1Department of Anesthesia, Childrens Hospital and Harvard Medical School, Boston, MA, USA. 2Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA. 3Department of Anaesthesia, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.*Corresponding author: Department of Anesthesia, Childrens Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
Accepted for publication: October 5, 2000
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Abstract |
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Br J Anaesth 2001; 86: 2239
Keywords: complications, epilepsy; neuromuscular block, vecuronium; children
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Introduction |
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We tested the hypothesis that, in children, long-term phenytoin or carbamazepine therapy alters vecuronium kinetics as a result of hepatic enzyme induction. By measuring plasma vecuronium concentration and its pharmacodynamic effects, we attempted to characterize the pharmacokinetic contribution to the accelerated recovery from vecuronium-induced paralysis occurring in children receiving chronic anticonvulsant therapy.
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Materials and methods |
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Pharmacodynamics of vecuronium
After induction of anaesthesia, the patients hand was secured to a splint in order to minimize movement artefacts during neuromuscular monitoring. Supramaximal square-wave stimuli were delivered to the ulnar nerve via surface electrodes at 2 Hz for 2 s and repeated every 20 s (train-of-four), and the evoked compound electromyogram (EMG) of the adductor pollicis muscle was recorded (Relaxograph NMT; Datex, Minneapolis, MN, USA). The maximal suppression of the EMG with vecuronium and time to recovery of T1/T0 to 0.1, 0.2, 0.25, 0.5, 0.75, 0.8, 0.9 and 1.0 were recorded. The recovery index (RI), calculated as the time taken for T1/T0 to recover from 2575%, was also measured.
Measurement of plasma vecuronium and 3-OH desacetylvecuronium concentrations
Blood samples were collected before and 5, 10, 15, 30, 60, 90, 120 and 240 min after administration of vecuronium. Plasma was separated, frozen immediately at 80°C and analysed later for concentrations of vecuronium and its principal metabolite, 3-OH desacetylvecuronium, using high-performance liquid chromatography with an electrochemical detector.14 Organon 7465 was used as the internal standard. The lower limit of the assay was 4 ng ml1 and the coefficient of variation was less than 10%.
Plasma vecuronium and 3-OH desacetylvecuronium concentrations were analysed by iterative non-linear least-squares regression techniques on observed concentrations, as described previously (Sigma Plot, Windows, version 4, Jandel, Sunnyvale CA, USA).15 The slope (beta) of the terminal log-linear phase of each plasma concentration time curve was determined by linear regression analysis. This slope was used to calculate the apparent elimination t1/2. The area under the plasma concentrationtime curve from time zero until the last detectable concentration was determined by the linear trapezoidal method. The residual area extrapolated to infinity was calculated as the final concentration divided by beta. These two areas were added to yield the total area under the plasma concentrationtime curve. The peak plasma concentration (Cmax) and the time at which the peak concentration occurred (tmax) were used as measures of the rate of appearance of drug in the systemic circulation. Coefficients and exponents from the fitted functions were used to calculate the following kinetic variables: total volume of distribution using the area method (Vd); and total clearance (Cl). The plasma concentration of vecuronium was also plotted against the percent inhibition of T1/T0.
Clinical pharmacokineticpharmacodynamic modelling
The time-averaged concentration data was fitted to a standard biexponential pharmacokinetic model. Using the models determined for each of the three data sets, the plasma vecuronium concentrations at the times corresponding to each effect level (a given recovery of T1/T0) were calculated. The resulting concentrationeffect pairs were plotted. A sigmoid pharmacokineticpharmacodynamoc model was chosen, and the following equation was used to describe the concentrationeffect relationship. Emax was assumed to equal 100% twitch depression.
where Emax=maximum effect, EC50=effect compartment concentration at 50% block and A=slope factor of the sigmoid curve.
Plasma AAG concentrations
AAG concentrations were assayed by radial immunodiffusion plates as described previously.8 Plasma was incubated for 24 h in wells treated with rabbit AAG antiserum in an agarose gel. This solution yielded a precipitin ring. The quantity of AAG in plasma was calculated from the standard curve of AAG 1002000 µg ml1. This AAG assay was highly specific and had no cross-reactivity with other proteins, including albumin, haemopexin and 2-macroglobulin. Correlation between individual AAG concentrations and the corresponding recovery index was analysed.
Statistical analysis
Neuromuscular recovery and the pharmacokinetic data of the three groups were compared by analysis of variance followed by Dunnetts multiple comparisons post hoc test. The Pearson productmoment correlation coefficient was calculated to assess the affect of AAG concentrations on the corresponding recovery indices. Data are presented as means (SD). P<0.05 was considered significant.
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Results |
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Pharmacokineticpharmacodynamic modelling of vecuronium
The concentrationtime data for the parent compound and the metabolite (3-OH desacetylvecuronium) in the three groups are shown in Fig. 1. Volumes of distribution were not different between the three groups. The elimination half-life was significantly shorter for the phenytoin and carbamazepine groups compared with control. There was increased clearance of vecuronium in the phenytoin and carbamazepine groups compared with control, which reached statistical significance in the carbamazepine group (Table 2). As indicated in Fig. 1B, the active metabolite, 3-OH desacetylvecuronium, was detected in all three groups at 1% of the parent drug concentration. The plasma concentration of vecuronium (parent drug only) plotted against recovery of T1/T0 to 10, 25, 50, 75 and 100% did not differ between groups (Fig. 2). Sigmoidicity in the pharmacodynamic analysis was evident, and thus a sigmoid pharmacokineticpharmacodynamic model was used to describe the concentrationeffect relationship. However, examination of the plots revealed no hysteresis, and thus an effect site distinct from the central compartment was not postulated (Fig. 2). There was also no difference in the EC50 and slope factor (A) between groups (Table 3).
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Discussion |
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Our study in children confirms previous studies in adult patients that chronic administration of either of the anticonvulsants phenytoin and carbamazepine induces resistance to the neuromuscular effects of vecuronium. The resistance was evidenced as a faster recovery of T1/T0 to given endpoints and a shorter recovery index relative to controls. Our data give further evidence that changes in the elimination half-life (tß) are at least partly responsible for the observed resistance to vecuronium. The trend for increased clearance of vecuronium was apparent in both groups and was statistically significant in the carbamazepine group.
Age-related differences in vecuronium pharmacology in normal patients have been reported.12 13 When compared with infants and adults, young children aged 310 yr had a higher ED95 for tracheal intubation.26 Furthermore, they had significantly shorter recovery times than infants and adults.12 13 The ED50 of vecuronium to produce depression of adductor pollicis twitch tension reported by Fisher and Miller was 19.0 µg kg1 for children and 15.0 µg kg1 for adults.12 These authors concluded that the increased volume of distribution in children mediated the increased requirement for vecuronium. In our study, the average age of the patients was 11 yr and the age distribution was similar between groups. Thus, age-related differences in elimination or distribution kinetics are not the cause of the faster recovery observed in the treatment groups.
The aetiology of the decreased sensitivity to NDNMB after prolonged anticonvulsant therapy may be multifactorial. Phenytoin and carbamazepine are both potent inducers of hepatic microsomal enzymes by induction of cytochrome P-450 isoenzyme III A4, resulting in enhanced elimination of many drugs.18 27 28 The decreased half-life and the trend for increased clearance in the anticonvulsant-treated group is consistent with the reports of Alloul and colleagues7 and Szenohradszky and colleagues 21 in adults, where enhanced elimination kinetics of vecuronium or rocuronium was observed in patients on anticonvulsants.
The potential for anticonvulsants to induce qualitative or quantitative changes at the neuromuscular junction, and therefore resistance to NDNMBs, is also present. A known side-effect of anticonvulsants is muscle weakness resulting from a decrease in the spontaneous and evoked quantal release of acetylcholine.5 18 In addition, these drugs also have effects that simulate the actions of curare-like drugs on the prejunctional membrane nerve terminal.29 30 Therefore, these anticonvulsant drugs behave prejunctionally like botulinum toxin and postjunctionally like NDNMBs. Thus, chronic exposure to anticonvulsant drugs may induce a denervation syndrome in which the expression of immature receptor isoforms leads to upregulation of acetylcholine receptors. 31 These upregulated acetylcholine receptors can either increase the effective dose or have altered sensitivity to NDNMB because of the expression of immature isoforms of the receptors.30 Animal and human studies have provided direct and indirect evidence for upregulation of acetylcholine receptors after chronic anticonvulsant therapy.8 32 Kim and colleagues reported a proliferation of acetylcholine receptors at the muscle membrane after chronic phenytoin therapy in rats.8 Furthermore, patients on anticonvulsant therapy had increased sensitivity to succinylcholine, consistent with the possibility of upregulated acetylcholine receptors.32
In our study, plasma concentrations of vecuronium at specific degrees of neuromuscular blockade did not differ significantly between the three groups. At first glance, this finding could be interpreted as a lack of difference between groups in drugreceptor kinetics or target organ sensitivity. This conclusion cannot be reached definitively on the basis of the findings of this study. A major metabolite of vecuronium is 3-OH desacetylvecuronium, which has potent neuromuscular blocking properties that can be additive or synergistic with its parent compound.33 Thus, it is possible that the concomitant presence of the metabolite in the plasma (and at the target tissues) confounded these observations. However, the plasma concentration of the metabolite was 1% of the parent compound, which would have a negligible effect on neuromuscular blockade.
Another possible cause of the resistance is alterations in plasma protein binding caused by anticonvulsant-induced increases in AAG concentrations.810 34 35 This protein can potentially bind to many cationic drugs, including NDNMBs, and thus reduce their efficacy and alter the unbound concentration. In the rat, long-term phenytoin administration resulted in increased concentrations of AAG and a decrease in the free concentration of metocurine, partially explaining the resistance.8 In our study, plasma concentrations of AAG in both anticonvulsant groups were not statistically different. The reason for this is unclear. We conclude that increased AAG concentrations did not significantly contribute to the resistance to vecuronium observed in this study. This conclusion is consistent with that of Hans and colleagues, who reported that elevated concentrations of AAG induced by chronic anticonvulsant therapy did not contribute to the rapid recovery from vecuronium blockade.35
In summary, this study confirms previous studies in adults that the resistance to vecuronium in children on chronic anticonvulsant therapy is partly related to increased metabolism. Previous studies have indicated altered drugreceptor kinetics as an additional cause of the resistance to NDNMBs. But the contribution of altered pharmacodynamics to the resistance to vecuronium could not be determined in this study. These results do not exclude the additional possibility of changes in target organ sensitivity to account for the resistance.
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Acknowledgements |
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References |
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