation (Sohn et al., 1982). Apparently, under the conditions of continuous infusion, the metabolic pathways of atracurium are more effective in rapidly restoring neuromuscular transmission than those of vecuronium. Donati and Bevan (1982, 1983) re-evaluated the continuous infusion of suxamethonium. They denied the need for limitation of the total dose of suxamethonium, because neostigmine 1.25-2.5 mg i.v. reversed the phase II block in all patients. However, now that we have a new generation of non-depolarizing drugs available we do not see any further need for the infusion of suxamethonium. Thus, the continuous infusion of vecuronium appears to be a satisfactory alternative to the incremental use of vecuronium or pancuronium. In procedures of l - 3 h duration the infusion technique provides surgical relaxation of a more consistent degree, and for a longer period of time, than does the repeated injection of either drug. The time required to stabilize neuromuscular blockade depends on the loading dose, on the time interval between injection of the loading dose and start of infusion, and on the rate of infusion. As a basic approach, for stable 90% block, the loading dose should be in the order of 1.5 times the cumulative EDW, and the same dose should be infused per hour. The infusion should be started within the first 10 min after the injection of the loading dose. ACKNOWLEDGEMENT
Vecuroniuni (Norcuron; Oig NC45) wa» kindly supplied by Organon International, OSS, The Netherlands REFERENCES
Buzello, W., and Noeldge, G. (1982). Repetitive administration of pancuronium and vecuronium (Org NC45, Norcuron) in patients undergoing long-lasting operations. Br. J. Anatah., 54,1151.
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after repeated bolus injections of the same drug. D'Hollander and colleagues (1982) studied the effects of an infusion of vecuronium started 10 min after the injection i.v. of a0.07-mg kg"1 loading dose and readjusted every 10 min for stable 90% twitch depression. The average maintenance dose (0.07 nig kg"1 h"1) and recovery time (22 min) obtained in their 40-60yr age group are consistent with the findings of the present study, where 11 out of the 12 patients were between 40 and 60 yr of age. However, the maintenance doses and the recovery times were subject to considerable individual variation. This was reflected also in our results and explains the poor response of one patient in group III to the constant infusion of vecuronium. The recovery time of vecuronium has been reported previously not to correlate with its total cumulative dose (Buzello and Noeldge, 1982). This finding has now been substantiated by the demonstration of identical recovery times following repeated bolus injections of 2 5% smaller doses (group II), and by the failure to demonstrate a correlation between the total dose infused and the recovery time (group III). Following the continuous infusion of vecuronium the mean recovery time was significantly longer than after its intermittent administration, suggesting that the two techniques generate different pharmacokinetic conditions. Sohn and colleagues (1982) proposed a three-compartment pharmacokinetic model where the uptake of the unchanged vecuronium was the main principle controlling the recovery of neuromuscular transmission, and it may be assumed that the infusion provides a more effective saturation of the third compartment than do intermittent injections. However, no pharmacokinetic data are available to support this view. In the study of Cronnelly and co-workers (1983) the infusion time (10 min) was too short to be comparable to the conditions of the present study. In contrast to our findings (table IV), d'Hollander and colleagues (1982) observed stable neuromuscular blockade 40 min after the injection of the loading dose, and only 9±4min elapsed from the end of infusion until recovery of 25% of control twitch tension. This difference is explained by the 10-min interval between loading dose and start of infusion and by the total dose of vecuronium which was 12-22% smaller than that in the present study. The infusion of atracurium O^mgkg"1 and O.SSmgkg-'h"1 has been studied recently (d'Hollander et al., 1983). The doses used were comparable to those of vecuronium in both their previous
BRITISH JOURNAL OF ANAESTHESIA
INFUSION OF VECURONIUM
Br.J.Amusth., 63, 31. Robertson, E. N., Booij, L. H. D. J., Fragen.R. J.,andCrul, J. F. (1983). rjiniral comparison of atracurium and vecuronium (OrgNC45). Br. J. Anatsth., 55,125. Sohn, Y. J., Bencini, A., Scaf, A. H. J., Kersten, U. W., Gregoretti, S., and Agoston, S. (1982). Pharmacokinetics of vecuronium in man. Anesthtsiology, 57, A256. Walts, L. E. (1973). "The boomerang"—a method of recording adductor pollicis tension. Can. Anaath. Soc. / . , 10, 70.
COMPARAISON ENTRE LE VECURONIUM EN PERFUSION CONTINUE ET VADMINISTRATION INTERMITTENTE DE PANCURONTUM ET DE VECURONIUM
INFUSION VON VECURONIUM UND REPETTERTE INJEKTION VON PANCURONIUM UND VECURONIUM IN DER KIJNISCHEN ANAESTHESIOLOGIE ZUSAMMENFASSUNG
An
drei
Gruppen
von
je
12 Patienten
wurde
unter
mlii^iy und mit Hilfe deS CVOzicrtCn
die neuromuskular blockierende Wirkung der Infusion von Vecuronium mit der repetienen Injektion von Pancuronium und Vecuronium vcrglichcn. Gruppe I iinf^ II erhielten initial 0.075 mg kg"1 Pancuronium bzw. Vecuronium und Erhaltungsdosen von 0.015mgkg~' jeweils bei Erholung der neuromuskulfiren Ubertragung auf 25% der Kontrollwcrte. Gruppe III erhielt Vecuronium als Initialdosis von ebenfalls 0.075 mgkg~' mit gleichzeitigem Start einer Infusion von 0.075mgkg"'h" 1 . Die Wirkungsdauer der Initialdosis betrug bei Pancuronium (Gruppe I) und Vecuronium (Gruppe II) 64 bzw. 25 Minuten. Erhaltungsdosen mussten bei Pancuronium alle 44 und bei Vecuronium alle 12 Minuten nachinjiziert werden. Unter Vecuroniuminfusion (Gruppe HI) stabilisierte sich eine konstante Muskelrelaxation im Mind bei 13% Resriiberleitung. Die Zeiten von Infusiansende bis 25% sowie von 25% auf 75% Erholung lagen bei 20 bzw. 26 Minuten. Beide Grossen korrelierten nicht mit der infundierten Gesamtdosis Vecuronium. Fur den klinischen Gebrauch entspricht die Initialdosis etwa dem 1.5fachenderED9o("0.07mgkg~ 1 Vecuronium) mit der gleichen Dosis pro Stunde als Infusion. Die Infusion soil innerhalb der ersten 10 Minuten nach Injektion der Initialdosis beginnen. COMPARACION ENTRE LA INFUSION CONTINUA DE VECURONIO Y LA ADMINISTRACION ENTERMITENTE DE PANCURONIO Y VECURONIO
RESUME
Nous avons compare les effets sur la transmission neuromusculaire d'injections discontinues iteratives de paocuronium ou de vecuronium et d'une perfusion continue de vecuronium chez 36 patients, a l'aide de la mesure de la hauteur du twitch. Les groupes I et II ont recu une dose de charge (0,075 mg kg"1) de pancuronium ou de vecuronium, suivies de doses d'entretien de 0,015mgkg-' lorsque la hauteur du twitch atteigriait 25% de la valeur controle. Le groupe III a recu une dose de charge de 0,075 mg kg"' de vecuronium, associee a une perfusion d'entretien commencee d'emblee, de 0,075mgkg~'h. Avec les injections iteratives de pancuronium (groupe I) ou de vecuronium (groupe II), les durees de bloc jusqu'a 25% de recuperation etaient respectrvement de 64 et de 25 min. Les doses d'entretien devraient etre injectees toutes les 42 min avec le pancuronium et toutes les 12 min avec le vecuronium. Les temps de recuperation de 25 a 75% de la hauteur initiale du twitch etaient 44 et 12 min. La perfusion continue de vecuronium (groupe III) indusait un bloc neuromusclaire constant a un niveau moyen de 87% de depression du twitch. Les durees, comprises entre la fin de la perfusion et une recuperation de 25% de la hauteur du twitch et entre 25 et 75% de recuperation atteignaicm, en moyenne, 20 et 26 min, respectivement. Ces valeurs n'etaient pas correlees avec la dose totale de vecuronium perfusee. En pratique cUnique, nous guggerons une dose de charge de 1,5 fcris la DE90 (environ 0,07 mg kg*1) guivie d'une perfusion horaire de la meme dose. La perfusion devrait etre mnmrTu^r moins de 10 min apres l'injection de la dose de charge.
SUMARIO
En 36 packntes, se llevaron a cabo comparaciones de los efectos de bloqueo neuromuscular de inyecciones de bolo repetidas de pancuronio o de vecuronio y de la infusion continue de vecuronio pot medio de la tension de contraccion evocada. Los grupos I y II recibieron una dosis de carga (0,075 mg kg"') de pancuronio o de vecuronio, respectivamente, seguida por dosis de mantenimiento de 0,015 mg kg"1 cuando la tension de contraccion habia recuperado un 25% del control. El grupo HI rccibio una dosis de carga de 0,075 mg kg"1 de vecuronio mas una infusion continue (imVtarfp sunultaneamente) de 0,075 mg kg" 1 h~'. Con inyecciones repetidas de pancuronio (Grupo I) o de vecuronio (Grupo II), la duracion del bloqueo con rccuperacion del 2 5% fue de 64 y de 25 min, respectivamente. Dosis de mantenimiento tuvieron que administrarse cada 42 min con pancuronio y cada 12 min con vecuronio. El tiempo de recuperacion del 25% al 75% de la tension de contraccion de control fue de 44 min contra 12 min. La infusion continua de vecuronio (Grupo III) produjo un bloqueo neuromuscular constante con "n nivel promedio del 87% de la depresion de la contraccion. El periodo entre el fin de la infusion y la recuperaci6n al 25%, y entre la recuperacion al 25%y al 75%, vario en promedio de 20 a 26 min respectivamente. Dichos valores no tenian correlacion algiina con la dosis total de vecuronio infmoHn Con fines dinicos practicos, se sugiere una dosis equivalente a 1,5 vez el ED90 (0,07 mg kg" 1 ), seguida por una infusion en la minmn dosis cada hora. La infusion debena iniciarse dentro de los 10 min de la inyeccionde la dosis de carga.
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Cronnelly, R., Fisher, D. M., Miller, R. D., GencarelH, P., Nguyen-Gruenke, L., and Castagnoli, N. (1983). Pharmacokinetics and pharmacodynamics of vecuronium (Org NC 45) and poncuronium in anesthetized humans. Ancsthtsiol<*y,58,405. Donati, F., and Bevan, D. R. (1982). Effect of enfhirane and fentanyl on the clinical characteristics of long term succinylcholine infusion. Can. Anatsth. Soc. / . , 29, 59. (1983). Long term sucdnylcboline infusion during isoflurane anesthesia. Anathtsiology, 58, 6. D'Hollander, A. A., Luyckx, C , Barvais, L., and DeVille, A. (1983). Pliniral evaluation of atracurium besylate requirement for a stable muscle relaxation during surgery: Lack of agerelated effects. Anathawlogy, 59, 237. Massauz, F., Nevelsteen, M., and Agoston, S. (1982). Age-dependent dose-response relationship of Org NC45 in anaesthetized patients. Br. J. Anaath., 54,653. Hughes, R., and Chappie, D. J. (1981). The pharmacology of atracurium: a new competitive neuromuscular blocking agent.
477
COMPARISON BETWEEN THE CONTINUOUS INFUSION OF VECURONIUM AND THE INTERMITTENT ADMINISTRATION OF PANCURONIUM AND VECURONIUM G. NOELDGE, H. HINSKEN AND W. BUZELLO SUMMARY
III received a 0.075-mg kg ' trading Hiw ntCTfiimniirinpl"« a mnriniinm infiirirm ( m i t i m w y ^ irimiih^ni-.
ously) delivering 0.075 mg kg" 1 h . With repeated injections of pancuronium (group I) or vecuronium (group II), the durations of blockade to 25% recovery were 64 and 25 min, respectively. Maintenance doses had to be injected every 42 min with pancuronium and every 12 min with vecuronium. The recovery rmvn from 25% to 75% of control twitch tension were 44 v. 12 min. The continuous infusion of vecuronium (group HI) produced -consistent neuromuscular blockade at an average level of 87% twitch depression. The times from the end of infusion to 25%, and from 25% to 75%, recovery averaged 20 and 26 min, respectively. These values did not correlate with the total dose of vecuronium infused. For clinical practice, the suggested loading dose is 1.5 rime* the F.D^ ( ° (1.07 mgkg" 1 ) followed by an infimirm of the Bmt dr«e per hniir. Thf infmrinn should be started within 10 min of the injection of the InaHing dose.
Having demonstrated previously that, during prolonged surgical procedures, bolus injections of vecuronium were required as frequently as every 10 min, Buzello and Noeldge (1982) suggested that the continuous infusion of this drug would be a more appropriate technique with which to maintain a consistent degree of neuromuscular blockade. This mode of administration' has been studied in the present paper. PATIENTS AND METHODS Thirty-six patients (ASA I and II) undergoing gynaecological surgery were studied after informed consent had been obtained. Individuals younger than 20 and older than 60 years of age, and those with conditions or medications known to affect the pharmacodynamics of neuromuscular blocking drugs were excluded from the study. All patients were premedicated with atropine 0.01 mg kg"1, pethidine 0.7mgkg~' and triflupromazine O.lSmgkg"1 i.m. 45min before the induction of anaesthesia which was accomplished with thiopentone 250-350mg and fentanyl 0.3-0.5mg. The G. NOELDGE, M.D.; H. HINSKEN, M.D.; W. BUZELLO,* M.D.;
Department of Anaesthe: anlogy, University Hospital, Hugstetter Str. 55, D-7800 Freiburg, Federal Republic of Germany. •Present address: Department of Anesthesiology, Texas Tech University School of Medicine, 4800 Alberta Ave., El Paso, Texas 79905, U.S.A.
trachea was intubated following neuromuscular blockade with a loading dose of pancuronium or vecuronium (see below) and anaesthesia was maintained with increments of fentanyl and nitrous oxide in oxygen (2:1). No halogenated inhalation anaesthetics were used. Ventilation was controlled, and neostigmine 0.015 mg kg"1 and atropine 0.01 mgkg"1 injected i.v. if residual neuromuscular blockade was present at the end of the procedure. Neuromuscular transmission was monitored by recording the evoked twitch tension of the adductor pollicis muscle with the aid of a boomerang force displacement transducer (Walts, 1973), further details of which have been described previously (Buzello and Noeldge, 1982). Neuromuscular blockade was achieved with pancuronium, or vecuronium, depending on the random assignment of the patient to three different experimental programmes (fig. 1): all patients received equal loading doses (0.075mgkg"1) of pancuronium (group I) or vecuronium (groups II, III). In groups I and II, onefifth of the loading dose (0.015mgkg"1) of pancuronium or vecuronium was repeated whenever neuromuscular transmission had recovered to 25% of control. In group III an i.v. infusion of vecuronium 0.075 mg kg"1 h"1 was started at the time of injection of the loading dose (0.075mgkg~ 1 ). The rate of infusion was kept constant during the operation © The Macmillan Press Ltd 1984
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 29, 2015
The neuromuscular blocking effects of repeated bolus injections of pancuronium, or vecuronium, and of the continuous infim'nn of vecuTonhim have been compared in 36 patients by means of evoked twitch rirwinn Groups I and II received a loading dose (0.075 mg kg"1) of pancuronium or vecuronium, respectively, ch followed by 0.015-mgkg do l hid recovered to 25% of control. Group
474
BRITISH JOURNAL OF ANAESTHESIA TABLE I. Patitnt data (mean ± SD) Group I: Group II: Group III: repetitive repetitive continuous pancuronium vecuromum vecuromum (II-12) (n = 12) (»= 12)
Age(yr) Weight (kg) Duration of anaestfa. (min) Duration of infusion (min)
50±ll 75± 11 185 ±70
42± 8 69±11 127±31
TABLE III. Indicts of nturomuscular transmission after a 0.075mgkg~l loading dost and O.OlS-mgkg'1 maintenance doses of pancuronium and vecuronium. Dur2s and DUT^ 25™ duration from end of injection of loading dose and maintenance dost, respectively, to recovery of 25% of control twitch tension (overall values); recovery time *> time from 25% to 75% of control twitch tension. Numbers art means± SD; n.s. ~ not significant; ***P < 0.005
46±10 67± 6 159±51
Group I: repetitive pancuronium
Group II: repetitive vecuronium
5.6±3.6 (n-12)
3.4±2.4 (n=12) 25±7 (n=12) 12±4 (n = 75) 5±1.7 (n- 12)
86±37 Time of onset (min)
Number of maint. doses per hour Average total of maint. doses (mgkg-'h- 1 ) Recovery time 25%-75% (min)
64±34 (n-12) 42 ±16 (n = 23) 1.7±0.7
0.075 (n=12) 15±7
0.025 (»-12) 44±22 (n-7)
RESULTS
Patients in the three groups were comparable with respect to age, weight and duration of anaesthesia (table I). The numbers of maintenance doses required in groups I and II are indicated in table II. The indices of neuromuscular blockade appropriate to the three different modes of administration are presented in tables III and IV. Figure 1 presents one individual tracing from each group. Within 1.5 to 6 min of the loading dose of either neuromuscular blocking drug, total neuromuscular blockade had been achieved in all patients, and there were no significant differences between the three groups. The duration of action of the loading dose of pancuronium (to 25% recovery of twitch tension (Dur25)) was of the order of 1 h (group I), being on average 2.6 times longer than that for vecuronium (group II). The maintenance doses of pancuronium acted for 3.5 times as long as those of vecuronium (DurItP25)- Correspondingly, the total requirement for neuromuscular blocker to maintain neuromuscular transmission below 25% of control was three TABLE II. Number of patitna requiring difftrtnl numbers ofmainunance doses with pancuronium and vecuronium (group land II) Number of r
Pancurunium Vecuronium
1
2
3
5
3
4 1 2
4
• l t n lane•r doses
5 6
7
2 3
1
8
9
10 11
2
1
Total 12 12
times greater with vecuronium. In group III (continuous infusion of vecuronium) the initial period of total blockade lasted for almost 1 h until an equilibrium was established at an average of 13% of control twitch tension. The degree of steady state blockade was subject to considerable individual variation, and in one patient the twitch tension stabilized at 60% of control. At the end of surgery, seven out of 12 patients in group I had recovered spontaneously to 75% of the control twitch tension. In groups II and III, nine of 12 patients receiving vecuronium had recovered spontaneously to 75% of the control twitch tension. Among these patients, the shortest recovery times
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irrespective of the resultant degree of blockade. The speed of onset, duration and reversal of neuromuscular blockade were taken from the individual tracings and calculated as means and standard deviations. Their definitions are given in tables III and IV. Students's t test was used to assess statistical significance. Linear regressions were calculated by the least squares method.
TABLE IV. Indices of neuromuscular transmission after a 0.075mgkg'1 loading dose and 0.075-mg kg~' h~l infusion of vecuronium (meant SD) Group III: continuous vecuronium Time of onset (min) Duration of infusion (min) Constant block % (% of control) Time from start of infusion to constant block (min) Recovery time 25%-75% (min) Time from end of infusion to 2 5% recovery (min) to 7 5% recovery (min)
2±0.5 86±37 13±23
n-12 n-12 n-12
57 ±21
n-12
26±6
n- 9
20 ±10 42 ±16
n-12 n= 9
INFUSION OF VECURONIUM
475
GROUP I 0.075 mg k g ' 1
PC
I
bolus I • increm.1
0.015 mg kg -1
•m.r
• AiL-
recovery time • 33 min GROUPII 0075 mgkg- 1 0015 mg kg-'
58 kg 49 yr
bolus • Infus.
70 kg 5 0 yr
30
60
120
90
150
min
FIG. 1. Individual tracings of neuromuscular blockade caused by repetitive i.v. infection of pancuronium (PC) and vecuronium (NC), and continuous i.v. infmrinn of vecuronhim.
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recovsry tim*i21mln
were seen with the repeated doses of vecuronium (table III, group II), while after the infusion of vecuronium and the incremental doses of pancuronium the recovery times were 1.7 and 2.9 times as long, respectively (tables HI and IV). In groups I and II the recovery times did not correlate with the number of maintenance doses administered. In group III, when the infusion was discontinued, about 20 min elapsed until twitch tension returned to 25% of control, and it took another 20 min to obtain 75% of control twitch tension (recovery time). There was a significant negative correlation between residual neuromuscular transmission at the end of infusion and the time from the end of the infusion to recovery of 25% of control twitch height (fig. 2). No correlation existed between residual neuromuscular transmission and recovery time (25-75%), nor did the recovery time (range 13-32 min) correlate with the duration of infusion (range 16-160min; r=0.3). Neostigmine 0.015mgkg~' i.v. was effective inreversingresidual neuromuscular blockade in all patients within 5-10 min.
injections was inconvenient from a practical point of view. The most satisfactory results were obtained with a continuous infusion of vecuronium, which provided adequate surgical relaxation for any desired period of time without evidence of cumulation. However, after the infusion of vecurOnium, recovery of neuromuscular transmission was slower than
DISCUSSION In operations of more than 1 h duration the administration of pancuronium by repeated i.v. injection provided adequate neuromuscular blockade: the disadvantages were related to an extremely variable duration of action and slow recovery. In contrast, the duration of action of equieffective doses of vecuronium was more predictable, and the final recovery of neuromuscular transmission occurred much more rapidly. However, the need for frequent
30 30 % t ransm tssion •t*ndof Infusion
bolus
- Infusion
time from and of infusion to M X recovery
at and of Infusion
FIG. 2. Correlation between residual neuromuscular transmission at end of infusion and recovery of twitch tension. Upper panel: tracing of evoked twitch tension. Diamond line •• duration of infusion; broken lint* —timefrom end of infusion to iccoveiy of 25% of control twitch tension; solid line«»recovery time (25-75%). Left panel: wgnifiram negative correlation between the level of neuromuscular transmission at end of infusion and time from end of infusion to 25% recovery. Right panel: no correlation between level of neuromuscular transmission at end of infusion and recovery time (25-75%).
476
study and our present study. They all represent about 1.6 times the 90% blocking dose of either drug (Robertson et al., 1983). The results with the infusion of atracurium are similar to the findings with the continuous administration of vecuronium except for the recovery time which was 7 min shorter with atracurium than with vecuronium. This difference may be a result of their different metabolic disposition. Hofmann elimination is the major metabolic pathway controlling the duration of action of atracurium (Hughes and Chappie, 1981). In contrast, vecuronium undergoes redistribution and excretion with very little metabolic degradation (Sohn et al., 1982). Apparently, under the conditions of continuous infusion, the metabolic pathways of atracurium are more effective in rapidly restoring neuromuscular transmission than those of vecuronium. Donati and Bevan (1982, 1983) re-evaluated the continuous infusion of suxamethonium. They denied the need for limitation of the total dose of suxamethonium, because neostigmine 1.25-2.5 mg i.v. reversed the phase II block in all patients. However, now that we have a new generation of non-depolarizing drugs available we do not see any further need for the infusion of suxamethonium. Thus, the continuous infusion of vecuronium appears to be a satisfactory alternative to the incremental use of vecuronium or pancuronium. In procedures of l - 3 h duration the infusion technique provides surgical relaxation of a more consistent degree, and for a longer period of time, than does the repeated injection of either drug. The time required to stabilize neuromuscular blockade depends on the loading dose, on the time interval between injection of the loading dose and start of infusion, and on the rate of infusion. As a basic approach, for stable 90% block, the loading dose should be in the order of 1.5 times the cumulative EDW, and the same dose should be infused per hour. The infusion should be started within the first 10 min after the injection of the loading dose. ACKNOWLEDGEMENT
Vecuroniuni (Norcuron; Oig NC45) wa» kindly supplied by Organon International, OSS, The Netherlands REFERENCES
Buzello, W., and Noeldge, G. (1982). Repetitive administration of pancuronium and vecuronium (Org NC45, Norcuron) in patients undergoing long-lasting operations. Br. J. Anatah., 54,1151.
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after repeated bolus injections of the same drug. D'Hollander and colleagues (1982) studied the effects of an infusion of vecuronium started 10 min after the injection i.v. of a0.07-mg kg"1 loading dose and readjusted every 10 min for stable 90% twitch depression. The average maintenance dose (0.07 nig kg"1 h"1) and recovery time (22 min) obtained in their 40-60yr age group are consistent with the findings of the present study, where 11 out of the 12 patients were between 40 and 60 yr of age. However, the maintenance doses and the recovery times were subject to considerable individual variation. This was reflected also in our results and explains the poor response of one patient in group III to the constant infusion of vecuronium. The recovery time of vecuronium has been reported previously not to correlate with its total cumulative dose (Buzello and Noeldge, 1982). This finding has now been substantiated by the demonstration of identical recovery times following repeated bolus injections of 2 5% smaller doses (group II), and by the failure to demonstrate a correlation between the total dose infused and the recovery time (group III). Following the continuous infusion of vecuronium the mean recovery time was significantly longer than after its intermittent administration, suggesting that the two techniques generate different pharmacokinetic conditions. Sohn and colleagues (1982) proposed a three-compartment pharmacokinetic model where the uptake of the unchanged vecuronium was the main principle controlling the recovery of neuromuscular transmission, and it may be assumed that the infusion provides a more effective saturation of the third compartment than do intermittent injections. However, no pharmacokinetic data are available to support this view. In the study of Cronnelly and co-workers (1983) the infusion time (10 min) was too short to be comparable to the conditions of the present study. In contrast to our findings (table IV), d'Hollander and colleagues (1982) observed stable neuromuscular blockade 40 min after the injection of the loading dose, and only 9±4min elapsed from the end of infusion until recovery of 25% of control twitch tension. This difference is explained by the 10-min interval between loading dose and start of infusion and by the total dose of vecuronium which was 12-22% smaller than that in the present study. The infusion of atracurium O^mgkg"1 and O.SSmgkg-'h"1 has been studied recently (d'Hollander et al., 1983). The doses used were comparable to those of vecuronium in both their previous
BRITISH JOURNAL OF ANAESTHESIA
INFUSION OF VECURONIUM
Br.J.Amusth., 63, 31. Robertson, E. N., Booij, L. H. D. J., Fragen.R. J.,andCrul, J. F. (1983). rjiniral comparison of atracurium and vecuronium (OrgNC45). Br. J. Anatsth., 55,125. Sohn, Y. J., Bencini, A., Scaf, A. H. J., Kersten, U. W., Gregoretti, S., and Agoston, S. (1982). Pharmacokinetics of vecuronium in man. Anesthtsiology, 57, A256. Walts, L. E. (1973). "The boomerang"—a method of recording adductor pollicis tension. Can. Anaath. Soc. / . , 10, 70.
COMPARAISON ENTRE LE VECURONIUM EN PERFUSION CONTINUE ET VADMINISTRATION INTERMITTENTE DE PANCURONTUM ET DE VECURONIUM
INFUSION VON VECURONIUM UND REPETTERTE INJEKTION VON PANCURONIUM UND VECURONIUM IN DER KIJNISCHEN ANAESTHESIOLOGIE ZUSAMMENFASSUNG
An
drei
Gruppen
von
je
12 Patienten
wurde
unter
mlii^iy und mit Hilfe deS CVOzicrtCn
die neuromuskular blockierende Wirkung der Infusion von Vecuronium mit der repetienen Injektion von Pancuronium und Vecuronium vcrglichcn. Gruppe I iinf^ II erhielten initial 0.075 mg kg"1 Pancuronium bzw. Vecuronium und Erhaltungsdosen von 0.015mgkg~' jeweils bei Erholung der neuromuskulfiren Ubertragung auf 25% der Kontrollwcrte. Gruppe III erhielt Vecuronium als Initialdosis von ebenfalls 0.075 mgkg~' mit gleichzeitigem Start einer Infusion von 0.075mgkg"'h" 1 . Die Wirkungsdauer der Initialdosis betrug bei Pancuronium (Gruppe I) und Vecuronium (Gruppe II) 64 bzw. 25 Minuten. Erhaltungsdosen mussten bei Pancuronium alle 44 und bei Vecuronium alle 12 Minuten nachinjiziert werden. Unter Vecuroniuminfusion (Gruppe HI) stabilisierte sich eine konstante Muskelrelaxation im Mind bei 13% Resriiberleitung. Die Zeiten von Infusiansende bis 25% sowie von 25% auf 75% Erholung lagen bei 20 bzw. 26 Minuten. Beide Grossen korrelierten nicht mit der infundierten Gesamtdosis Vecuronium. Fur den klinischen Gebrauch entspricht die Initialdosis etwa dem 1.5fachenderED9o("0.07mgkg~ 1 Vecuronium) mit der gleichen Dosis pro Stunde als Infusion. Die Infusion soil innerhalb der ersten 10 Minuten nach Injektion der Initialdosis beginnen. COMPARACION ENTRE LA INFUSION CONTINUA DE VECURONIO Y LA ADMINISTRACION ENTERMITENTE DE PANCURONIO Y VECURONIO
RESUME
Nous avons compare les effets sur la transmission neuromusculaire d'injections discontinues iteratives de paocuronium ou de vecuronium et d'une perfusion continue de vecuronium chez 36 patients, a l'aide de la mesure de la hauteur du twitch. Les groupes I et II ont recu une dose de charge (0,075 mg kg"1) de pancuronium ou de vecuronium, suivies de doses d'entretien de 0,015mgkg-' lorsque la hauteur du twitch atteigriait 25% de la valeur controle. Le groupe III a recu une dose de charge de 0,075 mg kg"' de vecuronium, associee a une perfusion d'entretien commencee d'emblee, de 0,075mgkg~'h. Avec les injections iteratives de pancuronium (groupe I) ou de vecuronium (groupe II), les durees de bloc jusqu'a 25% de recuperation etaient respectrvement de 64 et de 25 min. Les doses d'entretien devraient etre injectees toutes les 42 min avec le pancuronium et toutes les 12 min avec le vecuronium. Les temps de recuperation de 25 a 75% de la hauteur initiale du twitch etaient 44 et 12 min. La perfusion continue de vecuronium (groupe III) indusait un bloc neuromusclaire constant a un niveau moyen de 87% de depression du twitch. Les durees, comprises entre la fin de la perfusion et une recuperation de 25% de la hauteur du twitch et entre 25 et 75% de recuperation atteignaicm, en moyenne, 20 et 26 min, respectivement. Ces valeurs n'etaient pas correlees avec la dose totale de vecuronium perfusee. En pratique cUnique, nous guggerons une dose de charge de 1,5 fcris la DE90 (environ 0,07 mg kg*1) guivie d'une perfusion horaire de la meme dose. La perfusion devrait etre mnmrTu^r moins de 10 min apres l'injection de la dose de charge.
SUMARIO
En 36 packntes, se llevaron a cabo comparaciones de los efectos de bloqueo neuromuscular de inyecciones de bolo repetidas de pancuronio o de vecuronio y de la infusion continue de vecuronio pot medio de la tension de contraccion evocada. Los grupos I y II recibieron una dosis de carga (0,075 mg kg"') de pancuronio o de vecuronio, respectivamente, seguida por dosis de mantenimiento de 0,015 mg kg"1 cuando la tension de contraccion habia recuperado un 25% del control. El grupo HI rccibio una dosis de carga de 0,075 mg kg"1 de vecuronio mas una infusion continue (imVtarfp sunultaneamente) de 0,075 mg kg" 1 h~'. Con inyecciones repetidas de pancuronio (Grupo I) o de vecuronio (Grupo II), la duracion del bloqueo con rccuperacion del 2 5% fue de 64 y de 25 min, respectivamente. Dosis de mantenimiento tuvieron que administrarse cada 42 min con pancuronio y cada 12 min con vecuronio. El tiempo de recuperacion del 25% al 75% de la tension de contraccion de control fue de 44 min contra 12 min. La infusion continua de vecuronio (Grupo III) produjo un bloqueo neuromuscular constante con "n nivel promedio del 87% de la depresion de la contraccion. El periodo entre el fin de la infusion y la recuperaci6n al 25%, y entre la recuperacion al 25%y al 75%, vario en promedio de 20 a 26 min respectivamente. Dichos valores no tenian correlacion algiina con la dosis total de vecuronio infmoHn Con fines dinicos practicos, se sugiere una dosis equivalente a 1,5 vez el ED90 (0,07 mg kg" 1 ), seguida por una infusion en la minmn dosis cada hora. La infusion debena iniciarse dentro de los 10 min de la inyeccionde la dosis de carga.
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Cronnelly, R., Fisher, D. M., Miller, R. D., GencarelH, P., Nguyen-Gruenke, L., and Castagnoli, N. (1983). Pharmacokinetics and pharmacodynamics of vecuronium (Org NC 45) and poncuronium in anesthetized humans. Ancsthtsiol<*y,58,405. Donati, F., and Bevan, D. R. (1982). Effect of enfhirane and fentanyl on the clinical characteristics of long term succinylcholine infusion. Can. Anatsth. Soc. / . , 29, 59. (1983). Long term sucdnylcboline infusion during isoflurane anesthesia. Anathtsiology, 58, 6. D'Hollander, A. A., Luyckx, C , Barvais, L., and DeVille, A. (1983). Pliniral evaluation of atracurium besylate requirement for a stable muscle relaxation during surgery: Lack of agerelated effects. Anathawlogy, 59, 237. Massauz, F., Nevelsteen, M., and Agoston, S. (1982). Age-dependent dose-response relationship of Org NC45 in anaesthetized patients. Br. J. Anaath., 54,653. Hughes, R., and Chappie, D. J. (1981). The pharmacology of atracurium: a new competitive neuromuscular blocking agent.
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