1 Department of Anaesthesia and Intensive Care Medicine, Helsinki University Hospital, Helsinki, Finland. 2 Department of Anaesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland. 3 Department of Clinical Chemistry, Helsinki University Hospital, Helsinki, Finland. 4 Department of Anaesthesia and Intensive Care Medicine, Tampere University Hospital, Tampere, Finland
*Corresponding author: Department of Anaesthesiology and Intensive Care, PO Box 1777, FIN-70211 Kuopio, Finland. E-mail: merja.laisalmi@kuh.fi
Accepted for publication: July 18, 2003
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Abstract |
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Methods. Sixteen non-smoking and 17 smoking (>10 cigarettes day1) generally healthy women undergoing elective gynaecological surgery were given 1 MAC (minimum alveolar concentration)-hour standardized anaesthesia with enflurane in oxygenair mixture. The serum inorganic fluoride and renal function markers ß2-microglobulin, tumour-associated trypsin inhibitor (TATI) and serum creatinine were measured for 48 h.
Results. The greatest inorganic fluoride concentration was between 8.4 and 21.0 (mean 13.8 (SD 3.4)) µmol litre1 in the non-smokers and between 8.6 and 38.0 (18.7 (7.0)) µmol litre1 in the smokers; the mean difference was 4.9 µmol litre1 (95% confidence interval (CI) 1.08.8, P<0.05). Serum ß2-microglobulin, TATI and creatinine were not increased. Serum inorganic fluoride concentrations were significantly greater in the smokers compared with the non- smokers 1, 2, 3 and 6 h after 1 MAC-hour inhalation with enflurane (P<0.05). Inorganic fluoride concentrations were still increased 24 h after anaesthesia in both groups. Urine ß2-microglobulin and TATI creatinine ratio remained at low values during the whole 48-h period in both groups.
Conclusions. Regular smoking is associated with an increase in serum inorganic fluoride concentration after anaesthesia with enflurane, but there are no signs of renal damage.
Br J Anaesth 2003; 91: 8004
Keywords: anaesthetics volatile, enflurane; complications, smokers; enzymes, trypsin, inhibition; metabolism, inorganic fluoride; protein, ß2-microglobulin
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Introduction |
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Smoking is increasing among Finnish women,6 but little is known about the interaction of smoking with anaesthetic drugs. Tobacco smoke contains numerous components, some of which have been investigated regarding their pharmacological effects on the body. For example, nicotine and its main metabolite inhibit cytochrome P450 2EI (CYP2E1),7 the isoenzyme responsible for defluorination of fluorinated ether anaesthetics.4 8 In addition, the polyaromatic hydrocarbons found in tobacco smoke are potent inducers of drug metabolism9 and induction of liver enzymes in smokers increases the metabolism of antipyrine,10 pentazocine11 and theophylline.12
We noted that plasma inorganic fluoride concentrations seemed to be greater in smokers than in non-smokers after enflurane anaesthesia. Because our knowledge of fluoride metabolism in smokers is sparse, we designed this prospective clinical trial to determine whether smoking tobacco influences serum concentrations of inorganic fluoride after enflurane anaesthesia. Serum creatinine, ß2-microglobulin and tumour-associated trypsin inhibitor (TATI) were used to evaluate possible renal damage.
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Materials and methods |
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Anaesthesia was standardized. Diazepam 510 mg orally was used for premedication. The patients were given glycopyrrolate 0.2 mg and fentanyl 0.10.15 mg i.v., anaesthesia was induced with propofol 2.5 mg kg1 i.v., and tracheal intubation was facilitated with rocuronium 0.5 mg kg1 i.v.
Anaesthesia was maintained with 1.3 minimum alveolar concentration (MAC) of enflurane (the end-tidal concentration of enflurane was set at 2.1%) in 33% oxygenair mixture for 45 min, which corresponds to a 1 MAC-hour anaesthesia. A semiclosed breathing system with fresh gas flow of 3 litres min1 was used. The concentrations of inhalation gases and anaesthetics were monitored with a Datex AS/3 monitor (Datex-Ohmeda, Instrumed Corporation, Helsinki, Finland). The inhalation anaesthesia was discontinued after 45 min. Thus, all patients in both study groups were given 1 MAC-hour inhalation anaesthesia with enflurane.
After cessation of enflurane administration, the anaesthesia was continued with propofol infusion and the lungs were ventilated with oxygen 33% in nitrous oxide. Additional doses of fentanyl and neuromuscular blocking drug were given when needed.
Fluid therapy was standardized for the first 24 h. Patients were given Ringers solution 10 ml kg1 at induction of anaesthesia followed by an infusion of 5 ml kg1 h1 during surgery and in the recovery room. From the first postoperative day patients were allowed to drink ad libitum.
Venous blood samples for serum inorganic fluoride were collected before anaesthesia and 1, 2, 3, 6 and 24 h after the end of enflurane inhalation. Serum and urine samples for creatinine, ß2-microglobulin and TATI were collected at induction and on the first and second postoperative mornings. ß2-Microglobulin is a marker of renal tubular damage14 and TATI of glomerular filtration rate.15 The urinary catheter was inserted after the induction of anaesthesia for urine sampling. The urine markers were measured from spot samples to prevent the confounding effect of different urine volumes.16 The urinary catheter was removed when it was no longer clinically necessary.
The concentrations of inorganic fluoride were determined by a method modified from that of Fry and Taves.17 In brief, a fluoride-selective combination electrode (Orion model 96-09; Orion Research, Boston, MA, USA) was used for the measurement on Parafilm M (American National Can, Greenwich, CT, USA) placed on 16-mm cell culture wells. Before measurement, 200 µl of acetate buffer (acetateNaOH 1 mol litre1, pH 5.2, NaCl 1 mol litre1) and 10 µl of sodium fluoride 20 µmol litre1 were added to 190 µl of serum. The sensitivity of this assay was approximately 0.5 µmol litre1 and the interassay coefficient of variation was less than 8%.
The ß2-microglobulin concentration was determined using time-resolved fluoroimmunoassay (Delfia®; Wallac, Turku, Finland). Urine TATI was analysed by radioimmunoassay (Orion Diagnostica, Espoo, Finland). Serum and urine creatinine were analysed using a kinetic Jaffe method. The reference limits of the hospital laboratory are for serum TATI 02 nmol litre1, for urine TATI indexed to urinary creatinine 01.3 nmol mmol1 creatinine, and for serum and urine ß2-microglobulin respectively 0.6 3.0 mg litre1 and less than 0.25 mg litre1.
Statistics
We estimated the required sample size from our pilot observations, which found that the mean serum inorganic fluoride concentration was 12 (SD 4) µmol litre1 after enflurane anaesthesia in non-smoking women. From these data we estimated that 15 patients in each group would provide 80% power to detect a 35% difference in inorganic fluoride concentrations between the groups with a 0.05 level of significance.
The area under the serum fluoride concentration time curve from zero time to the 24 h blood sampling (AUCF µmol litre1) was calculated according to the linear trapezoidal rule.
Statistical analyses were with SPSS 9.0 (SPSS, Chicago, IL, USA). The 2-test was used for categorical variables. The independent samples two-tailed t-test was used to analyse values with a normal distribution (tested with Leavens test), and for skewed data we used the MannWhitney U-test. The Friedman test was used to compare inorganic fluoride concentrations observed over the different sample times. A P-value of
0.05 was considered statistically significant. The data are expressed as mean (SD) and minimummaximum unless otherwise stated.
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Results |
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Serum TATI and ß2-microglobulin values did not differ between the two groups. Urine TATI and the ß2-microglobulincreatinine ratio remained at small values during the study period and serum creatinine remained at the baseline in both study groups during the first 2 postoperative days (Table 2).
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Discussion |
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Enflurane is predominantly metabolized in the liver by cytochrome P450 2E1 isoform to inorganic fluoride.4 Tobacco smoke contains powerful inducers of cytochrome P450 enzymes and the induction of cytochrome P450 2E1 is the most likely reason for increased concentrations of inorganic fluoride after enflurane anaesthesia. However, the interaction between the components of tobacco smoke and anaesthetic inhalation agents is poorly investigated.
Inorganic fluoride concentrations seldom reach the renal toxic concentration of 50 µmol litre1 during short inhalation anaesthesia.1 In volunteers renal concentrating ability decreased when serum inorganic fluoride was maximal at only 33.6 µmol litre1 after enflurane anaesthesia.18 In the present study, one woman in the smokers group had a serum fluoride concentration of 38 µmol litre1 while the greatest concentration in the non-smokers group was 21 µmol litre1. It is probable that it is not the maximum concentration but rather the duration of raised inorganic concentrations (i.e. the area under the curve) which may affect the development of nephrotoxic effects after enflurane anaesthesia.19 Also, other reactive intermediate metabolites may be potential nephrotoxins. For example, alkaline degradation of enflurane produces halogenated alkenes that are conjugated further to possibly nephrotoxic thiol compounds.20
Renal tubular function remained stable in this study, as indicated by serum and urine ß2-microglobulin concentrations. The ß2-microglobulin is a low molecular weight protein produced predominantly by lymphocytes.14 It is filtered through the glomerulus and reabsorbed in the proximal tubules. Serum and urine ß2-microglobulin concentrations increase in patients with tubular damage. Increased serum concentrations of ß2-microglobulin have been measured in connection with high inorganic fluoride concentrations after sevoflurane anaesthesia.21 Serum concentrations of ß2-microglobulin are also influenced by immunological and stress reactions, and infections, because of the predominant production in lymphocytes. In our study, a possible influence of diurnal variation in serum ß2-microglobulin concentrations, with peak values in the morning,22 was minimized by sampling at the same time each morning. The urine markers were determined from spot samples and normalized to urinary creatinine. The use of spot samples may have affected the results, although this normalization to urine creatinine is commonly used to avoid the confusing effect of different urine volumes.16
A small amount of TATI is found in the serum and urine of healthy subjects, and serum TATI concentration has a negative correlation with glomerular filtration rate. If glomerular filtration rate is reduced, serum TATI increases with increased urinary excretion.15 In the present study the fluid therapy was standardized for the first 24 h after surgery and thereafter the patients were allowed to drink ad libitum. This may have affected the urinary marker results. TATI is used as a tumour marker for conditions such as ovarian cancer.23 This could have been a confounding factor in the present study.
We conclude that inorganic fluoride concentrations are increased markedly in smokers compared with non-smokers after 1 MAC-hour enflurane anaesthesia. Induction of cytochrome P450 enzymes by cigarette smoke is likely to be the cause. However, we did not find fluoride-induced nephrotoxicity.
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References |
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