1 Department of Anaesthesiology and 2 Centre for Reproductive Medicine, Department of Anaesthesiology, University Hospital A.Z. V.U.B., Flemish Free University of Brussels, Laarbeeklaan 101, B-1090 Brussels, Belgium
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Abstract |
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Key words: anaesthesia/arterial blood/follicular fluid/oocyte/propofol
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Introduction |
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This study evaluated the propofol concentrations in follicular fluid during general anaesthesia. Coetsier et al. (1992) had already demonstrated that propofol accumulation in follicular fluid was time dependent. Their conclusion was based on a pharmacokinetic profile using venous blood samples. However, it has been shown in animal studies that arterial and venous blood sampling may lead to a considerable difference in drug concentrations (Chung et al., 1997; Krejcie et al., 1997
) and that arterial sampling may be more accurate for the evaluation of distribution, elimination and pharmacodynamic effects (Chiou, 1989
). Since the accumulation of propofol in follicular fluid might have effects on IVF and early embryo development and thus might have important clinical and ethical implications, it was thought interesting to correlate follicular fluid propofol concentrations to arterial blood samples, since this information may further restrict the amount of propofol ultimately administered during anaesthesia. We therefore studied the propofol concentration in arterial blood and follicular fluid in patients undergoing transvaginal oocyte retrieval.
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Materials and methods |
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The patients received no premedication. An 18-gauge catheter was inserted in one arm and 500 ml Hartmann's solution was used as maintenance infusion. Induction of general anaesthesia (time = T0) consisted of pre-oxygenation by face mask, followed by 0.5 mg alfentanil (Rapifen®; Janssen Pharmaceuticals, Beerse, Belgium) and 2 mg.kg1 propofol (Diprivan®; Zeneca, Manchester, UK) i.v. Anaesthesia was maintained with a continuous infusion of propofol at 10 mg.kg1.h1 i.v. with additional 20 mg increments if necessary. Dosing and times of administration of these propofol supplements were recorded to the nearest minute. Ventilation was controlled by face mask with the patient breathing a 50% O2air mixture. Immediately after induction, a 20 gauge arterial catheter was inserted in the radial artery. Follicular fluid and arterial blood samples were aspirated simultaneously at 10, 15, 20, 30 and 40 min after the initial administration of propofol. The follicles whose follicular fluid was used to determine the follicular fluid concentration of propofol were aspirated separately and the aspiration system was flushed between aspirations. The infusion of propofol was discontinued at the beginning of the aspiration of the last follicle.
Blood samples were collected in oxalated tubes and stored as whole blood at 4°C. Follicular fluid was centrifuged at 1800 g for 5 min, to eliminate cellular components, e.g. cumulus cells, and frozen at 20°C. Follicular fluid samples that were macroscopically contaminated with blood were discarded. All blood and follicular fluid samples were analysed within 12 weeks of collection.
The concentration of propofol in blood and follicular fluid was determined by high-performance liquid chromatography (HPLC) with separation on a RP-18 column (Merck, Darmstadt, Germany) with acetonitrile (Lab-Scan Ltd, Stillorgan Industrial Park, Dublin, Ireland) (60)water (40)orthophosphoric acid (Merck) (0.2) after solid phase extraction on a cyclohexyl column (Varian, Harbor City, CA, USA), with thymol (Merck) as internal standard and fluorescence detection (excitation wavelength: 276 nm, emission wavelength: 310 nm). Further details of the HPLC method are available from the corresponding author. Separation of the propofol from the solvent front and the internal standard was confirmed on chromatograms performed earlier.
Statistical analyses included non-parametric tests (paired Wilcoxon test and Spearman rank correlation) and analysis of variance (ANOVA). Data are expressed as mean and SEM. All tests were performed at a significance level of 0.05.
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Results |
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Even with a continuous infusion of 10 mg.kg1.h1 of propofol, 24 patients (80%) moved when the speculum was placed or the aspiration needle was inserted and needed one or more additional doses of propofol. In seven patients (23%), an additional bolus of 0.5 mg alfentanil (opioid) was necessary.
Six follicular fluid samples were macroscopically contaminated with blood and were discarded. Data from two patients were excluded from analysis because of lost or coagulated blood samples. In all 78, concomitant blood and follicular fluid samples were analysed, as in several patients the surgical procedure lasted <30 min.
The concentration of propofol in arterial blood ranged from 1.40 to 12.10 µg.ml1. The mean concentrations of propofol in arterial blood are listed in Table I. Concentrations of propofol in follicular fluid were detectable within 10 min of i.v. propofol administration and ranged from 0.04 µg.ml1 to 0.21 µg.ml1. Except in four patients, the concentration of propofol in follicular fluid steadily increased with the duration of propofol infusion (Table I
). The amount of propofol present in follicular fluid was strongly related to the cumulative dose of propofol administered (Figure 1
). The concentration of propofol in the follicular fluid did not correlate with the arterial blood concentration of the drug (Figure 2
) nor to the plateau concentration of propofol achieved during the continuous infusion of this agent. The absorption of propofol in follicular fluid was time-dependent (P < 0.001) with an apparent clearance ratio from the blood to the follicular fluid of 6.04 ± 0.01% (range 1.915.5) as estimated from areas under the drug concentrationtime curves in blood and follicular fluid.
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Discussion |
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The mean follicular fluid propofol concentration observed in this study was 0.43 µg.ml1 after 30 min and 0.57 µg.ml1 after 40 min. Propofol was shown to be a parthenogenetic activator for denuded mice oocytes at a concentration of 0.4 µg.ml1 after 30 min incubation (Janssenswillen et al. 1997). Thus, the concentration of propofol in follicular fluid found here might induce deleterious effects on subsequent cleavage and fertilization.
Despite controversial reports with regard to the influence of propofol anaesthesia on implantation rates and clinical pregnancy rates in humans (Pierce et al., 1992; Vincent et al., 1995
; Rosenblatt et al., 1997
), caution seems warranted with the use of propofol for oocyte retrieval. The potential deleterious effects of this agent could be minimized by modifying the anaesthetic technique in order to limit the dose of propofol administered to <4 mg.kg1 (Figure 1
).
In conclusion, a propofol-based anaesthetic technique resulted in significant concentrations of this agent in follicular fluid, related to the dose administered and to the duration of propofol administration. The concentrations of propofol in follicular fluid were larger than those shown to exert parthenogenetic activity in mice oocytes. In the light of the deleterious effects of propofol on oocyte fertilization decribed in mouse models by others, the retrieved oocytes should be washed free of propofol. Taking into account the potential negative effects on human artificial reproductive technology, the total dose of propofol administered during anaesthesia should be strictly limited.
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Acknowledgments |
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Notes |
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References |
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Submitted on April 14, 1998; accepted on October 23, 1998.