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Departments of
*Anesthesiology and
Orthopaedic Surgery, Hanyang University; and
Department of Anesthesiology, Kwandong University, Seoul, Korea
Address correspondence and reprint requests to Kyo S. Kim, MD, Department of Anesthesiology, Hanyang University Hospital, 17 Haengdang dong, Songdong-Ku, Seoul 133–792, Korea.
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Abstract |
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Implications: We studied the dose-response relationships and the neuromuscular blocking effects of mivacurium and rocuronium during chronic isepamicin therapy in rabbits. Mivacurium and rocuronium have both a decreased effect and a shorter duration of action during chronic aminoglycoside antibiotic therapy in rabbits.
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Introduction |
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Patients receiving one or more antibiotic medications, usually for the treatment of infection or prophylactic use, are often encountered during anesthetic practice. Drug interactions between aminoglycoside antibiotics and neuromuscular blocking drugs are well known (5). Some in vitro and in vivo animal studies (6,7) and case reports (8) have shown that acutely administered aminoglycoside antibiotics potentiate the action of nondepolarizing muscle relaxants. In the clinical setting, however, patients with chronic osteomyelitis or sepsis receive aminoglycoside therapy chronically. There are no in vivo reports of pharmacological interactions of mivacurium or rocuronium when given during chronic concurrent aminoglycoside antibiotic therapy.
Through the generation of dose-response curves and the quantification of recovery from bolus doses of mivacurium and rocuronium, this study was undertaken to determine whether chronic exposure to isepamicin enhances the neuromuscular blocking effects of mivacurium and rocuronium in rabbits.
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Methods |
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The animals were anesthetized with IV propofol 1.5 mg/kg, and anesthesia was maintained with propofol 0.2 mg · kg-1 · min-1. A tracheostomy was performed and the lungs were ventilated with room air with an animal respirator. End-tidal carbon dioxide was monitored and maintained at 35–45 mm Hg. Rectal temperature was controlled at approximately 38°C with Blanketrol II (Cincinnati SubZero Products Inc., Cincinnati, OH) and heat lamps. 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 (ECG) 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.
The right hindleg was shaved, and a longitudinal incision was made along the anterior leg. Dissection was performed to expose the right tibialis anterior muscle and common peroneal nerve. The common peroneal nerve was stimulated supramaximally at the posterolateral aspect of the knee with 0.2-ms pulses derived from a peripheral nerve stimulator. Train-of-four (TOF) stimulation (2 Hz) was applied once every 10 s. The tendon of the tibialis anterior was attached to a 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 (San-ei Co., Tokyo, Japan). 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 (n = 28) in both the isepamicin and placebo groups were randomly assigned to receive mivacurium and rocuronium for each group.
The following predetermined doses of drugs were administered to subgroups of seven rabbits: mivacurium 10, 20, and 30 µg/kg in the placebo group (n = 7) and 20, 30, and 40 µg/kg in the isepamicin group (n = 7); rocuronium 40, 60, and 80 µg/kg in the placebo group (n = 7) and 60, 80, and 100 µg/kg in the isepamicin group (n = 7). The doses of mivacurium and rocuronium were different in the isepamicin and placebo groups because of corrections made 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. 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 using analysis of covariance. The effective dose resulting in 50% reduction of twitch tension (ED50) was calculated from the log-probit regression lines for each group.
Selection, anesthesia, and preparation for this part of the study were similar to those described in the dose-response measurements. After stable recording of neuromuscular transmission for 30 min, 28 rabbits were allocated randomly to receive mivacurium 0.18 mg/kg or rocuronium 0.6 mg/kg. 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; RI); 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 using linear regression analysis, analysis of covariance and one-way analysis of variance with Bonferroni correction for multiple comparisons among groups. Differences were considered statistically significant at P < 0.05. Values are reported as mean ± SD.
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Results |
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Discussion |
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Previous studies have shown that the aminoglycoside antibiotics have the ability to produce neuromuscular blockade and to prolong the actions of nondepolarizing neuromuscular blocking drugs. Studies suggest that antibiotics not only have a nondepolarizing muscle relaxant-like stabilizing effect on the postjunctional membrane, but may also decrease presynaptic acetylcholine release (6,7). The evoked acetylcholine release was reduced by aminoglycosides in the potency order of neomycin > streptomicin > gentamicin (9). The potency of neomycin was >1.6 times that of gentamicin and >3 times that of isepamicin (2). Shinoda et al. (3) reported that isepamicin at a high concentration, as well as other aminoglycoside antibiotics, depressed the twitch response of diaphragm to phrenic nerve stimulation in rats, but its action was the weakest among the aminolycoside antibiotics tested. For muscle relaxants, this enhancement is correlated with the acute administration of large doses of aminoglycoside antibiotics.
In the present study, rabbits chronically treated with isepamicin were markedly resistant to mivacurium and rocuronium. Several possible mechanisms have been proposed for the observed resistance to neuromuscular blockers seen with isepamicin, including increased metabolism via enzyme induction, alteration in sensitivity to acetylcholine at the receptor site, or an increased number of acetylcholine receptors. Crann et al. (10) detected no hepatic enzyme activity of gentamicin in nuclear, lysosomal/mitochondrial, or microsomal preparations. Lin et al. (4) reported that isepamicin undergoes no detectable biotransformation and does not accumulate on multiple dosing for 10 consecutive days by IM injection at doses of 7.5 mg/kg once daily or 7.5 mg/kg twice daily in humans. Gentamicin desensitized acetylcholine receptors much more rapidly than those expressed in the absence of gentamicin (11). Chronic neuromuscular blockade of acetylcholine receptors by competitive antagonists, even in the absence of immobilization or paralysis, can produce denervation-like changes, including a proliferation of the receptors (12). Hogue et al. (13) reported that chronic antagonism of the nicotinic acetylcholine receptors was achieved in rats by a subcutaneous infusion of d-tubocurarine for 2 wk. Chronic doses of d-tubocurarine can induce a proliferation of acetylcholine receptor number even in the absence of immobilization. The similarity between the effects of isepamicin and those of the nondepolarizing muscle relaxants studied to date (3) suggest that chronic isepamicin therapy may induce a proliferation of acetylcholine receptor number. On the basis of these studies, it is hypothesized that the maintenance of a therapeutic level of isepamicin over a period of time stimulates a state of chronic chemical denervation.
Inasmuch as continuous exposure to an acetylcholine downregulates acetylcholine receptors in the skeletal neuromuscular junction (14), a state of desensitization (15) and continuous antagonism of acetylcholine could, conversely, result in a state of hypersensitivity, as in cases of disuse atrophy (16) and motorneuron dysfunction (17). Matteo and Diaz1reported that the continuous use of d-tubocurarine for 72 h in cats provides some evidence for a chemical denervation effect after chronic antagonism of acetylcholine. At the end of the d-tubocurarine infusion, the cats were markedly resistant to d-tubocurarine. A continuous insufficiency in acetylcholine at the neuromuscular junction could then result in upregulation of receptors and lead to a state of receptor hypersensitivity such that the effect after subsequent exposure to nondepolarizing muscle relaxants would be diminished.
The neuromuscular blocking onset time of mivacurium 0.15 mg/kg and rocuronium 0.6 mg/kg are 3.7 min and 1.5 min, respectively, in healthy adult patients receiving nitrous oxide-opioid anesthesia (19,20). Increasing the dose to more than twice the ED95 accelerated the rate of onset of nondepolarizing relaxants (21). In our study, after the administration of mivacurium 0.18 mg/kg and rocuronium 0.6 mg/kg, maximal neuromuscular block developed in 1 ± 0.3 min and 0.4 ± 0.1 min, respectively. We suspect that this relatively rapid onset was due to the larger dose (6 x ED95) in rabbits than that (2 x ED95) used in the human investigation. The onset of rocuronium was more rapid than that of mivacurium (20), and the recovery of mivacurium was more rapid than that of rocuronium (19); we also found similar results (Table 1).
Spontaneous recovery of mivacurium 0.16 mg/kg to a TOF (70) is reported as 32.4 min in the rabbit (22), which corresponds to values in the present study. The recovery from mivacurium- and rocuronium-induced neuromuscular blockade was shortened in rabbits receiving chronic isepamicin therapy in the present study. Recovery from a paralyzing dose of neuromuscular relaxants could be explained by either a pharmacokinetic or pharmacodynamic mechanism. The dose-response data from the first phase of this study imply a pharmacodynamic alteration or, possibly, a change in initial volume of distribution (VD). Although there is no intuitive reason to suspect an increased VD in isepamicin-treated rabbits, in the absence of blood relaxants levels, one cannot exclude a pharmacokinetic explanation for these findings. However, the two relaxants have different mechanisms of elimination; therefore, we suspect that the pharmacodynamic changes at receptor sites due to isepamicin may be the main factor for the rapid recovery of two relaxants. At a TOF ratio of 70%, the single twitch response reached 95% value in rabbits, similar to that in humans (23).
The ED50 value of mivacurium (16.9 µg/kg) for propofol anesthesia in rabbits, similar to that reported by Kim et al. (22), is 30%–40% of that reported for humans (19). The ED50 value of 56.5 µg/kg for rocuronium calculated in this study is 40% of that reported for humans (20). Our findings indicate that mivacurium and rocuronium are approximately 3 times more potent in rabbits than in humans.
A clinically useful dose of isepamicin is 7.5–15 mg · kg-1 · d-1 (1,2), and we chose the large dose (20 mg · kg-1 · d-1) for the increased efficacy. Preliminary indications of decreased tissue accumulation suggested by pharmacokinetic and pharmacodynamic characteristics of isepamicin favor once-daily dosing (24). Once-daily dosing of aminoglycosides has consistently been less toxic than more frequent dosing in animals. Once-daily dosing of isepamicin has the potential to enhance efficacy, reduce toxicity, and lower administration costs (25). In this study, we chose once-daily dosing of isepamicin for 7 consecutive days for the clinical application.
A major limitation of the present study is that we were not able to obtain the acetylcholine receptor assay. We cannot demonstrate the major changes of junctional and extrajunctional acetylcholine receptors during chronic isepamicin therapy. These limitations preclude us from making any comments on the mechanisms of our results.
In conclusion, when used during concurrent isepamicin therapy, mivacurium and rocuronium have both a decreased effect and a shorter duration of action in rabbits. We suspect that patients receiving concurrent aminoglycoside therapy will require increased doses of nondepolarizing muscle relaxants.
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Acknowledgments |
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Footnotes |
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References |
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This article has been cited by other articles:
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  K. S. Kim, J. W. Jeon, M. S. Koh, J. H. Shim, S. Y. Cho, and J. K. Suh The Duration of Immobilization Causes the Changing Pharmacodynamics of Mivacurium and Rocuronium in Rabbits Anesth. Analg., February 1, 2003; 96(2): 438 - 442. [Abstract] [Full Text] [PDF]
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) or without (
) isepamicin and rocuronium with (
) or without (•) isepamicin in rabbits. Individual points represent mean (95% confidence intervals) twitch depression (percent control) with each dose (n = 7 each group).
