549
Neuromuscular and Francis F. Foldes MD, Hideo Nagashima MD, cardiovascular effects Hung D. Nguyen MD, Deryck Duncalf MO, Paul L. Goldiner MD of pipecuronium
Pipecuronium bromide (Arduan) is a bisquaternary, steroid- on heart rate or blood pressure. Pancuronium increased heart type neuromuscular blocking agent in clinical use in Eastern rate by about 20 per cent. Pipecuronium is preferable to Europe. Before its introduction into clinical practice in the USA, pancuronium for the production of muscular relaxation for in the first phase of this study the neuromuscular potency of relatively long operations, when it is desirable to avoid pipecuronium was determined under "balanced" and enflurane acceleration of heart rate. anaesthesia by the cumulative log dose-response method in 30 patients each. In the second phase the intubation and onset Le bromure de pipEcuronium (Arduan) est un curare biquater- times, clinical duration of the tirst and repeated doses, naire de type stEroi'dien employE en Europe de l' Est. Nous avons spontaneous recovery index, reversibility of its residual neuro- mesurE quelques unes de ses propriEtEs avant d'en recomman- muscular effect by an anticholinesterase and its effect on heart der l'usage clinique aux Etats-Unis. Dans un premier temps, rate and blood pressure was compared with the same variables nous avons dEterminE sa puissance en comparant la rEponse observed in patients, anaesthetized with identical techniques but neuromusculaire au Iogarythme de la dose cumulative chez deux who had received vecuronium or pancuronium. The neuromus- groupes de 30 patients. Nous avons dtabli que sa DEgs Eta# de cular potency of pipecuronium was greater under enflurane 23,6 +- 1,1 Ixg" kg -t (moyenne +- erreur-type) sous anesthEsie [ED95 = 23.6 • 1.1 Ixg. kg -t (mean +-- SEM)] than under d I'enflurane, et de 35,1 +- 17 Ixg. kg -I sous neurolepanesthE- balanced (ED95 = 35.1 • 17 tzg . kg -t ) anaesthesia. Pipecur- sie tandis que ces deter valeurs ~taient re+pectivement de: 27,4 onium was more potent than vecuronium under both balanced Ilg" kg -I et 45,8 Ixg' kg -t pour le vEcuronium. Dans un (ED95 = 45.8 txg" kg -I ) and enflurane anaesthesia (ED95 = deuxiEme temps, nous avons Etabli qu'en presence de conditions 2 7.4 Izg" kg- t). Following the administration of 2 x ED95 doses anesth~siques identiques, l' injection d' une dose Egale 2 • DEgs there were no clinically significant differences in the intubation s'accompagnait de temps de latence avant le debut d'action et or onset times of pipecuronium, vecuronium and pancuronium. l'instauration de conditions propices gt l'intubation virtueUe- Under balanced anaesthesia the clinical duration of 2 x EDg~ ment semblables pour le pipEcuronium, le pancuronium et le dose of pipecuronium (110.5 +- 0.3 rain) or pancuronium (I 15.8 vEcuronium tandis que sa durEe d'action s'Etablissait dans • 8.1 rain) were similar and about three times longer than that l'ordreg~ 110,5 +- 0,3 rain, 115,8 + 8,1 min et36,3 • 2, I rain et of vecuronium (36.3 +- 2.1 min). The recover), indices of son index de rEcupEration r 44,5 +. 8,2 rain, 41,3 • 4,2 rain et pipecuronium (44.5 +- 8.2 rain)andpancuronium (41.3 • 4.2 14,3 +- 1,4 rain pour ces mdmes produits. A latin de l' interven- rain) were also similar and about three times longer than that of tion, le bloc neuromusculaire rEsiduel dtait aussi facile d contrer vecuronium (14.3 • 1.4 rain). Residual neuromuscular block of avec un inhibiteur de la cholinesMrase quelque soit le myo- the three muscle relaxants could be equally well reversed by relaxant employE. Le pipEcuronium et le v~curonium g~ raison anticholinesterases at the end of anaesthesia. The 2 x ED95 d'une dose Egale d 2 x DE95 ne moditiErent ni la pression arM- doses of pipecuronium or vecuronium had no significant effect rielle ni la frEquence cardiaque tandis que cette "derni~re augmentait de 20 pour cent avec le pancuronium. II semble donc que si on veut utiliser un myorelaxant de longue durEe sans Key words accdldrer le pouls, on doive prEfErer le pipEcuronium au pan- COMPLICATIONS: cardiovascular; curonium. NEUROMUSCULAR RELAXANTS: pancuronium, pipecuronium, vecuronium. Pipecuronium bromide (Arduan) is a steroid base, bis- From the Department of Anesthesiology, Montefiore Medical quaternary neuromuscular blocking agent (muscle relax- Center, Albert Einstein College of Medicine, Bronx, NY ant) (Figure I). It has been used in Eastern Europe for the 10467. production of muscular relaxation during surgery, i-4 In Address correspondence to: Dr. F. F. Foldes, Department these studies the potency, speed of onset, and duration of of Anesthesiology, Montefiore Medical Center, I 11 East the neuromuscular effect of pipecuronium was found tc~ be 210th Street, Bronx, NY 10467. similar to those of pancuronium. Unlike pancuronium,
CAN] ANAESTH 1990/ 37:5/pp549-55 550 CANADIAN JOURNAL OF ANAESTHESIA
tion. Anaesthesia was maintained with a 2 L N20-1 L 02 CHEMICAL STRUCTURE gas mixture, 25-100 ixg increments of fentanyl and
o -~r occasionally with 25-100 mg thiopentone. With the V ~L~ f-"x._.-,J c"3 second anaesthetic technique, to be referred to as "enflu- CH~\%,'-x ~ Nx_/"c.~ N .2B," rane anaesthesia," premedication was the same as in the c./x___/oL...,LJ . balanced anaesthesia group. Anaesthesia was induced A with 3-5 mg. kg- i thiopentone and 3 L. rain- ~N20-2 L" Pipecuronium Bromide (Atduon| min- ~02 containing three per cent inspired concentration O-Ac O-Ac of enflurane for five minutes and two per cent thereafter .... " for five more minutes. Anaesthesia was maintained with <-~Io, v~v i ] ~'
Clinical studies Statistics In the clinical studies patients were given IV a single dose The statistical significance of the differences of the of 80 Ixg" kg -I pipecuronium, or 100 ~g'kg-~ vecuron- various parameters were determined with ANOVA fol- ium or pancuronium. Ventilation was assisted or con- lowed by Tukey's 5 test or by paired t test as indicated, P trolled until the force of contraction of the thumb < 0.05 was considered significant. decreased to 20-25 per cent of control. At this time the tracheas were intubated. The maximal neuromuscular Results effect and the time from the start of injection of the muscle The demographic data of the patients who participated in relaxant to the development of its maximal effect (onset our dose-response and clinical studies are summarized in time) and the time required for the return of the twitch Table 1. tension to 25 per cent of control after injection of the Dose-response studies initial dose (clinical duration) were recorded. Pipecuronium on a weight basis is more potent than Patients, in both the dose-response and clinical stud- vecuronium in patients under both balanced and enflurane ies, requiring muscular relaxation beyond the clinical anaesthesia and both muscle relaxants are more potent duration of the intubating dose were given 15 I.tg" kg -t with enflurane than with balanced anaesthesia (Table I1). incremental doses of one of the three muscle relaxants The dose-response regression lines of vecuronium under under balanced and 12 ~g. kg -I under enflurane anaes- balanced and enflurane anaesthesia are close to parallel thesia. Each patient received only one type of relaxant. (Figure 2). Recovery of neuromuscular transmission was allowed Since the doses of pipecuronium and vecuronium used to proceed spontaneously for as long as possible without before intubation were administered in several increments seriously delaying thd operating room schedule. In most the clinical duration of the "first" dose could not be patients, however, tile. residual neuromuscular block was determined in the dose-response studeos. The clinical antagonized either" with a mixture of 40 ~g.kg -~ duration of repeat doses (the time interval between the neostigmine and 15 p.g. kg-~ atropine in the pipecuron- administration of a repeat dose and the return ofT, to 25 ium or that of 0.5 mg-kg -I edrophonium and 10 per cent of control), the recovery index (time for the return i.tg.kg -t atropine in the vecuronium and pancuronium of TI from 25 to 75 per cent of control) and the effect of groups. The antagonists were injected over 60 sec. The Tt anticholinesterases on the residual neuromuscular block, (the force of contraction elicited by the first of TOF however, could be determined in these studies. After the impulses expressed as per cent of control) and the T4/TI return of neuromuscular transmission to 25 per cent of ratio was measured before and at 2, 5, 8 and 10 min after control following the initial doses of the two muscle the administration of the antagonists. relaxants there was no difference in the administration of Heart rate (monitored by ECG) and systolic and incremental doses of pipecuronium or vecuronium or of diastolic blood pressures (measured with Dinamap, Vital antagonists in the dose-response or clinical studies. Signs Monitor # 1846 SX, Criticare, Inc.), were recorded Thus, the clinical duration and recovery data obtained in before induction of anaesthesia, before the administration the dose-resp0nse studies will be considered together of 2 • ED95 dose of the muscle relaxant, before tracheal with those obtained in the clinical studies. intubation, before and at 2, 5, 8 and 10 min after the administration of the antagonist and otherwise at ten- Clinical studies minute intervals throughout anaesthesia. The neuromuscular variables determined after the single
TABLE I Demographicdata of patient populations
Sex Type of Muscle Number of Weight Study anaesthesia relaxant patients Age (kg) M F
Dose - response Balanced Pipccuronium 30 49.3• 71.6• 17 13 Vecuronium 18 ~.9• 73.2• 8 10 Enflurane Pipecuronium 30 46.6• 73.2• 16 14 Vecuronium 15 36.6• 73.8• 8 7
Clinical Balanced Pipecuronium 22 49.9• 76.4• 18 4 Vecuronium 10 43.3• 73.8• 4 6 Pancuronium 10 37.3• 76.9• 4 9
*Mean - SEM. 552 CANADIAN JOURNAL OF ANAESTHESIA
clinically unimportant. In contrast the clinical duration of IO0 I the intubating dose of vecuronium was about one-third of 0 ! those of pipecuronium or pancuronium (P < 0.001). 0 Similarly, in the few cases in which it was possible to / observe this variable, the recovery rate of vecuronium I was also about one-third of that of pipecuronium (P < 80. I I 0.001). / The clinical duration of the first maintenance doses of I vecuronium were also about one-third of those of pipecur- v I onium or pancuronium (P < 0.001) (Table IV). Under r,) I balanced anaesthesia the clinical duration of the first 15 60- o / Q3 i~g.kg -t repeat dose of vecuronium is also about one- I third of the same dose of vecuronium or pancuronium 0 (Table IV). There is a similar relationship in the clinical I U duration of the first repeat dose of 12 i~g. kg- I repeat dose I/1 "-1 40- of vecuronium and pipecuronium. The number of second E I o / and third repeat doses of pipecuronium was too small for valid statistical analysis of their clinical duration. For the Q.) I Z / Q Enflurane same reason it could not be determined whether or not I 0 Balanced pipecuronium has any cumulative effect. 20- I The residual neuromuscular effect of the three muscle I relaxants could be readily antagonized by anticholinester- I I ases. After balanced anaesthesia (Table V) when the residual pipecuronium block was reversed with neostigmine-atropine, the mean T4/Tt ratio was 0.75 at 8 0 min and 0.79 at 10 min. When vecuronium or pancuron- I0' 2'o :SO' 40 ium was reversed with edrophonium-atropine the mean T4Tt ratio was 0.86 and 0.78, respectively, at 2 min. Log Dose (~glkg) After enflurane anaesthesia, when the residual pipe- curonium block was reversed by neostigmine-atropine the FIGURE 2 The log dose-response regression line of the neuro- muscular effect of pipecuronium under balanced and enflurane T4/Tt ratio was 0.80 at 5 min (Table VI). Interestingly, anaesthesia. in this group, after the administration of the antagonist, the T4/T~ ratio returned towards control more rapidly than intravenous injection of 2 • ED95 doses of the three Tt. After antagonism of the residual vecuronium block muscle relaxants are summarized in Table III. The onset with edrophonium-atropine the mean T4/T~ ratio was 0.86 time of pipecuronium and pancuronium were very similar at 2 min. and both were shorter (P < 0.05) than that of vecuronium. The influence of the three muscle relaxants on heart rate The intubation time of pipecuronium was shorter (P < and systolic and diastolic blood pressure, summarized in 0.05) than that of vecuronium, but the difference was Table VII, indicate that pipecuronium and vecuronium
TABLE II The EDso, EDgo and EDg~ doses of pipecuronium and vecuronium under balanced and enflurane anaesthesia
Balanced anaesthesia Enflurane anaesthesia
Pipecuronium* Vecuroniumt Pipecuronium* Vecuroniumt 28 18 29 15
EDso 20.3• 1.1:1: 30.1 i3.3• 21.5 EDso 33.0 1.6 43.7 22. I • 1.0 26.7 EDso 35.1 --- 1.7 45.8 23.6-+ 1.1 27.4
*Determined with cumulative dose method. "t'Determined with individual dose method. :l:Mean --. SEM of number of observations. Foldes el al.: CLINICAL PHARMACOLOGY OF PIPECURONIUM 553
TABLEIII Neuromuscular effects under
Balanced anaesthesia Enflurane Variables Pipecuronium (22) Pancuronium (10) Vecuronium (15) Vecuronium (15)
Intubating dose (mg.kg -~) 0.08 0.10 0.10 0.08 Intubation time (min) 1.8 - 0. I* 2.2 • 0.3 2.6 • 0.2 2.8• Onset time (min) 3.6 - 0.4 3.7 • 0.5 5.9 • 1.0 4.8• Maximal block (%) 99.3 +--0.3 97.8 - I. 1 >100 >100 Clinical duration (min) 110.5• 115.8---8.1 36.3,,,2.1[" 41.4,,,2.9 Recovery index (min) 44.5 -'- 8.2 (3) 41.3 -'- 4.2 (4) 14.3 • 1.4[ (9) 21.0,,,3.1
*Mean --- SEM of number of observations indicated in parenthesis. tThe clinical duration and recovery index of vecuronium was shorter (P < 0.001) than those of pipecuronium or pancuronium.
TABLE IV Clinical duration of maintenance doses
Duration of maintenance doses* Type of Maintenance anaesthesia Compound dose (p,g . kg- J) First Second Third
Balanced Pipecuronium 15 51.5 --- 5.4 (29) 57.0 --- 5.3 (17) 57.7 +- 16.6 (3) Vecuronium 15 13.8 - 0.8t (42) 15.0 - 0.9t (36) 15.9--- 1.2t (32) Pancuronium 15 52.2 --- 9.2 (5) -- --
Enflurane Pipecuronium 12 58.1 ~ 4.2 (18) 50.2 ~ 6.3 (5) 66.8 • 20.6 (2) Vecuronium 12 16.9 --- 2.2t (12) 17.7 --+ 1.7; (I 1) 18.2 --- li (9)
*Mean --- SEM of number of observations in parenthesis. tSignificantly different (P < 0.001) from pipecuronium and pancuronium.
TABLE V Reversal of the residual neuromuscular block under balanced anaesthesia
P ipecuronium (44) P ancuronium (23) V ecuronium (1 I)
T: T4/T: T I T41Tt T I T41TI
Before reversal 37.3---3.3* 0.18---0.03 49.5-'-5.8 0.33+--0.04 77.2---7.4 0.33--.0.04 After reversalt 2min 58.2---3.8 0.47--0.04 76.8---5.5 0.78+--0.03 99.7---3.4 0.86---0.03 5 min 78. I - 3.6 0.67 -'- 0.03 83. I --+ 4.6 0.79 -+ 0.03 102.1 +-- 3.0 0.90 --- 0.02 8 min 88.0 --- 3.3 0.75 --- 0.02 84.5 _.+ 4.4 0.80 • 0.03 -- -- 10 min 92.0 - 3. I 0.79 - 0.02 ....
*Mean -'- SEM of number of observations indicated in parenthesis. tPipecuronium-induced block was reversed with ncostigmine, and both pancuronium- and vecuronium-induced blocks were reversed with edrophonium.
had no significant effect on these variables. The intubat- vecuronium were greater than that of pancuronium ing dose of pancuronium increased heart rate by about 20 determined by Donlon et al. 6 earlier. The time course of per cent (P < 0.01 ) and caused a moderate, not significant the neuromuscular effects of pipecuronium were found to increase of systolic blood pressure. be similar to those of pancuronium. In agreement with this, except for the greater steady state distribution Discussion volume (VDss) and plasma clearance (CI) the pharmaco- The neuromuscular potency of pipecuronium was found kinetic variables of pipecuronium and pancuronium were to be greater than that of vecuronium under both balanced reported to be similar. 7 and enflurane anaesthesia. Under balanced anaesthesia Pipecuronium and vecuronium, unlike pancuronium, the neuromuscular potencies of both pipecuronium and caused no elevation of the heart rate or blood pressure. 554 CANADIAN JOURNAL OF ANAESTHESIA
TABLE VI Reversalof the residual neuromuscular block under enflurane anaesthesia
Pipecuronium (27) Vecuronium (I 7)
7"1 T~/T~ T~ TJT~
Before reversal 35.0 - 2. I* 0.22 - 0.03 76.7 • 5. I 0.40 --- 0.04 After reversal'i" 2min 54.9• 0.63-+-0.02 101.0• 0.86-+0.03 5 min 66.9 • 2.7 0.80 • 0.02 104.2 • 2.3 0.91 -+ 0.01 8 min 72.2 - 2.7 0.85 -+ 0.01 -- -- 10 min 73.8 • 2.6 0.88 • 0.01 -- --
*Mean • SEM of number of observations indicated in parenthesis. tPipecuronium and vecuronium induced blocks were reversed with neostigmine and edrophonium, respectively.
TABLE VII Circulatory effects of the intubating dose of muscle relaxants under balanced anaesthesia
Pipecuronium (22) Pancuronium (10) Vecuronium (15) (0.08 rag. kg-O (0.10 rng . kg-O (0.10 rng . kg -t )
Heart rate Before injection of MR 76.2 • 3.8* 74.2 • 4.0 74.7 • 3.0 Before intubation 74.5 • 3.7 92.7 -+ 5.4t 76.9 • 2.8
Systolic blood pressure Before injection of MR 115.0 --- 4.5 129.4 - 5.4 119.4 - 4.2 Before intubation 108.7 • 4.4 144.6 • 13.7 114. I • 3. I
Diastolic blood pressure Before injection of MR 69.0 • 3.2 75.0 - 5.4 70.9 • 2.0 Before intubation 66.3 --- 2.9 82.3 - 7.9 70.4 • 2.3
*Mean -+ SEM of number of observations indicated in parenthesis. tSignificantly (P < 0.05) different from preinjection values.
The difference in the cardiovascular effects of pipecuron- contractility of the muscle fibre t~ and this effect is not ium and vecuronium on one hand, and those of pancuron- antagonized by neostigmine. In contrast in the vecuron- ium on the other hand, may be explained by differences ium-enflurane group after antagonism of the residual observed in their effect on the evoked release of norepi- neuromuscular block T t returned towards its control value nephrine from the isolated right atrium of the guinea-pig more rapidly than the Ta/T1 ratio. The probable explana- and on the force of contraction of the electrically tion of this apparent discrepancy is that the effect of stimulated atria. Pancuronium, because of its inhibitory enflurane on contractility of the muscle develops and effect on muscarinic receptors located on the noradrener- wears off slowly I~ and the mean - SEM duration of gic nerve terminals and the pacemaker cells of the right exposure to enflurane was 170.2 --- 19.1 min in the atria increases the evoked release of norepinephrine and pipecuronium and 87.4 -+ 8.8 min in the vecuronium the force of contraction of the electrically stimulated right group. atria.S These effects of pancuronium cause acceleration of Pipecuronium appears to be a suitable replacement for heart rate and elevation of blood pressure. Pipecuronium 9 pancuronium for the production of muscular relaxation of and vecuronium 8 have little or no inhibitory effect on relatively long duration in patients in whom elevation of these muscarinic receptors and consequently cause no heart rate has to be avoided. elevation of heart rate and blood pressure. It is of interest that in the group of patients in whom the References dose-response of pipecuronium was determined under 1 Alant O, Darvas K, Pulay !, Weltner J, Bihari I. First enflurane anaesthesia, after antagonism of the residual clinical experience with a new neuromuscular blocker, neuromuscular block, the Ta/TI ratio returned towards Pipecuronium bromide. Arzneimittel Forschung control more rapidly than TI (Table VI). The probable 1980; 30: 374-9. explanation of this finding is that enflurane inhibits 2 Bunjatjian A, Miheev V. Clinical experience with a new Foldes etal.: CLINICAL PHARMACOLOGY OF PIPECURONIUM 555
steroid muscle relaxant: pipccuronium bromide. Arzneimittel Forschung 1980; 30: 383-5. 3 Boros M, Szenoszradsky J, Marosi G, Toth 1. Comparative clinical study of pipecuronium bromide and pancuron- ium bromide. Arzneimittel Forschung 1980; 30: 389-93. 4 Tassonyi E, Szabo G, Vimlati L. Pipecuronium bromide (Arduan). In: Kharkevich DA (Ed.). Handbook of Experimental Pharmacology. Berlin: Springer Verlag, 1986; 590-616. 5 Weiner BJ. Statistical Principles of Experimental Design. New York, San Francisco, Toronto, London: McGraw- Hill, 1962; 83-104. 6 Donlon JV, Savarese J J, Ali HH, Teplik RS. Human dose-response curves for neuromuscular blocking drugs: a comparison of two methods of construction and analysis. Anesthesiology 1980; 53: 161-6. 7 Caldwell JE, Castagnoli KP, Canfell PC et al. Pipecuron- ium and pancuronium: comparison of pharmacokinetics and duration of action. Br J Anaesth 1988; 61: 693-7. 8 Foldes FF, Kobayashi O, Kinjo Met al. Presynaptic effect of muscle relaxants on the release of 3H-norepinephrine controlled by endogenous acetylcholine in guinea pig atrium. Neural Transm 1988; 76: 169-80. 9 Vizi ES, Kobayashi O, T6ro6sik 0 et al. Heterogeneity of presynaptic muscarinic receptors involved in modula- tion of transmitter release. Neuroscience 1989; 31: 259- 67. !0 Foldes FF, Nagashima H, Ohta Yet al. Modification of the neuromuscular blocking effect of vecuronium by various anesthetic agents. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J (Eds.). Clinical Experi- ences with Noreuron. Amsterdam: Excerpta Medica, 1983; 132-9.