Anesth Analg 2000;91:732-735
© 2000 International Anesthesia Research Society
GENERAL ARTICLES
The Mechanism of Pancuronium Potentiation of Mivacurium Block: Use of the Isolated-Arm Technique
Cyrus Motamed, MD,
Krassen Kirov, MD,
Thomas Lieutaud, MD, and
Philippe Duvaldestin, MD
Department of Anesthesia, Hôpital Henri-Mondor, Université Paris XII, Créteil, France
Address correspondence and reprint requests to Philippe Duvaldestin, MD, Department of Anesthesia, Hôpital Henri-Mondor, 51 avenue du Maréchal De Lattre de Tassigny, 94010, Créteil, France. Address e-mail to philippe.duvaldestin.{at}hmn.ap-hop-paris.fr
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Abstract
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The neuromuscular blocking effects of mivacurium are greatly enhanced when mivacurium is preceded by a subparalyzing dose of pancuronium. The mechanism of this potentiation has not been elucidated. This study investigated the effects of the anticholinesterase activity of a small dose of pancuronium on the neuromuscular blocking effects of mivacurium. Forty patients were enrolled in the study. The neuromuscular effects of 7.5 and 15 µg/kg pancuronium, followed by 50 and 100 µg/kg mivacurium, were assessed in Groups PM1 and PM2 (n = 20), respectively. The neuromuscular effects of 65 and 130 µg/kg mivacurium were assessed in Groups M1 and M2 (n = 20), respectively. One arm was excluded from circulation with a tourniquet, which was inflated before the injection of pancuronium and deflated 3 min after the injection of mivacurium. The plasma cholinesterase activity was measured before induction for all patients and 3 min after the injection of pancuronium for Groups PM1 and PM2. The plasma cholinesterase activity was decreased by 16% and 33% after pancuronium administration in Groups PM1 and PM2, respectively. In the nonexcluded arm, pancuronium significantly potentiated the effects of mivacurium. In the excluded arm, no significant block was detected for Groups M1 and M2, whereas the maximal degree of neuromuscular block was 79% and 100% for Groups PM1 and PM2, respectively. Using the isolated-arm technique, we suggest that pancuronium potentiation of the neuromuscular blocking effects of mivacurium is more likely attributable to an increase in the effective plasma concentration of mivacurium than to occupancy of postsynaptic acetylcholine receptors.
Implications: Using the isolated-arm technique, we suggest that pancuronium potentiation of the neuromuscular blocking effects of mivacurium is more likely attributable to an increase in the effective plasma concentration of mivacurium than to occupancy of postsynaptic acetylcholine receptors.
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Introduction
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Mivacurium, when preceded by pancuronium, acts as a long-lasting muscle relaxant (1). The potentiation of mivacurium by pancuronium has been characterized in several studies (1–9), and this potentiation is of much greater intensity, compared with other combinations of nondepolarizing muscle relaxants. A dose of pancuronium as small as 7.5 µg/kg considerably reduces mivacurium requirements during surgery (5); however, the mechanism of such potentiation remains unclear. Pancuronium, unlike other nondepolarizing blocking agents, inhibits plasma cholinesterase (Bche) activity (10) and, by this mechanism, may increase the bioavailability of mivacurium. In a previous study using the temporary exclusion technique, we demonstrated that the decrease in the plasma concentration of mivacurium is so rapid that the plasma concentration of mivacurium is decreased to less than effective levels as soon as 3 min after bolus administration (11). We hypothesized that this potentiation could be the result of a plasmatic phenomenon attributable to the anticholinesterase effect of pancuronium. Thus, we measured the effect of pancuronium on Bche and, by using the vascular exclusion technique, we could indirectly assess whether small doses of pancuronium could increase the effective concentration of mivacurium.
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Methods
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The study protocol was approved by the local ethics committee, and written, informed consent was obtained from each patient. Patients enrolled in the study were 18–65 yr old and were undergoing elective knee surgery under general anesthesia, with tracheal intubation. Patients with histories of renal, hepatic, or neuromuscular disease, those taking medications known to interfere with neuromuscular function or Bche activity, and those with anticipated difficult airways were excluded. Premedication was at the discretion of the anesthetist. Anesthesia was induced with fentanyl 3–4 µg/kg and propofol 2–2.5 mg/kg IV. Tracheal intubation was performed without muscle relaxants, and anesthesia was maintained with a mixture of 40% oxygen/60% nitrous oxide and 0.7% isoflurane (end-tidal). The palm skin temperature of the monitored hand was maintained at 33°C. The core temperature was measured by using a tympanic probe and was maintained between 35.5° and 36.5°C. Patients were divided, by using a computerized list of random numbers, into four groups, who received bolus administrations of muscle relaxants according to the following scheme: M1, mivacurium 65 µg/kg (n = 10); M2, mivacurium 130 µg/kg (n = 10); PM1, pancuronium 7.5 µg/kg, followed 3 min later by mivacurium 50 µg/kg (n = 10); PM2, pancuronium 15 µg/kg, followed 3 min later by mivacurium 100 µg/kg (n = 10). The 50% effective dose of pancuronium was estimated to be 37 µg/kg (3) and the 50% effective dose of mivacurium to be 58 µg/kg (3). Therefore, patients in Groups M1 and M2 were estimated to receive doses equivalent to those for Groups PM1 and PM2, respectively. Twelve additional patients were studied to assess the neuromuscular blocking effects of a single dose of pancuronium of 7.5 or 15 µg/kg, according to the study conditions. Bche levels were measured before the injection of muscle relaxant for all patients and 3 min after the injection of pancuronium for Groups PM1 and PM2. The monitoring of neuromuscular transmission consisted of assessment of the evoked response of the adductor pollicis muscle, with force transducers on both arms. The ulnar nerve was stimulated at the wrist by using a surface electrode and a supramaximal (60-mA) train-of-four stimulations every 12 s.
The following parameters were recorded: the time from the injection of the neuromuscular blocking drug to the first reaction (lag time), the maximal degree of neuromuscular block (Emax) (defined as the time from the injection to the first of three consecutive equal twitches), the time to obtain Emax (onset), the times from the injection to the return of 25%, 75%, and 90% of the initial evoked response, and the time of the return of the train-of-four ratio to 80%. On the second arm, vascular exclusion was performed, with a tourniquet inflated to a pressure 30% above the systolic pressure, before the injection of pancuronium in Groups PM1 and PM2 and before the injection of mivacurium in Groups M1 and M2. For all groups, the tourniquet was deflated 3 min after the injection of mivacurium.
After withdrawal, blood samples were immediately centrifuged; the serum component was separated and kept frozen at -75°C. Cholinesterase activity was measured by using a colorimetric method (Sigma Diagnostics, St. Louis, MO). The normal range of Bche activity is 3000–8000 IU/L.
Results are presented as the mean ± SD or as a percentage, as appropriate. The sample size was chosen on the basis of the results of previous investigations (1,4). Statistica software (version 5.0A; Statistica, Tulsa, OK) was used for data analysis. To compare patient characteristics, lag times, onsets of maximal block, Emax values, and Bche recovery times among groups, we used the t-test, one-way analysis of variance, or analysis of variance on ranks, depending on the distribution. To compare Bche levels before and after pancuronium injections, we used the paired t-test. P < 0.05 was considered statistically significant.
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Results
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No differences were seen among patients with respect to age (49 ± 21, 43 ± 16, 48 ± 8, and 53 ± 14 yr in Groups PM1, PM2, M1, and M2, respectively) and body weight (70 ± 13, 74 ± 10, 64 ± 8, and 65 ± 8 kg in Groups PM1, PM2, M1, and M2, respectively). Bche levels were within the normal range before muscle relaxant administration for all patients (Table 1) and were decreased by 16% and 33% (P < 0.05) 3 min after pancuronium administration in Groups PM1 and PM2, respectively. Compared with equipotent doses of mivacurium, the injection of 7.5 and 15 µg/kg pancuronium significantly enhanced the neuromuscular block induced by 50 and 100 µg/kg mivacurium (Table 1). In the nonisolated arm, Emax values were 93 ± 5% in Group PM1, compared with 75% ± 5% in Group M1, and 100% in Group PM2, compared with 87% ± 12% in Group M2 (P < 0.001). The times from injection to the return of 25%, 75%, and 90% of the initial evoked response and time of the return of the train of four ratio to 80% were significantly shorter in Groups M1 and M2 than in Groups PM1 and PM2, respectively (P < 0.05). In the nonisolated arm, the Emax of the pharmacodynamic effect of mivacurium alone was significantly less (P < 0.001) than that in the nonisolated arm, being 8% ± 4% and 19% ± 8% in Groups M1 and M2, compared with 79% ± 23% and 100% in Groups PM1 and PM2, respectively. Pancuronium 7.5 µg/kg alone did not decrease the twitch height but decreased the train-of-four ratio to 70%, whereas the Emax was 15% after the administration of pancuronium 15 µg/kg.
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Discussion
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This study showed that very small doses of pancuronium decreased Bche activity moderately in Group PM1 but significantly (33%) in Group PM2, and it confirmed that small doses of pancuronium greatly potentiated the effects of mivacurium. Our isolated-arm study showed that the pancuronium-mivacurium combination was very effective, in contrast to an equipotent dose of mivacurium alone.
The potentiation of different combinations of nondepolarizing muscle relaxants, especially mivacurium and pancuronium, has been extensively investigated (2–9), but no study has elucidated the mechanism of such potentiation. Although most other combinations of relaxants yield maximal enhancements of 30%–40% of the effect of an equipotent dose of a parent drug (12–16), the potentiation of mivacurium by pancuronium seems to be significantly greater (1–9). In previous isolated-arm experiments, we suggested that the plasma concentrations of mivacurium rapidly become ineffective in producing significant neuromuscular blocking effects (11). In the present study, we observed the same findings. By using temporary vascular exclusion of an upper limb with a tourniquet, we developed an indirect method of estimating the effective plasma concentration of mivacurium (11).
In patients with normal Bche levels, mivacurium is rapidly hydrolyzed, with a half-life for the active isomers of less than two minutes (17), so that only a small fraction of the initial dose is available for the neuromuscular junction. In patients with atypical Bche levels, mivacurium becomes a highly potent neuromuscular blocking drug, because its 95% effective dose has been estimated to be 10–15 µg/kg (18). We also suggest that mivacurium is so rapidly hydrolyzed in plasma that its plasma concentration decreases below the effective level within a few minutes (11).
The observation that, in the isolated arm, mivacurium remained active only when preceded by pancuronium can be explained by increases in the effective plasma concentrations of mivacurium because of Bche inhibition by pancuronium, rather than by increased occupancy of postsynaptic acetylcholine receptors. At the time of tourniquet deflation, the plasma concentrations of pancuronium can be considered negligible, because of decreases through tissue distribution and because of the small dose administered. Therefore, we think that significant occupancy of postsynaptic acetylcholine receptors in the isolated arm by pancuronium as an explanation for the potentiation is unlikely. The effects of tourniquet use and vascular exclusion have also been assessed during the onset of neuromuscular block (19,20). The onset of block and the maximal block by mivacurium were not affected when the tourniquet was inflated after 20% block had already been achieved and was deflated five minutes later (20). This finding supports our theory that it is the initial fraction of the dose that is delivered to the neuromuscular junction that determines the intensity and duration of the neuromuscular blocking effects of mivacurium (11).
The measurements of Bche activity before and three minutes after pancuronium administration demonstrate that, even at the small dose of 7.5 µg/kg, pancuronium inhibits Bche in vivo. Pancuronium 7.5 µg/kg produced a 16% decrease in Bche activity and a 300% increase in the duration of action of mivacurium (time from the injection to the return of 25% of the initial evoked response) in Group PM1. Pancuronium has significant anticholinesterase activity when measurements are made in vitro (10). In addition, our results are in agreement with a study on the potentiation of mivacurium by metoclopramide (21). Metoclopramide as a single IV bolus produced a nonsignificant in vivo reduction in the activity of Bche but a 30% increase in the duration of action of mivacurium (21). It must be emphasized that there is no correlation between the degree of inhibition of Bche activity and the magnitude of potentiation of mivacurium. Altogether, these findings highlight the limitations of studying enzyme inhibition using in vivo techniques. A shortcoming of our study is that we did not directly measure the plasma concentrations of mivacurium by repeated blood sampling; therefore, occupancy of acetylcholine receptors by pancuronium cannot be totally excluded. In summary, using the isolated-arm technique, we suggest that pancuronium potentiation of the neuromuscular blocking effects of mivacurium is more likely attributable to an increase in the effective plasma concentration of mivacurium, rather than occupancy of postsynaptic acetylcholine receptors by pancuronium.
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Accepted for publication April 24, 2000.
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Abstract
Introduction
