Anesth Analg 2003;96:438-442
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Duration of Immobilization Causes the Changing Pharmacodynamics of Mivacurium and Rocuronium in Rabbits
Kyo S. Kim, MD, PhD,
Jeong W. Jeon, MD,
Myoung S. Koh, MD,
Jae H. Shim, MD, PhD,
Sang Y. Cho, MD, PhD, and
Jung K. Suh, MD, PhD
Department of Anesthesiology, Hanyang University Hospital, Seoul, Korea
Address correspondence and reprint requests to Kyo Sang Kim, MD, PhD, Department of Anesthesiology, Hanyang University Hospital, #17 Haengdang dong, Sungdong gu, Seoul 133-792, Korea. Address e-mail to kimks{at}hanyang.ac.kr
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Abstract
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In the clinical setting, in patients with a cast, it is not known whether the monitoring of the neuromuscular paralysis induced by either mivacurium or rocuronium in the contralateral limb is the correct interpretation. We compared the dose-response relationships and the neuromuscular blocking effects of mivacurium and rocuronium in 56 anesthetized rabbits immobilized in a plaster cast for 2, 4, and 6 wk. Train-of-four stimuli were simultaneously applied every 10 s to both common peroneal nerves, and the force of contraction of both tibialis anterior muscles was measured. Immobilization was associated with a rightward shift of the mivacurium and rocuronium dose-response curves after the duration of the immobilized limb, whereas no shift occurred in the contralateral limb. The 50% effective dose values for 0, 2, 4, and 6 wk of immobilization in the immobilized limb of mivacurium were 15.1 ± 1.4, 18.2 ± 1.5, 21.5 ± 1.9, and 27.8 ± 2.5 µg/kg, respectively, and they were unchanged in the contralateral limb. The calculated 50% effective dose values for the correspondence of rocuronium were 48.1 ± 4.1, 56.2 ± 4.2, 64.8 ± 4.9, and 75.1 ± 5.5 µg/kg, respectively, and they were unchanged in the contralateral limb. The rabbits receiving mivacurium and rocuronium had a significantly accelerated recovery from neuromuscular blockade compared with the placebo group in the immobilized limb after the immobilized duration, whereas there were no differences in the contralateral limb. The results of the present study showed that immobilization disuse atrophy produced by casting led to the development of resistance to both mivacurium and rocuronium; however, no resistance was shown in the contralateral limb. The peripheral nerve stimulator could be applied on the nonimmobilized limb, which might be associated with a normal recording if either mivacurium or rocuronium was used as neuromuscular relaxants.
IMPLICATIONS: In the present study, we examined, in vivo, whether the duration of immobilization can alter the pharmacodynamics of mivacurium and rocuronium in an immobilized limb and/or a contralateral limb in rabbits. The immobilization disuse atrophy produced by casting led to the development of resistance to both drugs but no resistance was shown in the contralateral limb.
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Introduction
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Critically ill patients are invariably restricted to bed because of disease or they could be immobilized with plaster casts or pins, all of which can produce muscle atrophy (1,2). The phenomenon has been reproduced in dogs with limbs immobilized in a plaster cast (3). The immobilization increases the effective dose for 50% twitch depression (ED50) of d-tubocurarine, not only in muscles from the limb in the cast but also in those from contralateral limbs (4), whereas no change occurs with the diaphragm (5) in vitro. When the elicited response in the contralateral limb is used as a guide for the dose of long-acting nondepolarizing muscle relaxants, some patients may be given excessive doses of these relaxants. However, Ibebunjo et al. (6) reported that resistance to d-tubocurarine was not evident in the contralateral limb in rats. Previous in vivo and in vitro studies for the disuse atrophy associated with immobilization were mainly evaluated at 
4 wk of immobilization with old, long-acting muscle relaxants (3–8). The changing pharmacodynamics of shorter-acting muscle relaxants and their relationship to the duration of immobilization have not been evaluated.
The use of perioperative neuromuscular monitoring probably reduces the incidence of postoperative residual block even when short- or intermediate-acting neuromuscular relaxants are used (9). In the clinical setting, whether the monitoring of neuromuscular paralysis induced by either mivacurium or rocuronium in the contralateral limb is the correct interpretation in patients with a cast is not known. In the present study, we examined, in vivo, whether the duration of immobilization can alter the pharmacodynamics of mivacurium and rocuronium on an immobilized limb and/or a contralateral limb.
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Methods
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After approval by our institutional animal care and use committee, we used 56 adult Korean White rabbits of either sex, weighing 2.6–3.2 kg. The animals were randomly assigned to either the mivacurium group or the rocuronium group, and to which no cast was applied during 4 wk for the control (n = 14) or a cast during 2 wk (n = 14), 4 wk (n = 14), and 6 wk (n = 14) regardless of group, respectively. Animals underwent right hindlimb immobilization by means of a plaster cast where the knee and ankle were immobilized at 90° and the hip flexed. The cast was applied during IV thiamylal anesthesia (20 mg/kg) and required approximately 10 min. Casts were changed, as needed, every 5–7 days, and care was taken to avoid pressure injury. The rabbit could walk on three legs without dragging the casted paw. The animals were checked daily to verify that immobility was maintained and that there were no pressure points.
At the end of the immobilization period, each animal was anesthetized with propofol 1.5 mg/kg IV using a marginal vein of the left ear, and anesthesia was maintained with propofol 0.2 mg · kg-1 · min-1. A tracheostomy was performed and the lungs were ventilated with an animal respirator. End-tidal carbon dioxide was maintained at 35–45 mm Hg. Rectal temperature was controlled at approximately 38°C. The right ear vein was cannulated for mivacurium and rocuronium administration. A common carotid artery was cannulated for monitoring arterial blood pressure and intermittent analysis of arterial blood gases. A four-limb electrocardiogram was used for heart rate monitoring. IV fluid administration using a syringe pump was maintained at 6 mL · kg-1 · h-1 (0.9% NaCl) during the experiment.
Both hindlimbs were shaved, and a longitudinal incision was made along both anterior limbs. Dissection was performed to expose both tibialis anterior muscles and both common peroneal nerves. Both common peroneal nerves were simultaneously stimulated at the posterolateral aspect of the knee with supramaximal current derived from a peripheral nerve stimulator. Train-of-four (TOF) stimulation (2 Hz) was applied once every 10 s, and the time interval was adjusted so as not to interfere with other twitch responses. The tendon of both tibialis anterior muscles was attached to the force transducer with the use of 2.0 silk. The twitch response was quantified mechanomyographically with the preload tension. The mechanomyogram was recorded on a multichannel recorder. Neuromuscular block was quantified by the first twitch (T1) of the TOF.
After stable recording of neuromuscular transmission had been established for 30 min, rabbits, regardless of the period of the immobilization, were randomly assigned to receive either mivacurium (n = 28) or rocuronium (n = 28) for each period.
The following predetermined doses of drugs were administered to subgroups of 7 rabbits: mivacurium 10, 20, 30, or 40 µg/kg and rocuronium 40, 60, 80, or 100 µg/kg, respectively. The doses of mivacurium and rocuronium were determined with the corrections after a pilot study. Each dose of mivacurium and rocuronium was withheld until the muscle twitch had recovered from the preceding dose and had remained at baseline value for at least twice the duration of block of the preceding dose after the preliminary study. The neuromuscular response was recorded as the maximal depression of twitch tension, expressed as a percentage of the control value. The percent values for twitch depression in each group were transformed to probits and plotted against the logarithm of the dose. Regression lines were compared by using analysis of covariance. The ED50 value was calculated from the log-probit regression lines for each group.
The subsequent administration of either mivacurium 0.18 mg/kg or rocuronium 0.6 mg/kg was delayed by at least 2 h after complete recovery from the initial dose of neuromuscular relaxants. The twitch recordings were evaluated for the following variables: time from end of injection of mivacurium or rocuronium to maximal twitch suppression (onset); time from end of injection of the initial dose to recovery of T1 in the TOF to a value of 1%, 25%, 75%, and 95% of control twitch tension (T1 [1, 25, 75, 95]); time from 25% to 75% twitch recovery (recovery index); time from end of injection of the initial dose to a TOF ratio (T4/T1) of 70% (TOF [70]). At the end of the experiments, animals were given a lethal dose of pentobarbital and potassium chloride by IV injection.
Data were analyzed statistically by using linear regression analysis, analysis of covariance, and one-way analysis of variance with Bonferroni correction for multiple comparisons with the nonimmobilized limb after the immobilized durations. Differences were considered statistically significant at P < 0.05. Values were reported as mean ± SD.
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Results
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The immobilization was associated with a rightward shift of dose-response curves of mivacurium and rocuronium after the duration of the immobilized limb, whereas there was no shift in the contralateral limb (Figs. 1 and 2). The slopes for 0, 2, 4, and 6 wk of immobilization in the immobilized limb and the contralateral limb of mivacurium were 3.9 ± 0.7, 3.7 ± 0.8, 4.0 ± 0.6, 4.1 ± 0.5, 3.9 ± 0.6, 4.0 ± 0.7, 3.6 ± 0.6, and 4.2 ± 0.7, respectively. The slopes for the correspondence of rocuronium were 3.6 ± 0.5, 3.9 ± 0.6, 4.0 ± 0.4, 3.8 ± 0.7, 3.6 ± 0.6, 3.9 ± 0.7, 4.1 ± 0.4, and 4.3 ± 0.5, respectively. Although the slopes were not significantly different, the increases of the dose-response curves in the immobilized limb lie significantly to the right of the placebo (P < 0.001). In the contralateral limb, there were no differences of both slopes and locations among groups. As a result, the calculated ED50 values for 0, 2, 4, and 6 wk of immobilization in the immobilized limb and the contralateral limb of mivacurium were 15.1 ± 1.4, 18.2 ± 1.5, 21.5 ± 1.9, 27.8 ± 2.5, 14.6 ± 1.6, 15.7 ± 1.7, 16.1 ± 1.7, and 16.3 ± 2.0 µg/kg, respectively. The calculated ED50 values for the correspondence of rocuronium were 48.1 ± 4.1, 56.2 ± 4.2, 64.8 ± 4.9, 75.1 ± 5.5, 45.7 ± 4.6, 50.9 ± 4.7, 51.8 ± 4.8, and 51.1 ± 5.4 µg/kg, respectively. The ED50 values were significantly larger after the duration in the immobilized limb (P < 0.001), whereas there were no differences in the contralateral limb.
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Figure 2. Log dose-probit plot for twitch depression for mivacurium ( ) and rocuronium (•) in the immobilized limb in rabbits. Individual points represent mean (95% confidence intervals) twitch depression (percent control) with each dose (n = 7 each group).
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For both drugs studied, there were no differences between the placebo and immobilization groups in the time required to attain the maximal response in both immobilized limb and contralateral limb (Tables 1 and 2). The rabbits receiving mivacurium and rocuronium had a significantly accelerated recovery after the immobilized duration from neuromuscular blockade compared with the placebo group in the immobilized limb (P < 0.001), whereas there were no differences in the contralateral limb. The recovery index of the immobilized groups was significantly shorter than that of placebo after two relaxants in the immobilized limb (P < 0.001); however, there was no difference in the contralateral limb. TOF (70) values were similar to T1 (95) values in each group.
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Table 1. Onset and Recovery Times (min) in Rabbits Given Mivacurium 0.18 mg/kg After Immobilization During 2, 4, and 6 wk
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Table 2. Onset and Recovery Times (min) in Rabbits Given Rocuronium 0.6 mg/kg After Immobilization During 2, 4, and 6 wk
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Discussion
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In the present study, we demonstrated that immobilization was associated with a rightward shift of the dose-response curves of both mivacurium and rocuronium in the immobilized limb, whereas no shift occurred in the contralateral limb. The immobilized rabbits receiving both relaxants had a markedly accelerated recovery from neuromuscular blockade after the duration compared with the placebo in the immobilized limb, whereas there were no differences in the contralateral limb.
Previous observations have shown that disuse atrophy associated with immobilization involves resistance to nondepolarizing muscle relaxants (1–8). Fung et al. (8) reported that the metocurine plasma concentrations for 50% paralysis (IC50) were increased from 4 days after the cast in the immobilized leg. As in the guinea pig, the resistance to d-tubocurarine was evident from day 7 (4). In the present study, the resistance of both mivacurium and rocuronium was apparent from two weeks of immobilization as an increase in ED50. The resistance to d-tubocurarine that followed muscle disuse was associated with proliferation of immature acetylcholine receptors on the muscle at 7 and 14 days but not at 28 days (6). The ED50 of d-tubocurarine was maximally increased at two weeks, and then slightly decreased by the fourth week (4). However, in the present study, ED50 was continuously increased 1.5 times of both relaxants in the immobilized limb by 6 weeks after casting. The discrepancy among the various methods obviously creates some different results. We did not measure the acetylcholine receptors during the development of resistance to both compounds, but we suggest that possible mechanisms of the resistance to nondepolarizing relaxants are an increase of extrajunctional acetylcholine receptors (10), increased sensitivity to acetylcholine (11), or the changes in muscle mass, fiber size, and the ratio of endplate size to fiber size (6).
The pharmacodynamics of both relaxants in the contralateral limb evaluated simultaneously have not been reported previously. Waud et al. (4) reported that the noncasted limb muscle showed a resistance to d-tubocurarine in vitro. However, the behavior found in vitro does not reflect circulatory or pharmacokinetic variation continuously but, rather, reflects some changes in the neuromuscular junction itself. It is difficult to apply in vitro results to the clinical situation without metabolic elimination. Such resistance to metocurine in the contralateral limb was reported in another model by Fung et al. (8). However, Gronert et al. (7) reported that the degree of paralysis of d-tubocurarine in both normal gastrocnemius muscle and uncasted contralateral muscle from dogs was similar. Ibebunjo et al. (6) also reported that sham-immobilized tibialis muscles in adult rats did not differ from their contralateral controls in ED50 or recovery variables of d-tubocurarine. In the present study, no resistance to either mivacurium or rocuronium in the contralateral limb was apparent in the ED50 values or recovery courses. The reasons for this discrepancy are not clear, but we suspect the differential ability of neuromuscular compounds to the pre- and postjunctional receptors and different species.
Although the present results did not indicate significant differences after the different immobilization durations in the contralateral limb, a slight impediment to the overall mobility of the animal was seen, probably because the immobilization of one limb led to a slight shift of sensitivity.
The neuromuscular blocking onset times of mivacurium 0.18 and rocuronium 0.6 mg/kg in rabbits were 1 ± 0.3 and 0.4 ± 0.1 minutes, respectively (12), and we found corresponding results. The onset times of the corresponding doses of mivacurium and rocuronium in healthy adults were 3.7 and 1.5 minutes, respectively, when nitrous oxide-opioid anesthesia was administered (13,14). We suspect that this relatively rapid onset is attributable to the larger dose (6 x ED95) in rabbits than that (2 x ED95) used in the human investigation (12). Rocuronium has more rapid onset and slower recovery than mivacurium (13,14); we also found similar results.
Spontaneous recovery of mivacurium 0.18 and rocuronium 0.6 mg/kg in rabbits has been reported as 34.2 ± 4.8 and 48.8 ± 6.1 minutes, respectively (12), which corresponds to values in the present study. The recovery from mivacurium- and rocuronium-induced neuromuscular blockade was shortened in the immobilized hindlimb after the duration in the present study. Recovery from a paralyzing dose of neuromuscular relaxants could be explained by either a pharmacokinetic or pharmacodynamic mechanism. The two relaxants have different mechanisms of elimination; therefore, we suspect that the pharmacodynamic changes at receptor sites caused by the immobilization may be the main factor for the rapid recovery of these two relaxants.
A major limitation of the present study is that we were not able to obtain the acetylcholine receptor assay. We could not demonstrate the major changes of both junctional and extrajunctional acetylcholine receptors during the immobilization. This limitation precludes us from making any comments on the mechanisms accounting for our results.
In conclusion, immobilization disuse atrophy produced by casting led to the development of resistance to both mivacurium and rocuronium; however, no resistance was shown in the contralateral limb. The peripheral nerve stimulator could be applied to the nonimmobilized limb, and might yield a normal recording if either mivacurium or rocuronium are used as neuromuscular relaxants.
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Acknowledgments
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This work was supported by Research Fund HY-2001-66 of the Hanyang University.
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References
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Accepted for publication October 21, 2002.
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Abstract
Introduction
) and rocuronium (
in the contralateral limb in rabbits. Individual points represent mean (95% confidence intervals) twitch depression (percent control) with each dose (n = 7 each group).
