1 Departments of Obstetrics and Gynaecology and 2 Anaesthesia and Intensive Care, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR
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Abstract |
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Key words: anaesthesia/conscious sedation/IVF/oocyte retrieval/patient-controlled sedation
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Introduction |
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Patient-controlled sedation (PCS) allows the patients to take control of drug administration. The principle of PCS is based on the concept of patient-controlled analgesia (PCA) for post-operative pain relief. While PCA allows self-administration of i.v. analgesics according to individual needs, PCS enables self-titration of sedation in a similar fashion. Thus, a desired level of sedation and pain relief may be achieved with a customized minimal effective dose of sedative and analgesic (Herrick, 1996; Roseveare et al., 1998
). Furthermore, patient participation in dose titration may improve their sense of self-control and result in better patient satisfaction and operating conditions (Lefcourt, 1973
; Girdler et al., 2000
).
Previous reports have shown that the use of PCS during TUGOR is safe and effective (Zelcer et al., 1992; Dell and Cloote, 1998
). However, it is not known whether PCS is more effective than conventional physician-administered sedation (PAS). In this randomized controlled trial, we compared the effectiveness and safety of PCS using propofol-alfentanil admixture with PAS for conscious sedation during TUGOR.
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Materials and methods |
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Patient-controlled sedation
PCS was provided by a commercially available PCA pump (Model 3300, Graseby Medical, Watford, Herts, UK). A mixture of propofol (10 mg/ml) and alfentanil (50 µg/ml) was prepared. The PCA pump was programmed to deliver a bolus dose of 1 ml at 200 ml/h on patient's demand and the pump took 18 s to deliver the bolus, during which time it would not respond to a further demand. Thus, the effective lockout time was 18 s. After randomization and before the procedure, patients were instructed clearly on how to use the pump and were encouraged to press the demand button as often as required. The total number of PCS requested (total demands) and the number of demands that resulted in successful bolus delivery were recorded. We also calculated the demand/delivery ratio to indicate the effectiveness of PCS (McCoy et al., 1993). In this regard, patients with inadequate sedation or analgesia would be expected to make frequent requests over a short period of time. These requests may occur during the effective lockout period, resulting in unsuccessful demands and an increase in demand/delivery ratio. A ratio equal to one represents the most effective PCS system.
Physician-administered sedation
Patients assigned to the PAS group received an i.v. bolus of pethidine 1.5 mg/kg and diazepam 0.1 mg/kg 510 min prior to the procedure. Additional doses of pethidine 0.5 mg/kg were given when necessary as judged by the attending physician or upon the patient's request. This technique represents the standard method of sedation used for TUGOR in this unit.
All procedures were performed by L.P.C. or D.L.W.C. During operation, non-invasive arterial pressure, heart rate and pulse oximetry were measured at 5 min intervals. Intra-operative sedation and co-operation were scored according to 5-point sedation and co-operation scales respectively, as shown in Table I (Dell and Cloote, 1998
). Difficulty in retrieving oocytes was recorded as follows: easy to mildly difficult, moderately difficult or very difficult. During the procedure and 2 h afterwards, all patients were asked to evaluate the severity of pain and nausea using a 100 mm visual analogue scale (VAS; 0 mm = nil, 100 mm = worst imaginable). At the end of the procedure, both the patient's satisfaction and doctor's perception towards adequacy of pain and sedation control were rated using a similar VAS (0 mm = most dissatisfied, 100 mm = most satisfied). Patients who had previous oocyte retrievals under PAS and were currently randomized to PCS were also asked about their preferred type of sedation.
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During retrieval of the last two oocytes, venous blood and follicular fluid were collected for the measurement of propofol and alfentanil concentration using high-pressure liquid chromatography (Gin et al., 1991) and radioimmunoassay (Michiels et al., 1983
) respectively. Venous blood samples were stored at 4°C while follicular fluid was immediately centrifuged at 1800 g for 10 min to eliminate cellular components and frozen at 20°C until assay. The between-batch coefficients of variation for propofol and alfentanil were 6.7 and 4.6% respectively. The limit of detection was 2 ng/ml for propofol and 0.1 ng/ml for alfentanil.
IVF parameters including the number of oocytes retrieved, cycles with ICSI, fertilization rate, cleavage rate, number of embryos transferred or frozen and clinical pregnancy rate were recorded.
Statistics
Prospective power analysis was based on our pilot study of 30 patients undergoing TUGOR with conventional PAS. Given that the mean (± SD) pain score was 36 ± 16, we calculated that 47 patients per group would provide 90% power at 5% significance level to detect a 30% change in pain. With an estimated 10% drop-out rate, we based our study on a total sample size of 110. Data from this pilot study were not included in the final analysis.
Statistical analysis was performed with Statistical Packages of Social Sciences for Windows 10.1 (SPSS, Inc., Chicago, IL, USA). Categorical data were compared between groups using 2-test and continuous data were analysed by MannWhitney U-test. To test the validity of demand/delivery ratio as a measure of PCS effectiveness, we compared the ratio with the severity of pain, CSQ-8 score, and doctor and patient satisfaction using linear regression. P < 0.05 was taken to indicate statistical significance.
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Results |
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Haemodynamic parameters did not change during the operation. However, heart rate in the PAS group was significantly higher than in the PCS group (P < 0.01) and this may be related to the intrinsic vagolytic property of pethidine. Oxygen saturation was well maintained in all patients.
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Discussion |
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In the present study, PCS was delivered as frequent small boluses upon request. Thus, a desired level of sedation could be achieved rapidly if the demand button was pressed sufficiently often. We did not set a lockout interval between consecutive boluses. However, the time taken to infuse each dose imposed a brief refractory period (18 s) to the PCS system. We believe this effective lockout time protects patients from stacking of PCS demands and unintentional drug overdose. Only a third of the patient's demands were rejected by the PCS system, resulting in a demand/delivery ratio of 1.5. Given that the ratio correlated with patient satisfaction, these findings indicated that our current PCS setting was efficient in fulfilling patient requests. Any future modification of the PCS dose regimen should aim to achieve a demand/delivery ratio <1.5 in order to produce a better patient response.
It should be emphasized that neither the patient nor the physician was blinded to the treatment group. In this regard, patients may be less critical of their performance when given the option of controlling drug administration. Similarly, physicians' attitudes towards PCS may have altered patient's response. However, patient participation and physician interaction are key to the success of PCS. Thus, a double-blinded trial would not be feasible. Nevertheless, the endpoints were clearly defined and all investigators were familiar with the measurement scales; therefore, differences between the groups cannot be attributed entirely to treatment bias or measurement error.
We used a mixture of propofol and alfentanil to provide sedation and analgesia respectively. Both drugs are fast in onset but short acting, making them easy for dose titration and a popular combination for PCS. However, anaesthetics per se may adversely affect fertilization outcome. In mice, embryo cleavage was inhibited at propofol 10 ng/ml (Tatone et al., 1998), significant parthenogenetic activation was noted at 50 ng/ml (Janssenswillen et al., 1997
) and in-vitro maturation was suppressed at 10 000 ng/ml (Alsalili et al., 1997
). There are no data on the fecundability of oocytes during alfentanil administration. Although the embryo cleavage characteristics and fertilization in human oocytes were shown to be similar between propofol-alfentanil anaesthesia and paracervical blocks (Christiaens et al., 1998
) as well as in oocytes exposed to propofol (Ben-Shlomo et al., 2000
), it would be prudent to minimize the amount of anaesthetic delivered. PCS may be useful in reducing drug dosage. Accordingly, patients reduce their drug consumption as the desired level of sedation is achieved. Thus, the total drug consumed represents the minimal effective dose of sedative required. In this regard, Girdler et al. were able to reduce propofol administration by 30% using PCS in anxious dental patients (Girdler et al., 2000
). In the present study, the total propofol and alfentanil consumption (1.5 mg/kg and 7.9 µg/kg respectively) was less than that generally recommended for PAS (Sa Rego and White, 2000
). Consequently, the resultant concentrations of propofol and alfentanil were low in plasma and were not detected in follicular fluid samples and this is unlikely to produce any detrimental effect on the oocytes. Although we found no difference in the IVF parameters, including pregnancy outcomes between the two groups, our study was not primarily aimed at and was not powered for comparing pregnancy rates.
In summary, PCS using propofol and alfentanil can be a satisfactory and effective alternative to conventional diazepam-pethidine based PAS during TUGOR. Our results also demonstrate that PCS is safe and simple to administer and is associated with high patient satisfaction.
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Acknowledgements |
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Notes |
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References |
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Submitted on March 22, 2002; accepted on May 2, 2002.