British Journal of Anaesthesia, 2003, Vol. 90, No. 2 233-237
© 2003 The Board of Management and Trustees of the British Journal of Anaesthesia
Short Communications |
Sevoflurane anaesthesia does not induce the formation of sister chromatid exchanges in peripheral blood lymphocytes of children
1 Christian-Albrechts-University Kiel, Brunswiker Strasse 10, D-24105 Kiel, Germany. 2 University-Hospital Hamburg Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany
Corresponding author: Klinik und Poliklinik für Anästhesiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. E-mail: tkrause@uke.uni-hamburg.de
Accepted for publication: September 17, 2002
 |
Abstract |
|---|
 Top Abstract IntroductionMethods and resultsCommentReferences |
|---|
Background. Compound A, a degradation product of sevoflurane, has been demonstrated to induce sister chromatid exchanges (SCE) in Chinese hamster ovary cells in vitro as a marker for possible genotoxicity. We investigated the formation of SCE in mitogen-stimulated T-lymphocytes of 40 children undergoing sevoflurane anaesthesia for minor surgical procedures.
Methods. Anaesthesia was induced by inhalation of up to 8% sevoflurane and maintained at 2.5–3% in oxygen/nitrous oxide (65/35%) at a fresh gas flow of 3 litre min–1. Soda lime (humidity 12–15%) was used as a carbon dioxide absorbent. Blood was drawn directly before induction and after termination of anaesthesia. Twenty-five second division metaphases of mitogen-stimulated T-lymphocytes per blood sample were screened for SCE rates using standard techniques.
Results. Average duration of anaesthesia was 49.6 (SD 24.0) min. Before anaesthesia induction, 7.93 (1.23) SCE per metaphase were determined. After sevoflurane anaesthesia [1.40 (0.77) MAC h] 7.92 (1.19) SCE per metaphase were observed. Additionally, no differences were evident between male or female children.
Conclusion. Short-term administration of sevoflurane anaesthesia did not induce SCE in T-lymphocytes of children. No indication for a possible genotoxic effect has been observed.
Br J Anaesth 2003; 90: 233–5
Keywords: anaesthetics volatile, sevoflurane; metabolism, sevoflurane; toxicity, genotoxicity
|
Introduction |
|---|
|
TopAbstractIntroductionMethods and resultsCommentReferences |
|---|
Sister chromatid exchange (SCE) analysis in peripheral blood lymphocytes is a sensitive cytogenetic technique widely used for the investigation of suspected human mutagens and carcinogens.1 Under certain conditions, and upon contact with a carbon dioxide absorbent, sevoflurane might be degraded to a vinyl ether called Compound A.2 Vinyl ethers can damage DNA and produce SCE. Exposure to Compound A has been associated with the induction of SCE in Chinese hamster ovary (CHO) cells in vitro, at concentrations that might occur during low flow sevoflurane anaesthesia in humans.3 The formation of SCE after sevoflurane anaesthesia has not yet been reported. We studied the SCE frequencies in mitogen-stimulated T-lymphocytes derived from 40 children, before and after sevoflurane anaesthesia, undergoing minor surgical procedures.
|
Methods and results |
|---|
|
TopAbstractIntroductionMethods and resultsCommentReferences |
|---|
After obtaining IRB approval and written informed consent of parents, 40 children (12 female, 28 male), ASA classification I (n=33) and II (n=7), aged 1–14 years [mean 5.4 (SD 2.8) yr] were included. All received an oral midazolam premedication (0.2 mg kg–1) 1 h before anaesthesia. Anaesthesia [average duration 49.6 (24.0) min] was induced by inhalation of up to 8% sevoflurane in pure oxygen and maintained at 2.5–3% in oxygen/nitrous oxide (35/65%) at a fresh gas flow of 3 litre min–1. Soda lime (humidity 12–15%) was used as a carbon dioxide absorbent. Alfentanil (15–30 µg kg–1) or sufentanil (0.2–0.3 µg kg–1) were administered for pain relief. Blood was drawn before and directly after termination of anaesthesia and samples were coded. Cell cultures were established within the first 2 h after termination of surgery. SCE and cell preparations were performed according to the technique published by Perry and Evans.1 Cells were stained with acridine orange and 25 well-differentiated second division metaphases per blood sample were analysed under a fluorescence microscope. A power analysis (Instat 2.1, Graphpad Inc.) was performed on the basis of SCE data from our institution with an estimated 7.0 (1.2) SCE per metaphase. An increase of 1.0 SCE per metaphase was regarded as the smallest significant difference between groups. Including a type I error of
=0.05 and a type II error of ß=0.05, the required group size was calculated to be 39 patients. This analysis reached a power of 95%. Wilcoxon signed rank test and Mann–Whitney U-test (SPSS 9.0, SPSS Inc.) were performed to test for differences between groups (P<0.05). Data are mean (SD).1
|
Before induction of anaesthesia, 7.93 (1.23) SCE per metaphase were determined in children. After sevoflurane anaesthesia [1.40 (0.77) minimum alveolar concentration (MAC) h] an average rate of 7.92 (1.19) SCE per metaphase was obtained, thus demonstrating no significant changes in resulting SCE rates after sevoflurane challenge. Addi tionally, no differences were evident in girls [7.88 (1.67) vs 7.97 (1.44) SCE per metaphase] and boys [7.96 (1.02) vs 7.87 (1.09) SCE per metaphase].
|
Comment |
|---|
|
TopAbstractIntroductionMethods and resultsCommentReferences |
|---|
The SCE test is widely used for evaluating the ability of chemicals to induce DNA damage. Dose–response relationships have been reported for a wide variety of suspected mutagens and carcinogens.4 A direct exposure of CHO cells to Compound A above 27 p.p.m. has been reported to produce a dose-related increase in SCE formation in vitro, but the threshold for producing SCE increases has not been defined. Compound A is thought to act directly as an alkylating agent which does not require preceding metabolic activation before reaction with susceptible cellular targets, including DNA.3 It is generally accepted that, for suspected genotoxins, no safety threshold can be defined, as the induction of mutagenicity, or even carcinogenicity, might be induced by a single critical event in a single cell. However, a direct extrapolation of data derived from animal cell experiments in vitro to risk estimations in humans, is problematic because of large pharmacokinetic and pharmacodynamic species differences.
Our results indicate that short-term sevoflurane anaesthesia does not induce SCE ex vivo in children, even when administered at high doses of up to 8% at a fresh gas flow rate of 3 litre min–1. Compound A concentrations in the anaesthesia circuit using a fresh gas flow rate of 2 litre min–1 have been estimated to reach a maximum of 32 p.p.m.5 Sevoflurane concentration, ventilation, fresh gas flow rate and type, temperature and humidity of the carbon dioxide absorbent influence the formation of Compound A. Highest concentrations occur when fresh gas flow is low, and current USA Food and Drug Administration recommendations state that flow rates <2 litre min–1 are not recommended in a circle absorber system.6
To date, no available clinical data indicate that sevoflurane might be genotoxic in man. Our results support the safety of sevoflurane administration as no evidence for a possible genotoxic potential of sevoflurane in paediatric anaesthesia was observed. Nevertheless, it cannot be excluded that, under certain conditions during sevoflurane anaesthesia (e.g. with dry soda lime or at a low fresh gas flow rate), Compound A and further degradation products might be generated at a remarkable and possible genotoxic rate. It has been postulated that, chronic exposure to waste anaesthetic gases might cause genotoxicity in operating room personnel,7 but the results in humans are still conflicting.8 From the International Agency for Research on Cancer, volatile anaesthetics have been placed into the category of non-classifiable agents with respect to carcinogenicity in humans.9 Further investigations should clarify possible effects of long-term sevoflurane anaesthesia and chronic exposure to waste sevoflurane gases on the formation of SCE. Chemically inert carbon dioxide absorbents such as Amsorb®10 might be helpful to avoid degradation of sevoflurane to Compound A.
|
References |
|---|
|
TopAbstractIntroductionMethods and resultsCommentReferences |
|---|
1 Perry P, Evans HJ. Cytological detection of mutagen-carcinogen exposure by sister chromatid exchange. Nature 1975; 258: 121–5[CrossRef][Medline]
2 Morio M, Fujii K, Satoh N, et al. Reaction of sevoflurane and its degradation products with soda lime: toxicity of the by-products. Anesthesiology 1992; 77: 1155–64[Web of Science][Medline]
3 Eger EI II, Laster MJ, Winegar R, Han C, Gong D. Compound A induces sister chromatid exchanges in Chinese hamster ovary cells. Anesthesiology 1997; 86: 918–22[Web of Science][Medline]
4 Tucker JD, Preston RJ. Chromosome aberrations, micronuclei, aneuploidy, sister chromatid exchanges, and cancer risk assessment. Mutation Res 1996; 365: 147–59
5 Patel SS, Goa KL. Sevoflurane. A review of its pharmacodynamic and pharmacokinetic properties and its clinical use in general anesthesia. Drugs 1996; 51: 658–700[Web of Science][Medline]
6 Hiromichi B, Yukako I, Kazuyuki I. Effects of the water content of soda lime on compound A concentration in the anethesia circuit in sevoflurane anesthesia. Anesthesiology 1998; 88: 66–71[CrossRef][Web of Science][Medline]
7 Hoerauf KH, Wiesner G, Schroegendorfer KF, et al. Waste anaesthetic gases induce sister chromatid exchanges in lymphocytes of operating room personnel. Br J Anaesth 1999; 82: 764–6
8 Husum B, Niebuhr E, Wulf HC, Norgaard I. Sister chromatid exchanges and structural chromosome aberrations in lymphocytes in operating room personnel. Acta Anaesthesiol Scand 1983; 27: 262–5[Medline]
9 International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans. Suppl 7. Overall evaluations of carcinogenicity: An updating of IARC Monographs Vol. 1–42. Lyon, 1987; 93–5
10 Murray JM, Renfrew CW, Bedi A, McCrystal CB, Jones DS, Fee JPH. Amsorb. A new carbon dioxide absorbent for use in anesthetic breathing systems. Anesthesiology 1999; 91: 1342–8[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E Kadioglu, S Sardas, S Erturk, O Ozatamer, and A. Karakaya Determination of DNA damage by alkaline halo and comet assay in patients under sevoflurane anesthesia Toxicology and Industrial Health, April 1, 2009; 25(3): 205 - 212. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Chandrasekhar, P. V. Rekhadevi, N. Sailaja, M. F. Rahman, J. P. Reddy, M. Mahboob, and P. Grover Evaluation of genetic damage in operating room personnel exposed to anaesthetic gases Mutagenesis, July 1, 2006; 21(4): 249 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kaymak, E. Kadioglu, H. Basar, and S. Sardas Genoprotective role of vitamin E and selenium in rabbits anaesthetized with sevoflurane Human and Experimental Toxicology, August 1, 2004; 23(8): 413 - 419. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||