Department of Obstetrics & Gynaecology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China
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Abstract |
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Key words: anxiety/oocyte retrieval/pain/postoperative side-effects/premedication
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Introduction |
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We confirmed the efficacy of paracervical block (PCB) in conjunction with conscious sedation for pain relief during TUGOR, as the mean abdominal pain scores after giving PCB with 150 mg lignocaine were significantly reduced by 40 and 50% compared with placebo and no local injection respectively (Ng et al., 1999). In another randomized trial (Ng et al., 2001
) comparing the pain levels using PCB with and without conscious sedation, about 60% of patients had dizziness or drowsiness in the postoperative period, whether they received conscious sedation or not. Based on this finding, it was postulated that these postoperative side-effects might result from the routine use of anxiolytic premedication given to our patients prior to TUGOR to relieve anxiety and induce sedation. However, the role of routine premedication for reducing anxiety has not been established in the literature (Forrest and Brown, 1977
, Alpert et al., 1989
; Kanto et al., 1996
).
The aim of this randomized double-blinded placebo-controlled study was to compare the preoperative anxiety level, pain levels during TUGOR and postoperative side-effects between patients receiving anxiolytic premedication and placebo given prior to TUGOR using conscious sedation and PCB. The hypothesis was a reduction of postoperative side-effects when routine anxiolytic premedication was not given prior to the retrieval.
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Materials and methods |
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Ovarian stimulation regimens, gamete handling, standard insemination and ICSI were as previously described (Ng et al., 2000). A maximum of three normally cleaving embryos were replaced into the uterine cavity.
Assignment
Patients were all counselled individually about the procedure and the possible risks of TUGOR by a medical doctor on the day of HCG injection. The details of PCB and TUGOR have been previously described (Ng et al., 1999). On the day of TUGOR, patients were randomized according to a computer-generated randomization list in sealed envelopes to receive (i) premedication i.e. 50 mg pethidine (Antigen Pharmaceutics Ltd., Roscrea, Ireland) and 25 mg promethazine (Phenergan®, M&B, Essex, UK) or (ii) placebo i.e. normal saline i.m. 30 min prior to the retrieval. All had PCB using 10 ml of 1.5% lignocaine (Weimer Pharma, Rastatt, Germany) and conscious sedation consisting of 5 mg diazepam (Valium; Roche, Basel, Switzerland) and an i.v dose of 25 mg pethidine. Patients were encouraged to receive a repeated dose of i.v. sedative/analgesia (5 mg diazepam/25 mg pethidine) during TUGOR, if they felt the procedure was too painful.
Assessment of anxiety levels, pain levels, postoperative side-effects and sedation scale
Nurses who were not involved in the retrieval procedure asked patients about the anxiety level, pain levels and postoperative side-effects. Basal anxiety levels were assessed by both the Chinese version of the State Anxiety Questionnaire (Shek, 1993) and a 100 mm linear visual analogue scale (VAS, 0 = none to 100 = most severe) on admission for TUGOR. The preoperative anxiety level was evaluated by the 100 mm linear VAS just before the retrieval, usually 30 min after premedication or placebo.
Pain levels were measured by a 100 mm linear VAS (0 = none to 100 = intolerable). Prior to premedication and TUGOR, patients were asked to give pain levels related to venepuncture, transvaginal scanning, the insertion of an i.v. cannula and the anticipated oocyte retrieval. The maximum levels of vaginal and abdominal pain during TUGOR were rated by patients shortly after TUGOR. Patients were asked again to rate the present vaginal and abdominal pain 4 h after TUGOR before discharge. Severity of postoperative side-effects including nausea, vomiting, drowsiness and dizziness were rated by patients into four grades: none, mild, moderate and severe. They were asked to give the satisfaction score regarding the pain control of this retrieval: excellent, satisfactory, fair and unsatisfactory.
The surgeon (EHYN/BM) recorded the levels of sedation during the retrieval according to an established scale (Ramsay et al., 1974). Level 1: Patient anxious and agitated or restless or both; Level 2: Patient co-operative, orientated and tranquil; Level 3: Patient responsive to commands only; Level 4: Asleep and a brisk response to loud auditory stimulus; Level 5: Asleep and a sluggish response to loud auditory stimulus; Level 6: Asleep and no response to loud auditory stimulus.
Masking
Both the patient and the doctor carrying out the retrieval were blind to premedication or placebo, which was given by a nurse not involved in the retrieval procedure or in assessing patients' anxiety and pain levels. The codes for premedication or placebo were broken only after the completion of the study.
Statistical analysis
TUGOR was timed from the first vaginal puncture to the removal of the needle after aspiration of all follicles >10 mm on both sides. Retrieval rate was the proportion of punctured follicles that contained an oocyte. Implantation rate was defined as the proportion of embryos transferred resulting in an intrauterine gestational sac.
Our previous study (Ng et al., 2001) showed that about 60% of patients receiving only premedication and PCB experienced dizziness or drowsiness in the postoperative period. Assuming that a 50% reduction of the postoperative side-effectsfrom 60 to 30%as acceptable when anxiolytic premedication is not used, the sample size required would be 50 in each arm to give a test of significance of 0.05 and a power of 0.8 (Sigmastat; Jandel Scientific, San Rafael, CA, USA). The primary outcome measures were preoperative anxiety level, pain levels during TUGOR and severity of postoperative side-effects. As the data were not normally distributed, results were given as medians (2.597.5th centiles). Statistical tests were carried out by MannWhitney U-test,
2-test and Wilcoxon ranked sum test, where appropriate. Correlation was assessed by the Pearson method and multiple regression analysis with the least-squares regression was applied to evaluate importance of various parameters in predicting abdominal pain level during TUGOR. P-value (two-tailed) of < 0.05 was taken as significant.
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Results |
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Analysis
Demographic data of patients are given in Table I. There were no differences in age of women, body mass index (BMI), proportion of primary infertility, causes of infertility, and the type of treatment between the premedication group and the placebo group. The duration of TUGOR, the number of follicles punctured and the number of oocytes obtained were comparable in the two groups (Table II
). Four (8.0%) patients in the premedication group and another four (8.0%) in the placebo group requested a repeated dose of i.v. sedation during the retrieval.
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Discussion |
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Infertile patients undergoing IVF/embryo transfer treatment are under great stress and tend to be very anxious before the oocyte retrieval. Therefore, all our patients received anxiolytic premedication prior to the retrieval procedure, although this routine practice has been questioned, especially for short outpatient surgical procedures (Forrest and Brown, 1977, Alpert et al., 1989
; Kanto et al., 1996
). It has been suggested that a frank preoperative discussion is all that is necessary to effectively allay anxiety in many patients. On the other hand, patients may have different expectations as 3% of outpatients undergoing dilatation of the cervix and curettage of the uterine cavity performed under general anaesthesia desired no premedication while 80% preferred a combination of axiolytic and hypnotic premedication (Korttila et al., 1981
).
The premedication group and the placebo group had similar demographic characteristics, ovarian response, duration of TUGOR and clinical outcome. On admission, both groups had comparable basal anxiety levels as shown by the State Anxiety Questionnaire and a 100 mm linear VAS. We could not find any significant correlation between state anxiety score and basal anxiety level measure by VAS although others have demonstrated a good correlation between State Anxiety Questionnaire and VAS used to assess the anxiolytic effects of premedication (Abdul-Latif et al., 2001). The state anxiety scores of our patients were similar to that of infertile Italian women undergoing TUGOR (Ardenti et al., 1999
).
Preoperative anxiety level was significantly higher than the basal level in the placebo group while the corresponding anxiety levels were similar in the premedication group. Our study subjects included only patients who had previous attempts at TUGOR at our centre during which they received anxiolytic premedication and conscious sedation with or without PCB. They were fully aware of the details of the procedure and would be expected to be different from patients undergoing their first attempt at TUGOR in terms of anxiety level. We anticipate that an even more remarkable increase in preoperative anxiety level might be encountered in those undergoing the first retrieval attempt without anxiolytic premedication, although similar state anxiety levels were found in patients undergoing first, second and third cycles (Ardenti et al., 1999).
Both groups appeared to have similar basal pain thresholds as they rated similar pain levels during venepunture, transvaginal scanning and setting up for an i.v. catheter. The reason for a significantly lower anticipated pain level during TUGOR in the placebo group was unknown. Pain levels during the last attempt of TUGOR were not compared because not all patients in this study had assessment of pain levels during previous attempts at TUGOR. Our results clearly indicated an increase in vaginal and abdominal pain levels during TUGOR and 4 h after TUGOR when anxiolytic premedication was not administered, although the difference in these pain levels 4 h after TUGOR between the premedication group and the placebo group may not be clinically significant. Lower pain levels in the premedication group may be related to a lower preoperative anxiety level and a higher percentage of Level 34 sedation in this group. Using multiple regression analysis, preoperative anxiety level achieved the best value in predicting abdominal pain level during TUGOR. High preoperative anxiety level is also associated with increased intraoperative anaesthetic requirements during general anaesthesia (Maranets and Kain, 1999).
There were no differences in the percentage of postoperative side-effects regarding nausea, vomiting and dizziness between the premedication group and the placebo group. However, patients receiving anxiolytic premedication reported significantly higher percentages of moderate/severe drowsiness, compared with those receiving placebo only. The high percentage of drowsiness during the postoperative period might be related to the use of promethazine, which is a phenothiazine antihistamine with anti-emetic and sedative properties. The duration of promethazine can be up to 12 h which presents a problem for short day case procedures, such as TUGOR, which has only a 1020 min duration (Trout et al., 1998). Other choices of anxiolytic premedication such as midazolam may be more useful in alleviating anxiety before short day surgical procedures and inducing sedation without causing moderate/severe drowsiness in the postoperative period (Lindahl, 1990
; Kuganeswaran et al., 1999
).
Although both groups gave similar satisfaction scores regarding pain control, four (8%) patients in the placebo group considered the pain control in the retrieval as being unsatisfactory. As shown in our previous study (Ng et al., 2001), patients who indicated fair/unsatisfactory grades in the satisfaction scale had significantly higher vaginal and abdominal pain levels during TUGOR than those who indicated excellent/satisfactory grades. Patients who were not satisfied with the pain control in this attempt might experience a higher preoperative anxiety level and more pain in the next attempt, creating a vicious cycle.
In conclusion, this randomized double-blinded study demonstrated that anxiolytic premedication prevented an increase of preoperative anxiety level and reduced pain levels during oocyte retrieval. Routine use of anxiolytic premedication was associated with a higher percentage of moderate/severe drowsiness in the postoperative period, which might be related to different choices of drugs. Patients should be fully counselled about the advantages and disadvantages of routine anxiolytic premedication prior to receiving this medication. Further studies should be performed to find out the best drug or combination of drugs and to define the appropriate dose for anxiolytic premedication.
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Notes |
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References |
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Submitted on October 18, 2001; accepted on January 7, 2002.