1 Department of Anaesthesiology, Hôtel Dieu, C.H.U. Nantes, France. 2 Société dEtude des Risques Toxiques, Nantes, France*Corresponding author: Service dAnesthésie et de Réanimation Chirurgicale, Hôtel - Dieu, F-44093 Nantes Cedex 01, France
Accepted for publication: June 17, 2002
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Abstract |
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Methods. To test this hypothesis, 45 children less than 48 months of age undergoing sevoflurane anaesthesia were enrolled in a prospective open clinical trial. The 24 h urine fluoride excretion was measured in five groups of children (A, <4 months; B, 4 to <8 months; C, 812 months; D, >1224 months; and E, >2448 months old). An index of sevoflurane metabolism (ISM) was calculated as the ratio of fluoride excretion, cumulative expiratory sevoflurane concentrations measured every minute during anaesthesia, and body surface area. ISM values were median (IQ 2575%).
Results. ISM was lower in group A (n=9, 18.9 (11.229.5) than group C (n=11, 44.2 (37.553.5), P<0.05), group D (n=7, 52.6 (45.868.4), P<0.01) and group E (n=9, 53.6 (50.785), P<0.001). Median ISM expressed as a function of median age, exponentially increased with a rapid increase during the first months of life, followed by a slower increase after 10 months of age.
Conclusion. These results suggest that, in children less than 48 months, sevoflurane metabolism parallels postnatal development of CYP2E1.
Br J Anaesth 2002; 89: 6936
Keywords: anaesthetics volatile, sevoflurane; children; kidneys, urine; metabolism, sevoflurane
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Introduction |
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This study was undertaken to explore the effect of age on the metabolism of sevoflurane in small children, by measuring the postoperative fluoride urinary excretion.
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Methods |
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The bladder was emptied after induction of anaesthesia by manual abdominal pressure. If a urinary catheter was not required, a bag was stuck on the skin for urinary collection during the first 24 h after the beginning of sevoflurane anaesthesia. The child was only included in the study at the time of the urine collection if no urine leakage was observed during this period. It was necessary to screen 70 children before definitively including 45 patients in the study because of urine leakage during the 24-h urine collection.
After mixing and measuring the 24-h urine collection, a sample was frozen at 20°C until measurement of fluoride concentration. The fluoride urine concentrations were determined with an ion-selective electrode.7 Its performance was checked by an Interlaboratory Control program, managed by the Canadian toxicologic centre in Quebec (CHUQ, Sainte-Foy). The intra-essay coefficient of variation was 1.24, 0.21 and 0.48% for fluoride concentrations of 13, 53, and 133 µM, respectively. The inter-essay coefficient of variation was 4 and 4.2% for fluoride concentrations of 64 and 223 µM, respectively.
The ISM was calculated using the urinary fluoride excretion during the first 24 h, the exposure to sevoflurane, and the body surface area, as follows:
ISM=100x(FxU)/(ExS)
with F being urine fluoride concentration (µm litre1), U being 24-h urine volume (litre), E being exposure to sevoflurane (% min), and S being body surface area (m2) [calculated using (4W+7)/(W+90), where W is weight (kg)].
The exposure to sevoflurane (E) was estimated by the sum of the expiratory sevoflurane concentrations that were measured every minute during sevoflurane administration. Measurements were made using an infra-red based, multigas module (SAM module, Marquette electronicsTM, Milwaukee, USA) and sidestream sampling with a flow rate of 250 ml min1. Rise time (delay before automatic return to zero to avoid contamination of measurement by previous sampling) was less than 600 ms and the accuracy equal to 5% of the reading.
Data are expressed as medians (interquartile range 2575%). The ISM were compared in five groups of children (A, <4 months of age; B, 4 to <8 months; C, 812 months; D, >1224 months; and E, >24 months) using KruskalWallis analysis of variance. P<0.05 was considered statistically significant. If P was significant, KruskalWallis analysis was followed by a Dunns multiple comparison test.
Statistical analysis was performed on the Statview® 4.5 software (Abacus Concepts Inc., Berkeley, CA, USA). A relation between the median values of ISM and the age of each group was searched for by non-linear regression analysis using Prism, version 3.02 (Graph Pad software Inc.).
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Results |
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Discussion |
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Data concerning the metabolism of sevoflurane in children are limited to two previous studies.3 9 Those findings were correlated with our study: they have, respectively, shown smaller plasma fluoride peaks between 1 and 6 months,3 and a lower area under the curve of plasma fluoride in children aged from 1 to 12 yr,9 than in adults.
Fluoride production is related both to the administered dose of sevoflurane and to the CYP2E1 level activity.10 Fluoride urinary excretion probably reflects more accurately the fluoride production than plasma concentrations, and has been used to demonstrate the role of CYP2E1 in the hepatic biotransformation of sevoflurane.11 However, the use of urinary excretion standardized to sevoflurane exposure and body surface area in this study is original and has not been validated previously. The concept was guided by the need to take into account both variable exposures to sevoflurane, and physiological variables that are better indexed to body surface area than to body weight.
A limitation of our conclusion is the existence of extrahepatic metabolism of sevoflurane,12 explained by the expression of CYP2E1 in the lung, small intestine, and brain, albeit to a lesser extent than in the liver.5 In human hepatic microsomes, the rate of defluorination of sevoflurane has been shown to be well-correlated with liver CYP2E1 activity and selective inhibition.4
One of the clinical implications of the present study is that sevoflurane is the first substrate of CYP2E1 that could be used as an in vivo probe of its activity in children. Until now, chlorzoxazone, a centrally acting neuromuscular blocking agent, remained the only in vivo probe for CYP2E1 phenotyping in adults.13 Because of the absence of pharmacological data, its safety in childhood has not been established. Several factors regulate CYP2E1 activity. Developmental expression is one of the keys factors. CYP2E1 is absent or barely detectable in the fetal liver, developing post-natally. Ontogenesis relates to the developmental variation in enzyme activity during growth. Knowledge of the ontogenesis of CYP2E1 resulted from in vitro studies using post-mortem liver samples from children of varying postnatal age.6 Further implications of the immature metabolism of sevoflurane in infants and small children relate to nephrotoxicity from fluoride production.
More than 100 specific exogenous substrates of CYP2E1 have been identified, in addition to a number of endogenous ones.5 14 Low CYP2E1 activity could be protection against the toxicity of drugs or compounds that undergo activation by CYP2E1 to produce metabolites that are cytotoxic or genotoxic, such as halothane and acetaminophen. Oxidative hepatic metabolism of halothane by CYP2E1 mediates an immune-based fulminant hepatic necrosis, because of the production of a reactive trifluoroacetyl halide.15 The lower incidence of this rare but fatal side-effect in children,16 rather than in adults, could be explained by a lower CYP2E1 activity. The toxicity of acetaminophen is related to its transformation by CYP2E1 in presence of overdose or hepatic gluthation depletion, to a toxic metabolite identified as N-acetyl-p-benzoquinone imine.17 In mice, this toxicity is delayed, if expression of the CYP2E1 is lacking.18 Pretreatment by propylene glycol, that inhibits CYP2E1, also prevents hepatic necrosis.17 It is generally accepted that children are less susceptible than adults to acetaminophen toxicity because of developmental differences in its metabolism.19 One of these differences could be a lower CYP2E1 activity.
In conclusion, the allometric variation of fluoride excretion after sevoflurane anaesthesia during the first years of life, confirms previous in vitro data about CYP2E1 ontogenesis.
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Acknowledgement |
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References |
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