Fractional curettage is a common procedure for investigating causes of abnormal uterine bleeding in perimenopausal women in developing countries. Fractional curettage is usually performed under a local anesthesia, paracervical block, which has been used for minor gynecologic procedures since 1925.1 The paracervical block is shown to be effective for pain reduction during fractional curettage, but the pain intensity under paracervical block is still considered moderate pain.2,3 The reason that paracervical block cannot totally alleviate the pain during fractional curettage can be partly explained by the neuroanatomy of the uterus and cervix.4,5 The paracervical block relieves pain in the lower part of the uterus and cervix by blocking nerve impulses that are conveyed through the uterovaginal plexus, but it may not be effective for pain in the upper part of the uterus, which has a different innervation. Intrauterine anesthesia, by infusion of local anesthesia into the uterine cavity, has theoretical action by blocking nerve endings in the uterine corpus and fundus. The effectiveness of intrauterine anesthesia for pain relief in gynecologic procedures that involve the uterine cavity has been demonstrated in many studies.6–9 It is logical to add intrauterine anesthesia to the paracervical block to enhance the anesthetic effect.
The main objective of the present study was to compare the effectiveness of the paracervical block plus intrauterine anesthesia with the paracervical block alone for the reduction of a maximum pain score during fractional curettage. Moreover, other outcomes, including pain profile during fractional curettage, number of patients with pain score more than 4 cm, patients' global satisfaction, types and incidence of adverse events, and serum lidocaine profile were also reported.
MATERIALS AND METHODS
A double-blinded, randomized, placebo-controlled trial was carried out in the Obstetrics and Gynecology Department, Faculty of Medicine, Siriraj Hospital, Mahidol University, Thailand. The study was conducted in accordance with the ethical principles stated in the most recent version of the Declaration of Helsinki and was approved by institutional review board of the faculty.
The study population consisted of women with abnormal uterine bleeding who were scheduled for fractional curettage, excluding patients who were virgins or those who had the American Society of Anesthesiologists (ASA) physical status class more than II, genital organ infection, profuse uterine bleeding, a history of lidocaine hypersensitivity, a history of impaired liver function, pregnant, or unable to understand how to score a 10-cm visual analog scale (VAS) pain score. Eligible patients were informed about the study protocol and invited to participate in the study without coercion. A signed informed consent was obtained before taking demographic data.
Patients were allocated to either control or experimental groups by simple randomization. An investigator who was not involved with the recruitment produced experiment codes using a computer-generated list of random numbers. The codes were individually contained in a sealed opaque envelope, which was sequentially numbered. An independent nurse who had no contact with the participants opened the envelope and prepared the trial medications accordingly.
The trial medication was intrauterine anesthesia, either 5-mL 0.9% saline for the control group or 5-mL 2% lidocaine (Xylocaine, AstraZeneca, Bangkok, Thailand) for the experimental group. The trial medications were identical in physical appearance (ie, a clear colorless solution) and were contained in identical 10-mL disposable syringes without labeling. Therefore, the gynecologist who performed fractional curettage, the nurse who monitored the patients, and the patients were blinded to the experiment. The administration of anesthesia and fractional curettage was performed by the same gynecologist (M.R.) to minimize risk and technical variation.
The operative procedures were performed under the aseptic technique as described in the following. The patient was placed in a modified lithotomy position. Pulse, blood pressure, and oxygen saturation (SpO2) were continuously monitored using Life Scope, model OPV-1500K (Nikon Kohden Corporation, Tokyo, Japan). A heparin lock using a 20-gauge venous catheter was inserted into a superficial vein of the nondominant hand for drawing blood samples and for safety purposes. The paracervical block technique was modified from previous reports.2 Briefly, 5 mL of 1% lidocaine with 1:100,000 epinephrine was injected through a 23-gauge spinal needle at the 3 and 9 o'clock positions of the cervicovaginal reflection at approximately 1 cm depth. The intrauterine anesthesia was provided immediately after the paracervical block. The trial medication was gently instilled into the uterine cavity through a 2-inch, 18-gauge venous catheter inserted through the cervical canal until its hub plugged into the cervical os. The catheter was left in that position for 3 minutes to prevent a back flow of the instilled solution and to allow 3-minute contact time. The fractional curettage was accomplished through the following steps: The anterior lip of the cervix was grasped with a single-toothed tenaculum; the endocervical curettage was performed using a Sims curette no. 00 (5 mm in the greatest diameter); the cervix was dilated to Hegar no. 5 if necessary; the uterine depth was measured using a sound device; and then the uterine curettage was performed using the same curette. The patients were observed for 60 minutes in a recovery room. Pulse, blood pressure, and SpO2 were continuously monitored and manually recorded immediately after the insertion of the retractor, the paracervical block, the intrauterine anesthesia, the endocervical curettage, the uterine curettage, and at 15, 30, and 60 minutes postoperation. All possible adverse effects were observed and recorded until the patients were discharged. Follow-up appointments were scheduled 14 days after the operation.
The primary outcome was a maximum pain score assessed by 10-cm VAS. The pain score was measured immediately after the insertion of the retractor, the endocervical curettage, the uterine curettage, and at 15, 30, and 60 minutes postoperation. In case the patient had intolerable pain, the procedure was terminated immediately, and the pain score was recorded. A rescue analgesic medication (intravenous fentanyl 1–2 μg/kg) was provided at the patient's request. The secondary outcomes included the number of patients who had a maximum pain score more than 4, the requirement of rescue medication, the success rate of fractional curettage, each patient's global satisfaction index, the preferred anesthesia for future fractional curettage, and the immediate and delayed adverse events. Venous blood samples were taken before and at 15, 30, and 60 minutes after the paracervical block. Serum was separated and frozen at –20°C until assayed for a serum lidocaine concentration using a high-performance liquid chromatography under a technique previously reported.10
Sample size was calculated with the formula for comparing means of 2 independent populations under the following conditions: type I error = 0.05 (2-sided), type II error = 0.1 (power= 90%), meaningful difference between the control and experimental groups in the maximum pain score assessed by 10-cm VAS = 2 cm,11 standard deviation of 10-cm VAS pain score in Thai patients undergoing fractional curettage under paracervical block = 2.4 cm,3 and with the assumption of equal variance. The sample size in each group was 31 cases. Statistical analyses were performed with SPSS 11.0 for Windows (SPSS Inc, Chicago, IL).
Analyses of the efficacy outcomes were based on both intent-to-treat and per-protocol population. All tests of hypotheses were conducted at the 2-sided and 0.05 level of significance. Continuous data were tested for normality using histogram, normal Q-Q plot, and Kolmogorov-Smirnov test. Because the pain score was not normally distributed, the Mann-Whitney U test and the Freidman nonparametric 2-way analysis of variance12 were used to examine the differences between the study groups in the maximum pain score and the pain profile, respectively. The Student t test and the χ2 test (or Fisher exact test, as appropriate) were used to analyze continuous and categorical data, respectively. The repeated-measures analysis of variance was used to analyze profiles of pulse, blood pressure, and SpO2.
The number needed to treat and its 95% confidence interval (CI) were calculated based on the absolute risk reduction (ARR): NNT = 1/ARR; whereas the absolute risk reduction was the reduction in the proportion of the patients who had a pain score greater than 4 in the experimental group compared with that in the control group. The number needed to treat was calculated from a secondary outcome, because the proportion of the patients with a pain score greater than 4 had clinical importance in that the patients should be treated.13
Patients were recruited from April to October 2003. Seventy eligible patients were enrolled (Fig. 1); 4 patients were excluded according to the exclusion criteria (3 cases due to profuse uterine bleeding, and 1 case due to pyometra). Therefore, 33 patients were allocated to each group. There were another 2 patients, one in each group, who were both excluded due to spillage of the anesthetic agent during paracervical block, and which led to receiving an extra dose of lidocaine. As a result, these 2 patients were not treated according to the protocol, and their pain was unable to be evaluated in the same fashion as the other patients. These 2 patients were excluded from the per-protocol analysis but included in the intent-to-treat analysis using median, minimum and maximum imputation of pain scores.
The two groups were comparable in age, body mass index, education, socioeconomic status, menopausal status, parity, uterine depth, and pathological diagnosis (Table 1). The experimental group had more cases with a history of prior curettage and more procedures needing cervical dilation than the control group.
The intent-to-treat analysis using median imputation (Table 2) demonstrated that the median value of the maximum pain score was significantly lower in the experimental group than in the control group (2.3 versus 4.7 cm, P = .022). The proportion of patients with a pain score greater than 4 cm was significantly lower in the experimental group than in the control group (33.3% versus 60.6%, P = .026). The absolute risk reduction was 27.3% (95% CI 2.6–41.5%) and the number needed to treat was 3.7 (95% CI 2.4–38.5). The intent-to-treat analyses using maximum and minimum imputations and the per-protocol analysis also gave results similar to the above outcomes. The pain profile during the procedure (Fig. 2) demonstrated that the experimental group had statistically significantly less pain (P = .035), especially at the endocervical curettage and the uterine curettage steps (P = .005 and 0.021, respectively). There was no difference between the 2 groups in the success rate of fractional curettage, the patients' global satisfaction index, and the preferred anesthesia for future fractional curettage (Table 2). None of the patients requested termination of fractional curettage or the rescue medication. The per-protocol analysis of the secondary outcomes demonstrated similar results.
Safety monitoring during the procedure (Fig. 3) showed no difference between the 2 groups in the profiles of pulse rate (P = .201), mean arterial blood pressure (MAP; P = .954), and oxygen saturation (SpO2; P = .452). The pulse rate and MAP slightly increased during administration of the anesthesia and then decreased to lower than the baseline. None of the patients had a pulse rate less than 60 beats per minute (bpm) or MAP less than 70 mm Hg. The SpO2 during the operation and the postoperative period did not change from the baseline. The types and incidences of immediate or delayed adverse events were similar in both groups (Table 2).
The serum lidocaine level was not different between the 2 groups at any time point (Fig. 4). The majority of patients had lidocaine concentration less than 3 μg/mL at 15 minutes after paracervical block. Of note, more than 50% of the blood samples had a lidocaine concentration less than the detectable level of 1 μg/mL. The highest lidocaine level, which was 4.99 μg/mL, was found in a control group case.
Previous studies reported either a positive or null effect of intrauterine anesthesia for pain relief during various gynecologic procedures. Intrauterine anesthesia seems to be effective in postmenopausal women and with procedures using small-diameter flexible instruments,6–9 but it is not effective in procedures using large-diameter rigid instruments.14–18 It is possible that the cervical pain caused by the latter instruments masks the anesthetic effect of the intrauterine anesthesia. Therefore, in the present study, the blocking of pain at both the cervix and the corpus could demonstrate overall pain relief during the fractional curettage. The effect had both statistical significance and clinical importance as shown by the significant reduction in the proportion of patients who had a pain score greater than 4. The positive effect of the intrauterine anesthesia was present even though the experimental group was confounded with factors that had negative impacts on the results (ie, more patients with history of prior uterine curettage and more procedures needing cervical dilation).
The addition of intrauterine anesthesia enhanced the anesthetic effects of a paracervical block without increasing the incidence of adverse effects. In the present study, adverse effects occurred in fewer than 30% of the patients. All of the adverse effects were mild and resolved within a few minutes. The most common adverse effect found in the present study was cardiovascular stimulation, including palpitations and an increase in blood pressure. These adverse effects were not typical of lidocaine, which usually causes bradycardia and hypotension.19,20 The cardiovascular stimulation in the present study would be the adverse effect of epinephrine supplemented in the lidocaine solution for paracervical block to slow the absorption rate and to reduce the toxic effects of lidocaine. In spite of these benefits, the anesthetic agents with epinephrine should not be used in the patients with cardiovascular risks.
In the present study the dosage of lidocaine in the control group was 100 mg. The highest blood level was 4.99 μg/mL, which was less than the toxic level of 8.7 μg/mL.21 The addition of 100 mg lidocaine intrauterinely did not affect the maximum blood level, implying that the systemic absorption of the intrauterine lidocaine was at a negligible level. The findings were different from those reported by Edelman et al,17 who demonstrated that the intrauterine lidocaine significantly increased serum lidocaine levels during the termination of a first-trimester pregnancy. It was possible that intrauterine absorption in patients with abnormal uterine bleeding was much lower than that in pregnant women. Moreover, the paracervical block using lidocaine supplemented with epinephrine might constrict the blood vessels around the uterus. As a consequence, the intrauterine absorption was further reduced.
The incremental cost incurred from the intrauterine anesthesia in the present study was approximately 3 U.S. dollars. The cost was calculated from charges for one vial of 2% lidocaine, a disposable syringe, a venous catheter, and a drawing needle. Although charge is not equal to acquisition cost, the 2 numbers would be nearly equal in a nonprofit hospital. The incremental cost calculated via this means would add approximately 10% to the total expense that the patient had to pay for the fractional curettage at Siriraj Hospital. Because the number needed to treat was approximately 4, an incremental medical care cost to prevent a case with a pain score greater than 4 was 12 U.S. dollars.
In conclusion, the combination of paracervical block and intrauterine anesthesia is more effective than paracervical block alone in the reduction of maximum pain during fractional curettage. The addition of intrauterine anesthesia does not increase the adverse effects of paracervical block. Although the addition of intrauterine anesthesia, using 2% lidocaine, seemed not to increase the adverse effects over those of paracervical block alone, it would be safer if the total dose of lidocaine could be reduced. Therefore, further study to evaluate the effectiveness of intrauterine anesthesia, using a lower dose of lidocaine (either a lower concentration or less volume) or another technique of paracervical block (eg, Glick technique) is recommended.
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