1 Department of Obstetrics and Gynecology, 2 Anaesthesiology, HaEmek Medical Centre, Afula, 3 Laboratory of Toxicology and Clinical Pharmacology, Rambam Medical Center, Haifa and 4 Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel
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Abstract |
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Key words: embryo quality/oocyte fertilization/propofol
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Introduction |
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Propofol is chemically unrelated to earlier anaesthetic drugs. This highly lipophilic agent has a fast onset and short, predictable duration of action due to its rapid penetration of the bloodbrain barrier and distribution to the central nervous system (CNS; Kanto and Gepts, 1989). It is very popular for a host of ambulatory procedures including oocyte retrieval (Rosen et al., 1991
; Coetsier et al., 1992
; Moscona et al., 1995
; Tontisirin et al., 1996
). Although some reports have not found any detrimental effect of propofol on assisted reproduction outcome, a recent report challenged its safety (Tatone et al., 1998
). Recently it has been shown that when total i.v. anaesthesia is maintained with continuous propofol pump, a gradual, time dependent, linear increase of its concentrations is observed in FF (Christiaens et al., 1999
). Interestingly, no possible biological effects were detected. In an attempt to document possible differences in fertilization rates and early embryo development potentially attributable to propofol, we separated first aspirated from last aspirated oocytes during propofol/fentanyl induced anaesthesia for oocyte retrieval.
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Materials and methods |
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The time elapsed from the initial administration of propofol to the aspiration of the last follicle was recorded. Vaginal aseptic cleansing was done under anaesthesia. In 32 patients predicted to have at least 15 oocytes, the oocytes were divided and kept in groups according to the sequence of aspiration. Thus, about a third of the oocytes were designated `early', a third were designated `last' and all the rest were called `intermediate'. The three respective groups were handled and kept separately until embryo transfer (or cryopreservation). In 17 patients out of this group FF from the first and last follicles were collected separately. Special care was taken to ascertain that the last aspirated follicle would be approximately the same size as the first. If not blood tainted (11 cases), FF were kept frozen (20°C) in glass vacuum tubes, covered with aluminium foil for later analysis of propofol concentrations. Propofol concentrations were determined using modified high-pressure liquid chromatography (Knibbe et al., 1998). In brief, for the mobile phase, a mixture of acetonitrile/distilled water/trifluoroacetic acid (70:30:0.1 v/v/v) was used. Calibrations with varying dilutions of propofol in either FF or distilled water were done using 1% propofol vials for i.v. injection. No difference was found between the two solvents. Aliquots of 0.5 ml from each sample were mixed vigorously with 1 ml acetonitrile and centrifuged. A sample of 60 µl from the supernatant was passed through Prodigy 5 µm ODS (3), 250x4.6 mm column (Phenomenex Inc., Torrance, CA, USA). Retention time was 6.38 min. The limit of detection was 3 ng/ml and coefficient of variation at 125 ng/ml was 7%.
Power considerations indicated that if the effect of propofol was expected to decrease fertilization rate after intracytoplasmic sperm injection (ICSI) from 75 to 60%, then a cohort of 151 oocytes would be needed in each group for a reliable negative conclusion (power of 0.8; P < 0.05). Statistical calculations included regression analysis, Student's t-test (paired), MannWhitney U test and 2 test as applicable.
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Results |
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Discussion |
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The shift in popularity of oocyte retrieval technique to the exclusive use of the transvaginal route has significantly shortened the duration of the procedure as well as the degree of pain involved. Nevertheless, concerns still exist regarding possible detrimental effects of anaesthetic agents on the quality of oocytes and the corresponding embryos. In this regard, there are also some studies in animals which give some support to this concern (Janssenswillen et al., 1997). A recent study (Christiaens et al., 1999
) gave a solid demonstration of the fact that follicle-contained oocytes are exposed to increasing concentrations of propofol as anaesthesia continues. Although we observed the same trend, we could not demonstrate a correlation between the concentrations in FF and the duration of anaesthesia. This may be attributed to the relatively small number of patients tested for FF concentrations of propofol (n = 11) or the discontinuous mode of propofol administration that we employed. In this regard it is striking that the total dose of propofol which we administered to our patients was lower than that reported by Christiaens et al. (1999), as was the mean operation time. Whereas they reported doses of propofol up to 10 mg/kg, we never had a dose higher than 5 mg/kg, the mean being 2.54 (±0.76) mg/kg. It is not surprising therefore, that the concentrations of propofol that we measured in FF were markedly lower. Nevertheless, motivated by the concern that exposure of the last retrieved oocytes to more propofol compared to early retrieved oocytes could damage the quality of the resulting embryos, we recorded their respective in-vitro outcome. As far as such a limited observation as ours can predict lasting only during the extracorporal time of incubation, this is not the case. A caveat, however, is the difference in the overall duration and cumulative doses of propofol given by us compared with those reported by Christiaens et al. (1999).
In conclusion, we did not demonstrate a detrimental effect of the rising concentrations of FF propofol on oocyte quality. However, we cannot rule out the possibility that the short duration of our retrieval procedures and the consequent low FF propofol concentrations contributed to this result.
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Notes |
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References |
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Submitted on April 18, 2000; accepted on June 30, 2000.