Use of Flurbiprofen ester in 4-dimensional hysterosalpingography : could it effectively relieve pain during infertility examination?

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Long Tan, Shi-ji Wu, Ai-lin Ma, Shi-mei Li, Shang-lan Zhou, Shen Zhang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2875202/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective The purpose of this article is to investigate the analgesic effect of flurbiprofen ester injection continuous intravenous drip in transvaginal 4-dimensional hysterosalpingography (TVS 4D-HyCoSy). Methods Two hundred thirty patients who underwent TVS 4D-HyCoSy for infertility from May 2018 to August 2021 at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, were selected. They were grouped according to tubal patency, flurbiprofen ester use, and uterine cannula diameter, i.e., bilateral tubal patency group and nonbilateral tubal patency group, atropine group and atropine + flurbiprofen ester group, and coarse tube group and fine tube group, to compare the analgesic effect during TVS 4D-HyCoSy, pain relief effect between groups, record the incidence of adverse effects, and analyze the factors related to the influence of pain. Results 1. The atropine + flurbiprofen ester group had significantly fewer adverse effects in the former patients compared with the atropine group; 2. Flurbiprofen ester continuous intravenous infusion was effective for analgesia after ultrasound tubal contrast. Flurbiprofen ester continuous intravenous infusion was effective in relieving pain within 30 minutes after imaging regardless of the patency of the fallopian tubes; 3. The addition of flurbiprofen ester significantly relieved pain in the fine tube group in those with bilateral patency of the fallopian tubes and in the thick tube group and fine tube group in those with nonbilateral patency of the fallopian tubes; 4. Multifactorial analysis of pain relief during imaging suggested that the use of flurbiprofen for bilateral tubal patency had a significant positive effect on pain relief within 30 minutes after the examination, AUC 0.732; 95% CI: 0.665-0.798. Conclusion Bilateral tubal patency and flurbiprofen will have a significant positive effect on pain relief. The analgesic effect of flurbiprofen ester injection with continuous drip started before TVS 4D-HyCoSy was good, and the pain relief effect was significant within 30 minutes after examination with few adverse effects, which is worthy of clinical promotion. Analgesia Atropine Flurbiprofen ester 4-dimensional hysterosalpingography Figures Figure 1 Figure 2 Figure 3 Introduction In recent years, the declining fertility rate has become a widespread concern in Chinese society, and the proportion of infertility among women of childbearing age in China is increasing year by year, among which tubal factors are the primary cause of female infertility, accounting for 30%-35% [1-2]. Transvaginal hysterosalpingo-contrast sonography (TVS 4D-HyCoSy), which can dynamically display the size and shape of the uterine cavity and check the patency of the fallopian tubes in real time, has been widely used for fertility assessment in infertile women. Our team started to work on the research and clinical application of HyCoSy in 2010 and found that HyCoSy has high specificity and sensitivity (86.3% specificity and 93.5% sensitivity) for the diagnosis of tubal patency [3]. Relevant domestic and international studies have also confirmed the high specificity and sensitivity of HyCoSy for tubal and uterine cavity assessment [4-10]. However, during TVS 4D-HyCoSy intubation and contrast operation, patients often experience pain, vomiting and other adverse effects, especially pain that can cause tubal spasm, resulting in a higher false positive rate and lower accuracy [11]. Atropine is the currently applied antispasmodic drug and is often used by intramuscular injection 30 minutes before imaging, but studies have found that the effect of atropine in dilating the cervical canal is weak and the analgesic effect is not obvious [12]. Flurbiprofen ester belongs to a new type of NSAID, mainly consisting of flurbiprofen and its encapsulated lipid microspheres, which is targeted compared with other NSAIDs and has been widely used for postsurgical analgesia [13], but no studies related to its application to TVS 4D-HyCoSy have been reported. Therefore, this study was proposed to investigate the analgesic effect of flurbiprofen ester injection continuous drip in TVS 4D-HyCoSy. 1 Information and Methods 1.1 General Information Two hundred thirty patients proposed for TVS 4D-HyCoSy for infertility from May 2018 to August 2021 at our hospital were selected and grouped according to tubal patency, use of flurbiprofen ester, and uterine cannula diameter, i.e., bilateral tubal patency group (Figure 1) and nonbilateral tubal patency group(Figure 2), atropine group versus atropine + flurbiprofen ester group, and coarse tube group and fine tube group. General statistics were based on tubal patency, i.e., bilateral tubal patency group (139 cases) and nonbilateral tubal patency (91 cases). General data such as age, years of infertility, history of dysmenorrhea, endometrial thickness at the time of examination, and tube diameter using a uterine cannula were compared between the two groups. The study was approved by the medical ethics committee of our hospital, and informed consent was obtained from the patients. 1.2 Inclusion and exclusion criteria Inclusion criteria. ① Sexually normal women who have a desire to have children without using contraception and are not pregnant. ② after treatment of tubal pregnancy. ③ Those who understood the method of this study and signed the informed consent form. Exclusion criteria. ① Patients with peptic ulcers. ② patients with severe hepatic, renal and hematologic dysfunction. ③ patients with severe heart failure and hypertension. ④ Patients with a history of allergy to flurbiprofen ester, atropine or contrast agent components. ⑤ Patients with aspirin asthma or a prior history of it. ⑥ Patients who are using Eloxacin, Lomefloxacin, Norfloxacin. 1.3 Methodology 1.3.1 Preoperative preparation Before the examination, a detailed medical history was taken, gynecological examination, routine leucorrhoea and STD examination were performed, and the patient was instructed to abstain from sexual intercourse after menstruation during the examination cycle. The examination should be performed 5-10 d after menstruation or at the latest 20 days after menstruation if the patient has a long menstrual cycle. The urine and stool were emptied before the examination. In the atropine group, 0.5 mg of atropine sulfate (Henan Runhong Pharmaceutical Co., Ltd., production batch number: 20180711) was given intramuscularly 30 min before TVS 4D-HyCoSy; in the combined atropine + flurbiprofen ester group, 0.5 mg of atropine sulfate (as above) was given intramuscularly 30 min before TVS 4D-HyCoSy, and 20 mg of flurbiprofen ester was started 10 min before contrast cannulation. Flurbiprofen ester (Hubei Noon Pharmaceutical Co., Ltd., production lot number: 3E171H) was added to 100 ml saline for continuous intravenous infusion. 1.3.2 Inspection method After moderate filling of the patient's bladder, the bladder was placed in the cystotomy position, disinfected and toweled. A coarse-tube 12-gauge Foley catheter was placed, while 2 ml of 0.9% sodium chloride solution was injected into the balloon to occlude the endocervical opening. The balloon size was adjusted according to the patient's height and uterine size to determine the passage tube to the endocervical opening without detachment. Or 1.5 ml of 0.9% sodium chloride solution with fine COOK hysterosalpingography tube parameters (for those with no history of pregnancy and no history of hysterosalpingation). The contrast agent was selected from SonoVue (BRACCO), and 5 mL of 0.9% NaCl solution was added to form a suspension. Two milliliters of the suspension was removed, and 18 mL of 0.9% NaCl solution was added to dilute the contrast agent. Bilateral fallopian tubes and pelvic contrast coating were observed dynamically to assess the patency of the fallopian tubes. If the first imaging of the fallopian tubes was poor or suggested possible obstruction, a second tubal imaging was performed after the lavage treatment. Adverse reactions such as pain, dizziness, and allergy were also recorded in patients. 1.4 Observed indicators and assessment methods (1) To observe the patency of the uterine tubes in both groups. Tubal patency is divided into bilateral patency and nonbilateral patency (obstruction of one or both tubes). (2) Pain level scoring criteria The imaging procedure was divided into three stages: during the placement of the scrotal speculum and the placement of the balloon catheter (T1), during the injection of contrast medium/throughput (T2) and within 30 min after extubation (T3). Pain was assessed, observed and recorded as felt by the patients. The pain level was evaluated by visual analog scoring (NRS) by patients according to the pain level, with a score of 0-10 representing no pain to severe pain, with higher scores being more severe: 0 (no pain), 1-3 (mild pain), 4-6 (moderate pain), 7-10 (severe pain); pain relief was defined as relief of pain level after the examination compared with that at the time of examination (T3→T2), i.e., severe or moderate pain is reduced to mild pain or no pain. ② Adverse reactions during intubation and examination were recorded, including allergy, dizziness, nausea, vomiting, limb numbness, palpitations, etc. 1.5 Statistical methods SPSS 26.0 statistical software was used for data analysis, and the measurement data conforming to a normal distribution were expressed as the mean ± standard deviation (` x±s). A t test was used for comparisons between two groups. The count data were expressed as c ² test was used for comparisons between groups. The difference was considered statistically significant at P < 0.05, and logistic regression analysis was used for multifactorial analysis. 2 Results 2.1. Comparison of general information There were 139 cases in the bilateral tubal patency group, age 21-43 years, mean age 31.68±4.60 years, mean years of infertility 2.08±1.67 years, mean thickness of the endometrium at the time of examination 7.49±1.89 mm; 91 cases in the nonbilateral tubal patency group, age 23-43 years, mean age 32.99±4.91 years, mean years of infertility 2.94±2.81 years, and using t test, there was a statistically significant difference in age and years of infertility between the two groups (P=0.042, 0.009) and no statistically significant difference in endometrial thickness (P=0.221). In the bilateral tubal patency group, 65.5% (90/139) had dysmenorrhea, and 74.1% (103/139) used a coarse tube; in the nontubal patency group, 64.8% (59/91) had dysmenorrhea, and 69.2% (63/91) used a coarse tube. Using the c ² test, there was no statistically significant difference in the history of dysmenorrhea or the thickness of the intubated tube between the two groups (P=0.922, 0.420). 2.2 Comparison of the incidence of adverse reactions Among the 78 patients in the atropine group, there were 21 cases of nausea and dizziness, 12 cases of facial flushing, 3 cases of blurred vision, and 2 cases of numbness in the limbs, with an adverse reaction rate of 48.71%; 6 cases of nausea occurred among 152 patients in the atropine + flurbiprofen ester group, with an adverse reaction rate of 3.9%. The incidence of adverse reactions in the atropine + flurbiprofen ester group was lower than that in the atropine group, and the difference was statistically significant (P=0.000). 2.3 Comparison of analgesic effects during TVS 4D-HyCoSy The comparison of pain levels regarding the tubal imaging procedure in the bilateral tubal patency versus nonbilateral tubal patency groups, with atropine alone versus the combination of atropine + flurbiprofen ester, is shown in Table 1. Table 1. Comparison of pain levels during tubal imaging Pain assessment period Pain grading Grouping Percentage of moderate-to-severe pain (%) P During intubation II-III degree Bilateral patency of the fallopian tubes 54.7 (76/139) 0.303 Non-bilateral patent fallopian tubes 61.5 (56/91) Atropine 56.4 (44/78) 0.829 Atropine + flurbiprofen ester 57.9 (88/152) During inspection II-III degree Bilateral patency of the fallopian tubes 39.6 (55/139) 0.000 Non-bilateral patency of the fallopian tubes 68.1 (62/91) Atropine 50.0 (39/78) 1.000 Atropine + flurbiprofen ester 50.0 (76/152) After inspection II-III degree Bilateral patency of the fallopian tubes 12.9 (18/139) 0.847 Non-bilateral patency of the fallopian tubes 12.1 (11/91) Atropine 21.8 (17/78) 0.003 Atropine + flurbiprofen ester 7.9 (12/152) 2.4 Comparison of pain relief between groups (1) Pain relief in the atropine versus atropine + flurbiprofen ester groups is compared in Table 2. Table 2. Comparison of pain relief between atropine and atropine + flurbiprofen ester in tubal imaging Projects Grouping Number of cases Relief No relief P Bilateral tubal patency group (N1 = 139 cases) Atropine 29 17 12 0.001 Atropine + flurbiprofen ester 62 58 4 Non-bilateral tubal patency group (N2 = 91 cases) Atropine 49 22 29 0.001 Atropine + flurbiprofen ester 90 63 27 2. In those with bilateral patent fallopian tubes, flurbiprofen ester use was compared in the thick tube group with pain relief in the thin tube group in Table 3. Table 3. Comparison of pain relief between the thick tube and thin tube groups in bilaterally patent fallopian tubes Grouping Coarse tube Fine tube No relief Relief No relief Relief Atropine 25 15 2 7 Atropine + flurbiprofen ester 21 42 6 21 P 0.278 0.001 3. In nonbilateral tubal patency, flurbiprofen use was compared with pain relief in the thick-tube group versus the thin-tube group, as shown in Table 4. Table 4. Comparison of pain relief in thick and thin tubes in the non-bilateral tubal patency group Grouping Coarse tube Fine tube No relief Relief No relief Relief Atropine 8 14 4 3 Atropine + flurbiprofen ester 4 37 0 21 P 0.000 0.000 2.5 Multifactor logistic regression analysis for pain relief during tubal angiography Patient age, years of infertility, history of dysmenorrhea, endometrial thickness, tube diameter of insertion, tubal patency, and flurbiprofen continuous drip were analyzed for pain relief correlation, and the statistically significant (p < 0.05) univariate indicators containing flurbiprofen continuous drip, thick tube, and bilateral tubal patency as independent variables and pain relief as the dependent variable were analyzed by binary logistic regression. The results suggested that flurbiprofen continuous drip and bilateral tubal patency had a significant positive relationship with pain relief, while tube diameter did not significantly affect pain relief (Table 5), and the ROC curve AUC of this model was 0.732 (95% CI: 0.665-0.798)（Figure 3）. Table 5. Multi-factor logistic regression analysis of pain relief during tubal angiography Variables B Standard Error Wald P OR (95% CI) Coarse tube (vs. fine tube) -0.703 0.381 3.395 0.065 0.495 (0.235-1.046) Bilateral tubal patency (vs. non-bilateral tubal patency) 1.134 0.345 10.824 0.001 3.107 (1.581-6.103) Flurbiprofen esters (vs. flurbiprofen-free) 1.356 0.317 18.277 0.000 3.881 (2.084-7.226) 3 Discussions The main clinical methods to determine tubal patency include laparoscopic fluid staining, X-HSG and TVS 4D-HyCoSy, which have their own advantages and disadvantages. Laparoscopic fluid staining, which is the "gold standard", is an invasive test [14] and has disadvantages such as high invasiveness, high cost and anesthesia risk, so it is usually used as a second-line verification or treatment after confirming obstruction by HSG. There may be a risk of iodine allergy. Hysterosalpingography (HyCoSy) is an ultrasound examination of the uterus and fallopian tubes to assess tubal patency with a transcervical contrast agent (air saline or microbubble contrast) [15]. According to several scholars, HyCoSy has been found to have a therapeutic role in addition to showing high accuracy in evaluating tubal patency [16,17]. However, patients often exhibit varying degrees of pain and discomfort during a series of operations during HyCoSy examination, mainly in the form of adverse reactions such as dizziness, nausea, vomiting and even shock that patients may experience. According to the literature, pain during tubal imaging often causes tubal spasm, leading to an increased rate of false-positive test results [11]. Therefore, how to alleviate pain during and after the examination has become a focus of concern for clinicians and patients. Possible causes of pain from HyCoSy include psychological tension, excessive speed of contrast pushing, size of the contrast catheter balloon, and the patient's own diseases, such as uterine adhesions, cervical stenosis, and inflammation [18], while most pain levels actually occur as a result of a combination of these factors. It has been suggested that HyCoSy triggers the most intense pain with cervical dilation [19]. In contrast, Guzel et al. concluded that the most intense pain was caused by increased pressure in the uterine cavity during contrast injection [20]. Our study found that preoperative injection of atropine was not effective in relieving patients' pain, which is consistent with the literature [21] . Flurbiprofen ester has been widely used in surgical procedures, such as brain surgery, upper abdominal surgery, and gynecological surgery, and significant analgesic effects have been achieved [13,22-23]. In the present study, we tried to introduce flurbiprofen ester continuous drip into uterine tubal ultrasonography. Flurbiprofen ester is a nonsteroidal analgesic with significant analgesic effects for various types of pain and targeted effects on inflammation and surgical sites [21,23]. After entering the site of action through the carrier lipid microspheres, flurbiprofen ester is released by the carrier and rapidly hydrolyzed by the action of carboxyl lipase to produce flurbiprofen, which has a significant inhibitory effect on prostaglandin synthesis, which in turn produces analgesic effects. The drug has a high safety factor, rapid onset of action and long-lasting analgesic effect [21,24]. In this study, we found that the addition of flurbiprofen ester continuous intravenous drip to the routine preoperative injection of atropine had a certain effect on analgesia during ultrasound tubography, which was mainly reflected after the examination (P = 0.003), and it was not significant for analgesia during intubation and examination, probably because 1. during TVS 4D-HyCoSy, the pain during intubation and examination operation was the most, 2. the high level of patient tension during intubation and examination operations, as well as pain-inducing factors such as cervical dilation and increased pressure in the uterine cavity during contrast injection. 3. After the examination, the catheter was removed, the patient's tension was relaxed, and flurbiprofen ester was more likely to play an objective role. We also found that at the time of examination, patency of the fallopian tube had a significant positive significance for analgesia (P = 0.000), and at the time of catheterization and after examination, patency of the fallopian tube had no significant effect on analgesia, which suggests that patency of the fallopian tube may be one of the main causes of pain during HyCoSy. Flurbiprofen ester under continuous intravenous drip conditions was effective in relieving pain within 30 minutes after imaging, regardless of the patency of the fallopian tube. In conclusion, the patency of the fallopian tube affects pain during the examination, and flurbiprofen ester continuous intravenous infusion is effective in relieving pain. During HyCoSy, flurbiprofen ester continuous intravenous infusion had a significant positive effect on pain relief during ultrasound tubography. Although the addition of flurbiprofen ester was not significant for pain relief during uterine tubal ultrasonography in those with bilateral patent tubes and thick tubes, the addition of flurbiprofen ester was significant for pain relief within 30 minutes after ultrasonography in those with bilateral patent tubes and thin tubes and in those with nonbilateral patent tubes for possible reasons, including because the effect of the catheter on pain disappeared after removal of the tube. Second, women with thick tubes, all of whom had been pregnant or delivered and had a history of hysterectomy, may be less nervous and more tolerant of pain. Third, those with bilateral patent fallopian tubes and with thin tubes, who had no history of pregnancy and no history of hysterectomy, may be more nervous and less tolerant of pain. In addition, we found by multifactorial binary logistic regression analysis that the pain relief rate within 30 minutes after surgery in those with bilateral patent tubes was 3.107 times higher than that in those with nonbilateral patent tubes, and the pain relief rate within 30 minutes after surgery in those with flurbiprofen was 3.881 times higher than that in those with atropine alone, which further indicated that flurbiprofen ester could effectively relieve patients' pain. Moreover, our study also found that the incidence of adverse reactions (excluding pain and dry mouth) was significantly lower in the flurbiprofen ester group than in the atropine alone group, and it also relieved the psychological burden of the patients during the imaging process to some extent. In conclusion, flurbiprofen ester continuous drip has a good analgesic effect in patients with TVS 4D-HyCoSy; in particular, the pain relief effect after examination is significant, and it can reduce the incidence of adverse reactions in contrast examination to a certain extent, which is worthy of clinical promotion and application. Declarations Acknowledgements We would like to thank the researchers of the included studies and the participants for their contributions. Author contributions All authors contributed to the design and implementation of the study. LT and SJW: writing—original draft, collected and analyzed data; ALM and SML: writing—review and editing, collected and analyzed data; SLZ: writing—review and editing; SZ and PXC: supervision, writing—review and editing; ND and BML: conceptualization, supervision, writing—review and editing. All authors read and approved the final manuscript. Funding This work was supported in part by National Natural Science Foundation of China (Grant No.82060320 and No.82260348) and the Natural Science Foundation of Xinjiang Uygur Autonomous Region (Grant No.2021D01C009) Availability of data and materials The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Dr. Na Di, e-mail address: [email protected] Ethics approval and consent to participate This study was approved by the Ethics Committee of the Sun Yat-sen Memorial Hospital of Sun Yat-sen University (SYSKY-2022-479-01). Consent for publication Not applicable. Competing interests The authors declare no competing interests. Author details 1 Department of Ultrasound, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang Road West, Guangzhou 510120, China. 2 Department of Ultrasound, the First People’s Hospital of Kashi Prefectrue, No. 120 Yingbin Avenue, Kashi ,Xinjiang 844000, China. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2875202","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":198038011,"identity":"c785668a-2d5e-4d72-83f5-183525102415","order_by":0,"name":"Long Tan","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Long","middleName":"","lastName":"Tan","suffix":""},{"id":198038012,"identity":"f83c3888-bd67-4603-ac37-b27fe44f24b6","order_by":1,"name":"Shi-ji Wu","email":"","orcid":"","institution":"the First People’s Hospital of Kashi Prefectrue","correspondingAuthor":false,"prefix":"","firstName":"Shi-ji","middleName":"","lastName":"Wu","suffix":""},{"id":198038013,"identity":"f69eeee6-7359-44e7-8250-efec1b2755d1","order_by":2,"name":"Ai-lin Ma","email":"","orcid":"","institution":"the First People’s Hospital of Kashi Prefectrue","correspondingAuthor":false,"prefix":"","firstName":"Ai-lin","middleName":"","lastName":"Ma","suffix":""},{"id":198038014,"identity":"85de59f6-806b-4f70-9691-f0299ebde8a0","order_by":3,"name":"Shi-mei Li","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shi-mei","middleName":"","lastName":"Li","suffix":""},{"id":198038015,"identity":"53b7b220-d6fa-46f6-ab5d-a8d28af5a4a1","order_by":4,"name":"Shang-lan Zhou","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shang-lan","middleName":"","lastName":"Zhou","suffix":""},{"id":198038016,"identity":"060b87e1-557f-4e9f-bbe9-0b16c9ac1668","order_by":5,"name":"Shen Zhang","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shen","middleName":"","lastName":"Zhang","suffix":""},{"id":198038017,"identity":"1c0e13ee-126a-4eff-b803-cec0c8c9c4e0","order_by":6,"name":"Pei-xin Chen","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pei-xin","middleName":"","lastName":"Chen","suffix":""},{"id":198038018,"identity":"df706b54-6d4a-4428-8ee6-e918acf698dd","order_by":7,"name":"Bao-ming Luo","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bao-ming","middleName":"","lastName":"Luo","suffix":""},{"id":198038019,"identity":"4f655c40-eb64-4d5c-9ede-cf5c892159ae","order_by":8,"name":"Na Di","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYDCCwwwMjB8qGBjY2OFCCYS1MEucAWphJlrLASDmbQMSRGvhO8578IPkvG3yfMwMzJ95/hxm4GfPMWD4uQO3FsnDfMkShdtuG7YxM7BJ87YdZpDseWPA2HsGtxaDwzwGEpLbbjOCtDDzNhxmMLiRY8DM2IZXi/EP3jm37dtgDrMnQouZBG/D7USgFgZpHjagLRIEtEgCtVhLHLud3AZUJjm3LZ1H4syzgoO9eLTwnT9jfPNDzW3b+e3Nhz+8+WMtx9+evPHBTzxakABjAxMPAwMPiHmAKA1gTT+IVjoKRsEoGAUjCQAA3LZKUs9eTBcAAAAASUVORK5CYII=","orcid":"","institution":"Sun Yat-sen Memorial Hospital","correspondingAuthor":true,"prefix":"","firstName":"Na","middleName":"","lastName":"Di","suffix":""}],"badges":[],"createdAt":"2023-04-29 05:29:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2875202/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2875202/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":36784502,"identity":"59021359-31b5-4e8b-9b9b-8fc8556ab877","added_by":"auto","created_at":"2023-05-10 16:32:56","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":33338,"visible":true,"origin":"","legend":"\u003cp\u003eBilateral tubal patency\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2875202/v1/66e9a6b600ef67254fb9d10d.jpeg"},{"id":36784503,"identity":"9cfb65c2-2fe1-4a4f-a52b-3d6fe6f82d81","added_by":"auto","created_at":"2023-05-10 16:32:56","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":28620,"visible":true,"origin":"","legend":"\u003cp\u003eNonbilateral tubal patency\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2875202/v1/cede74b3b2a0bd81c7695e74.jpeg"},{"id":36784501,"identity":"7441378d-92a4-4f2c-82fc-7cfa5b7ee0f4","added_by":"auto","created_at":"2023-05-10 16:32:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":26760,"visible":true,"origin":"","legend":"\u003cp\u003eFlurbiprofen to relieve tubal angiography pain ROC curve\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-2875202/v1/78266afcc49de3ad2cfd211c.png"},{"id":41213848,"identity":"ab3df9e7-e908-473f-bf5b-bebd9e80bc80","added_by":"auto","created_at":"2023-08-08 03:22:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":304501,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2875202/v1/5a6a2510-b847-4e62-a285-107703d4bdb7.pdf"},{"id":36784608,"identity":"b053efa8-7f39-46e5-a2f9-14e29ebf8b57","added_by":"auto","created_at":"2023-05-10 16:40:56","extension":"docx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":12615,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-2875202/v1/3665b3b01c27d655a8e3d160.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Use of Flurbiprofen ester in 4-dimensional hysterosalpingography : could it effectively relieve pain during infertility examination?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn recent years, the declining fertility rate has become a widespread concern in Chinese society, and the proportion of infertility among women of childbearing age in China is increasing year by year, among which tubal factors are the primary cause of female infertility, accounting for 30%-35% [1-2]. Transvaginal hysterosalpingo-contrast sonography (TVS 4D-HyCoSy), which can dynamically display the size and shape of the uterine cavity and check the patency of the fallopian tubes in real time, has been widely used for fertility assessment in infertile women. Our team started to work on the research and clinical application of HyCoSy in 2010 and found that HyCoSy has high specificity and sensitivity (86.3% specificity and 93.5% sensitivity) for the diagnosis of tubal patency [3]. Relevant domestic and international studies have also confirmed the high specificity and sensitivity of HyCoSy for tubal and uterine cavity assessment [4-10]. However, during TVS 4D-HyCoSy intubation and contrast operation, patients often experience pain, vomiting and other adverse effects, especially pain that can cause tubal spasm, resulting in a higher false positive rate and lower accuracy [11]. Atropine is the currently applied antispasmodic drug and is often used by intramuscular injection 30 minutes before imaging, but studies have found that the effect of atropine in dilating the cervical canal is weak and the analgesic effect is not obvious [12]. Flurbiprofen ester belongs to a new type of NSAID, mainly consisting of flurbiprofen and its encapsulated lipid microspheres, which is targeted compared with other NSAIDs and has been widely used for postsurgical analgesia [13], but no studies related to its application to TVS 4D-HyCoSy have been reported. Therefore, this study was proposed to investigate the analgesic effect of flurbiprofen ester injection continuous drip in TVS 4D-HyCoSy.\u003c/p\u003e"},{"header":"1 Information and Methods","content":"\u003cp\u003e1.1 General Information\u003c/p\u003e\n\u003cp\u003eTwo hundred thirty patients proposed for TVS 4D-HyCoSy for infertility from May 2018 to August 2021 at our hospital were selected and grouped according to tubal patency, use of flurbiprofen ester, and uterine cannula diameter, i.e., bilateral tubal patency group (Figure 1) and nonbilateral tubal patency group(Figure 2), atropine group versus atropine + flurbiprofen ester\u0026nbsp;group, and coarse tube group and fine tube group. General statistics were based on tubal patency, i.e., bilateral tubal patency group (139 cases) and nonbilateral tubal patency (91 cases). General data such as age, years of infertility, history of dysmenorrhea, endometrial thickness at the time of examination, and tube diameter using a uterine cannula were compared between the two groups. The study was approved by the medical ethics committee of our hospital, and informed consent was obtained from the patients.\u003c/p\u003e\n\u003cp\u003e1.2 Inclusion and exclusion criteria\u003c/p\u003e\n\u003cp\u003eInclusion criteria.\u0026nbsp;①\u0026nbsp;Sexually normal women who have a desire to have children without using contraception and are not pregnant.\u0026nbsp;②\u0026nbsp;after treatment of tubal pregnancy.\u0026nbsp;③\u0026nbsp;Those who understood the method of this study and signed the informed consent form.\u003c/p\u003e\n\u003cp\u003eExclusion criteria.\u0026nbsp;①\u0026nbsp;Patients with peptic ulcers.\u0026nbsp;②\u0026nbsp;patients with severe hepatic, renal and hematologic dysfunction.\u0026nbsp;③\u0026nbsp;patients with severe heart failure and hypertension.\u0026nbsp;④\u0026nbsp;Patients with a history of allergy to flurbiprofen ester, atropine or contrast agent components.\u0026nbsp;⑤\u0026nbsp;Patients with aspirin asthma or a prior history of it.\u0026nbsp;⑥\u0026nbsp;Patients who are using Eloxacin, Lomefloxacin, Norfloxacin.\u003c/p\u003e\n\u003cp\u003e1.3 Methodology\u003c/p\u003e\n\u003cp\u003e1.3.1 Preoperative preparation\u003c/p\u003e\n\u003cp\u003eBefore the examination, a detailed medical history was taken, gynecological examination, routine leucorrhoea and STD examination were performed, and the patient was instructed to abstain from sexual intercourse after menstruation during the examination cycle. The examination should be performed 5-10 d after menstruation or at the latest 20 days after menstruation if the patient has a long menstrual cycle. The\u0026nbsp;urine and stool were emptied before the examination. In the atropine group, 0.5 mg of atropine sulfate (Henan Runhong Pharmaceutical Co., Ltd., production batch number: 20180711) was given intramuscularly 30 min before TVS 4D-HyCoSy; in the combined atropine + flurbiprofen ester group, 0.5 mg of atropine sulfate (as above) was given intramuscularly 30 min before TVS 4D-HyCoSy, and 20 mg of flurbiprofen ester was started 10 min before contrast cannulation. Flurbiprofen ester (Hubei Noon Pharmaceutical Co., Ltd., production lot number: 3E171H) was added to 100 ml saline for continuous intravenous infusion.\u003c/p\u003e\n\u003cp\u003e1.3.2 Inspection method\u003c/p\u003e\n\u003cp\u003eAfter moderate filling of the patient\u0026apos;s bladder, the bladder was placed in the cystotomy position, disinfected and toweled. A coarse-tube 12-gauge Foley catheter was placed, while 2 ml of 0.9% sodium chloride solution was\u0026nbsp;injected into the balloon to occlude the\u0026nbsp;endocervical opening. The balloon size was adjusted according to the patient\u0026apos;s height and uterine size to determine the passage tube to the endocervical opening without detachment. Or 1.5 ml of 0.9% sodium chloride solution with fine COOK hysterosalpingography tube parameters (for those with no history of pregnancy and no history of hysterosalpingation). The contrast agent was selected from SonoVue (BRACCO), and 5 mL of 0.9% NaCl solution was added to form a suspension. Two milliliters of the suspension was removed, and 18 mL of 0.9% NaCl solution was added to dilute the contrast agent. Bilateral fallopian tubes and pelvic contrast coating were observed dynamically to assess the patency of the fallopian tubes. If the first imaging of the fallopian tubes was poor or suggested possible obstruction, a second tubal imaging was performed after the lavage treatment. Adverse reactions such as pain, dizziness, and allergy were also recorded in patients.\u003c/p\u003e\n\u003cp\u003e1.4 Observed indicators and assessment methods\u003c/p\u003e\n\u003cp\u003e(1) To observe the patency of the uterine tubes in both groups.\u003c/p\u003e\n\u003cp\u003eTubal patency is divided into bilateral patency and nonbilateral patency (obstruction of one or both tubes).\u003c/p\u003e\n\u003cp\u003e(2) Pain level scoring criteria\u003c/p\u003e\n\u003cp\u003eThe imaging procedure was divided into three stages: during the placement of the scrotal speculum and the placement of the balloon catheter (T1), during the injection of contrast medium/throughput (T2) and within 30 min after extubation (T3). Pain was assessed, observed and recorded as felt by the patients. The pain level was evaluated by visual analog scoring (NRS) by patients according to the pain level, with a score of 0-10 representing no pain to severe pain, with higher scores being more severe: 0 (no pain), 1-3 (mild pain), 4-6 (moderate pain), 7-10 (severe pain); pain relief was defined as relief of pain level after the examination compared with that at the time of examination (T3\u0026rarr;T2), i.e., severe or moderate pain is reduced to mild pain or no pain.\u0026nbsp;②\u0026nbsp;Adverse reactions during intubation and examination were recorded, including allergy, dizziness, nausea, vomiting, limb numbness, palpitations, etc.\u003c/p\u003e\n\u003cp\u003e1.5 Statistical methods\u003c/p\u003e\n\u003cp\u003eSPSS 26.0 statistical software was used for data analysis, and the measurement data conforming to a normal distribution were expressed as the mean \u0026plusmn; standard deviation (`\u0026nbsp;x\u0026plusmn;s). A t test was used for comparisons between two groups. The count data were expressed as\u0026nbsp;\u003cem\u003ec\u003c/em\u003e\u003cem\u003e\u0026sup2;\u0026nbsp;\u003c/em\u003etest \u003cem\u003ewas\u0026nbsp;\u003c/em\u003eused for comparisons between groups. The difference was considered statistically significant at P \u0026lt; 0.05, and \u003cem\u003elogistic\u0026nbsp;\u003c/em\u003eregression analysis was used for multifactorial analysis.\u003c/p\u003e"},{"header":"2 Results","content":"\u003cp\u003e2.1. Comparison of general information\u003c/p\u003e\n\u003cp\u003eThere were 139 cases in the bilateral tubal patency group, age 21-43 years, mean age 31.68\u0026plusmn;4.60 years, mean years of infertility 2.08\u0026plusmn;1.67 years, mean thickness of the endometrium at the time of examination 7.49\u0026plusmn;1.89 mm; 91 cases in the nonbilateral tubal patency group, age 23-43 years, mean age 32.99\u0026plusmn;4.91 years, mean years of infertility 2.94\u0026plusmn;2.81 years, and using t test, there was a statistically significant difference in age and years of infertility between the two groups (P=0.042, 0.009) and\u0026nbsp;no statistically significant difference in endometrial thickness (P=0.221). In the bilateral tubal patency group, 65.5% (90/139) had dysmenorrhea, and 74.1% (103/139) used a coarse tube; in the nontubal patency group, 64.8% (59/91) had dysmenorrhea, and 69.2% (63/91) used a coarse tube. Using \u003cem\u003ethe\u003c/em\u003e\u003cem\u003ec\u003c/em\u003e\u003cem\u003e\u0026sup2; test, there was\u0026nbsp;\u003c/em\u003eno statistically significant difference in the history of dysmenorrhea or the thickness of the intubated tube between the two groups (P=0.922, 0.420).\u003c/p\u003e\n\u003cp\u003e2.2 Comparison of the incidence of adverse reactions\u003c/p\u003e\n\u003cp\u003eAmong the 78 patients in the atropine group, there were 21 cases of nausea and dizziness, 12 cases of facial flushing, 3 cases of blurred vision, and 2 cases of numbness in the limbs, with an adverse reaction rate of 48.71%; 6 cases of nausea occurred among 152 patients in the atropine + flurbiprofen ester group, with an adverse reaction rate of 3.9%. The incidence of adverse reactions in the atropine + flurbiprofen ester group was lower than that in the atropine group, and the difference was statistically significant (P=0.000).\u003c/p\u003e\n\u003cp\u003e2.3 Comparison of analgesic effects during TVS 4D-HyCoSy\u003c/p\u003e\n\u003cp\u003eThe comparison of pain levels regarding the tubal imaging procedure in the bilateral tubal patency versus nonbilateral tubal patency groups, with atropine alone versus the combination of atropine + flurbiprofen ester, is shown in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Comparison of pain levels during tubal imaging\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003ePain assessment period\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003ePain grading\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.05154639175258%\" valign=\"top\"\u003e\n \u003cp\u003eGrouping\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage of moderate-to-severe pain (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.185567010309279%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.587628865979383%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eDuring intubation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eII-III degree\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.05154639175258%\" valign=\"top\"\u003e\n \u003cp\u003eBilateral patency of the fallopian tubes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003e54.7 (76/139)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.185567010309279%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0.303\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"55.73770491803279%\" valign=\"top\"\u003e\n \u003cp\u003eNon-bilateral patent fallopian tubes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.26229508196721%\" valign=\"top\"\u003e\n \u003cp\u003e61.5 (56/91)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.74626865671642%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.298507462686565%\" valign=\"top\"\u003e\n \u003cp\u003e56.4 (44/78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.955223880597014%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0.829\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"55.73770491803279%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine + flurbiprofen ester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.26229508196721%\" valign=\"top\"\u003e\n \u003cp\u003e57.9 (88/152)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.587628865979383%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eDuring \u0026nbsp;inspection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eII-III degree\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.05154639175258%\" valign=\"top\"\u003e\n \u003cp\u003eBilateral patency of the fallopian tubes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003e39.6 (55/139)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.185567010309279%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0.000\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"55.73770491803279%\" valign=\"top\"\u003e\n \u003cp\u003eNon-bilateral patency of the fallopian tubes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.26229508196721%\" valign=\"top\"\u003e\n \u003cp\u003e68.1 (62/91)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.74626865671642%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.298507462686565%\" valign=\"top\"\u003e\n \u003cp\u003e50.0 (39/78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.955223880597014%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"55.73770491803279%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine + flurbiprofen ester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.26229508196721%\" valign=\"top\"\u003e\n \u003cp\u003e50.0 (76/152)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.587628865979383%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eAfter inspection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eII-III degree\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.05154639175258%\" valign=\"top\"\u003e\n \u003cp\u003eBilateral patency of the fallopian tubes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003e12.9 (18/139)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.185567010309279%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0.847\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"55.73770491803279%\" valign=\"top\"\u003e\n \u003cp\u003eNon-bilateral patency of the fallopian tubes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.26229508196721%\" valign=\"top\"\u003e\n \u003cp\u003e12.1 (11/91)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.74626865671642%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.298507462686565%\" valign=\"top\"\u003e\n \u003cp\u003e21.8 (17/78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.955223880597014%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"55.73770491803279%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine + flurbiprofen ester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.26229508196721%\" valign=\"top\"\u003e\n \u003cp\u003e7.9 (12/152)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2.4 Comparison of pain relief between groups\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; (1)\u0026nbsp;Pain relief in the\u0026nbsp;atropine versus atropine + flurbiprofen ester groups\u0026nbsp;is compared in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eComparison of pain relief between atropine and atropine + flurbiprofen ester in tubal imaging\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\" valign=\"top\"\u003e\n \u003cp\u003eProjects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.916666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eGrouping\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003eRelief\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003eNo relief\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Bilateral tubal patency group\u003c/p\u003e\n \u003cp\u003e(N1 = 139 cases)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.916666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0.001\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.13725490196079%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine + flurbiprofen ester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.568627450980394%\" valign=\"top\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNon-bilateral tubal patency group\u003c/p\u003e\n \u003cp\u003e(N2 = 91 cases)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.916666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0.001\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.13725490196079%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine + flurbiprofen ester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.568627450980394%\" valign=\"top\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2. In those with bilateral patent fallopian tubes, flurbiprofen ester use was compared in the thick tube group with pain relief in the thin tube group in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Comparison of pain relief between the thick tube and thin tube groups in bilaterally patent fallopian tubes\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.43434343434343%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eGrouping\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCoarse tube\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFine tube\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eNo relief\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003eRelief\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eNo relief\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003eRelief\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.43434343434343%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.121212121212121%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.121212121212121%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.43434343434343%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine + flurbiprofen ester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.121212121212121%\" valign=\"top\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.121212121212121%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.43434343434343%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0.278\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0.001\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;3. In nonbilateral tubal patency, flurbiprofen use was compared with pain relief in the thick-tube group versus the thin-tube group, as shown in Table 4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Comparison of pain relief in thick and thin tubes in the non-bilateral tubal patency group\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.43434343434343%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eGrouping\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCoarse tube\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFine tube\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eNo relief\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003eRelief\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eNo relief\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003eRelief\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.43434343434343%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.121212121212121%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.121212121212121%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.43434343434343%\" valign=\"top\"\u003e\n \u003cp\u003eAtropine + flurbiprofen ester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.121212121212121%\" valign=\"top\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.161616161616163%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.121212121212121%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.43434343434343%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0.000\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0.000\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2.5 Multifactor \u003cem\u003elogistic\u0026nbsp;\u003c/em\u003eregression analysis for pain relief during tubal angiography\u003c/p\u003e\n\u003cp\u003ePatient age, years of infertility, history of dysmenorrhea, endometrial thickness, tube diameter of insertion, tubal patency, and flurbiprofen continuous drip were analyzed for pain relief correlation, and the statistically significant (p \u0026lt; 0.05) univariate indicators containing flurbiprofen continuous drip, thick tube, and bilateral tubal patency as independent variables and pain relief as the dependent variable were analyzed by binary logistic regression. The results suggested that flurbiprofen continuous drip and bilateral tubal patency had a significant positive relationship with pain relief, while tube diameter did not significantly affect pain relief (Table 5), and the ROC curve AUC of this model was 0.732 (95% CI: 0.665-0.798)（Figure 3）.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u003c/strong\u003e Multi-factor \u003cem\u003elogistic\u0026nbsp;\u003c/em\u003eregression analysis of pain relief during tubal angiography\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eB\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eStandard Error\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.278350515463918%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eWald\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.278350515463918%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eOR (95% CI)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eCoarse tube (vs.\u0026nbsp;fine tube)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e-0.703\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e0.381\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.278350515463918%\" valign=\"top\"\u003e\n \u003cp\u003e3.395\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.278350515463918%\" valign=\"top\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003e0.495\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(0.235-1.046)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eBilateral tubal patency (vs.\u0026nbsp;non-bilateral tubal patency)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e1.134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e0.345\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.278350515463918%\" valign=\"top\"\u003e\n \u003cp\u003e10.824\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.278350515463918%\" valign=\"top\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003e3.107\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.581-6.103)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eFlurbiprofen esters (vs.\u0026nbsp;flurbiprofen-free)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e1.356\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e0.317\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.278350515463918%\" valign=\"top\"\u003e\n \u003cp\u003e18.277\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.278350515463918%\" valign=\"top\"\u003e\n \u003cp\u003e0.000\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003e3.881\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(2.084-7.226)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"3 Discussions","content":"\u003cp\u003eThe main clinical methods to determine tubal patency include laparoscopic fluid staining, X-HSG and TVS 4D-HyCoSy, which have their own advantages and disadvantages. Laparoscopic fluid staining, which is the \u0026quot;gold standard\u0026quot;, is an invasive test [14] and has disadvantages such as high invasiveness, high cost and anesthesia risk, so it is usually used as a second-line verification or treatment after confirming obstruction by HSG. There may be a risk of iodine allergy. Hysterosalpingography (HyCoSy) is an ultrasound examination of the uterus and fallopian tubes to assess tubal patency with a transcervical contrast agent (air saline or microbubble contrast) [15]. According to several scholars, HyCoSy has been found to have a therapeutic role in addition to showing high accuracy in evaluating tubal patency [16,17]. However, patients often exhibit varying degrees of pain and discomfort during a series of operations during HyCoSy examination, mainly in the form of adverse reactions such as dizziness, nausea, vomiting and even shock that patients may experience. According to the literature, pain during tubal imaging often causes tubal spasm, leading to an increased rate of false-positive test results [11]. Therefore, how to alleviate pain during and after the examination has become a focus of concern for clinicians and patients. Possible causes of pain from HyCoSy include psychological tension, excessive speed of contrast pushing, size of the contrast catheter balloon, and the patient\u0026apos;s own diseases, such as uterine adhesions, cervical stenosis, and inflammation [18],\u0026nbsp;while most pain levels actually occur as a result of a combination of these factors. It has been suggested that HyCoSy triggers the most intense pain with cervical dilation [19]. In contrast, Guzel et al. concluded that the most intense pain was caused by increased pressure in the uterine cavity during contrast injection [20].\u003c/p\u003e\n\u003cp\u003eOur study found that preoperative injection of atropine was not effective in relieving patients\u0026apos; pain, which is consistent with the literature\u003csup\u003e[21]\u003c/sup\u003e. Flurbiprofen ester has been widely used in surgical procedures, such as brain surgery, upper abdominal surgery, and gynecological surgery, and significant analgesic effects have been achieved [13,22-23]. In the present study, we tried to introduce flurbiprofen ester continuous drip into uterine tubal ultrasonography. Flurbiprofen ester is a nonsteroidal analgesic with significant analgesic effects for various types of pain and targeted effects on inflammation and surgical sites [21,23]. After entering the site of action through the carrier lipid microspheres, flurbiprofen ester is released by the carrier and rapidly hydrolyzed by the action of carboxyl lipase to produce flurbiprofen, which has a significant inhibitory effect on prostaglandin synthesis, which in turn produces analgesic effects. The drug has a high safety factor, rapid onset of action and long-lasting analgesic effect [21,24].\u003c/p\u003e\n\u003cp\u003eIn this study, we found that the addition of flurbiprofen ester continuous intravenous drip to the routine preoperative injection of atropine had a certain effect on analgesia during ultrasound tubography, which was mainly reflected after the examination (P = 0.003), and it was not significant for analgesia during intubation and examination, probably because 1. during TVS 4D-HyCoSy, the pain during intubation and examination operation was the most, 2. the high level of patient tension during intubation and examination operations, as well as pain-inducing factors such as cervical dilation and increased pressure in the uterine cavity during contrast injection. 3. After the examination, the catheter was removed, the patient\u0026apos;s tension was relaxed, and flurbiprofen ester was more likely to play an objective role. We also found that at the time of examination, patency of the fallopian tube had a significant positive significance for analgesia (P = 0.000), and at the time of catheterization and after examination, patency of the fallopian tube had no significant effect on analgesia, which suggests that patency of the fallopian tube may be one of the main causes of pain during HyCoSy. Flurbiprofen ester under continuous intravenous drip conditions was\u0026nbsp;effective in relieving pain within 30 minutes after imaging, regardless of the patency of the fallopian tube. In conclusion, the patency of the fallopian tube affects pain during the examination, and flurbiprofen ester continuous intravenous infusion is effective in relieving pain.\u003c/p\u003e\n\u003cp\u003eDuring HyCoSy, flurbiprofen ester continuous intravenous infusion had a significant positive effect on pain relief during ultrasound tubography. Although the addition of flurbiprofen ester was not significant for pain relief during uterine tubal ultrasonography in those with bilateral patent tubes and thick tubes, the addition of flurbiprofen ester was significant for pain relief within 30 minutes after ultrasonography in those with bilateral patent tubes and thin tubes and in those with nonbilateral patent tubes for possible reasons, including because the effect of the catheter on pain disappeared after removal of the tube. Second, women with thick tubes, all of whom had been pregnant or delivered and had a history of hysterectomy, may be less nervous and more tolerant of pain. Third, those with bilateral patent fallopian tubes and with thin tubes, who had no history of pregnancy and no history of hysterectomy, may be more nervous and less tolerant of pain. In addition, we found by multifactorial binary \u003cem\u003elogistic\u0026nbsp;\u003c/em\u003eregression analysis that the pain relief rate within 30 minutes after surgery in those with bilateral patent tubes was 3.107 times higher than that in those with nonbilateral patent tubes, and the pain relief rate within 30 minutes after surgery in those with flurbiprofen was 3.881 times higher than that in those with atropine alone, which further indicated that flurbiprofen ester could effectively relieve patients\u0026apos; pain.\u003c/p\u003e\n\u003cp\u003eMoreover, our study also found that the incidence of adverse reactions (excluding pain and dry mouth) was significantly lower in the flurbiprofen ester group than in the atropine alone group, and it also relieved the psychological burden of the patients during the imaging process to some extent.\u003c/p\u003e\n\u003cp\u003eIn conclusion, flurbiprofen ester continuous drip has a good analgesic effect in patients with TVS 4D-HyCoSy; in particular, the pain relief effect after examination is significant, and it can reduce the incidence of adverse reactions in contrast examination to a certain extent, which is worthy of clinical promotion and application.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the researchers of the included studies and the participants for their contributions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the design and implementation of the study. LT and SJW: writing\u0026mdash;original draft, collected and analyzed data; ALM and SML: writing\u0026mdash;review and editing, collected and analyzed data; SLZ: writing\u0026mdash;review and editing; SZ and PXC: supervision, writing\u0026mdash;review and editing; ND and BML: conceptualization, supervision, writing\u0026mdash;review and editing. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported in part by National Natural Science Foundation of China (Grant No.82060320 and No.82260348) and the Natural Science Foundation of Xinjiang Uygur Autonomous Region (Grant No.2021D01C009)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets used and/or analyzed during the current study are available\u0026nbsp;\u003c/p\u003e\n\u003cp\u003efrom the corresponding author on reasonable request. Dr. Na Di, e-mail address: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of the Sun Yat-sen Memorial Hospital of Sun Yat-sen University (SYSKY-2022-479-01).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Ultrasound, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang Road West, Guangzhou 510120, China.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eDepartment of Ultrasound, the First People\u0026rsquo;s Hospital of Kashi Prefectrue, No. 120 Yingbin Avenue, Kashi ,Xinjiang 844000, China.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePournourali M, Tarang A, Farzadi Haghighi S, Yousefi M, Bahadori MH. Polymorphism variant of MnSOD A16V and risk of female infertility in northern Iran. Taiwan J Obstet Gynecol. 2016;55:801e803.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSteinkeler JA, Woodfield CA, Lazarus E, Hillstrom MM. Female Infertility: A systematic approach to radiologic imaging and diagnosis. Radio Graphics. 2009;29(5):1353\u0026ndash;1370.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou L, Zhang X, Chen X, et al. Value of three-dimensional hysterosalpingo-contrast sonography with SonoVue in the assessment of tubal patency. Ultrasound Obstet Gynecol. 2012;40(1):93\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLim CP, Hasafa Z, Bhattacharya S, Maheshwari A. Should a hysterosalpingogram be a first line investigation to di-agnose female tubal subfertility in the modern subfertility workup? Hum Reprod 2011;26:967\u0026ndash;971.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuciano DE, Exacoustos C, Johns DA, Luciano AA. Can hysterosalpingo-contrast sonography replace hysterosalpin-gography in confirming tubal blockage after hysteroscopic sterilization and in the evaluation of the uterus and tubes in infertile patients? Am J Obstet Gynecol 2011;204:79.e1-e5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuciano DE, Exacoustos C, Luciano AA. Contrast ultra-sonography for tubal patency. J Minim Invasive Gynecol 2014;21:994\u0026ndash;998.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraziano A, Lo Monte G, Soave I, Caserta D, Moscarini M, Marci R. Sonohysterosalpingography: a suitable choice in infertility workup. J Med Ultrason 2013;40:225\u0026ndash;229.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoro F, Tropea A, Selvaggi L, Scarinci E, Lanzone A, ApaR. Hysterosalpingo-contrast sonography (HyCoSy) in the assessment of tubal patency in endometriosis patients. Eur J Obstet Gynecol Reprod Biol 2015;186:22\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalles-Sastre L, Engels-Calvo V, R\u0026iacute;os-Vallejo M, Serrano-Gonz\u0026aacute;lez L, Garc\u0026iacute;a-Espantale\u0026oacute;n M, Royuela A, De la Cuesta R, P\u0026eacute;rez-Medina T. Prospective Study of Concordance Between Hysterosalpingo-Contrast Sonography and Hysteroscopy for Evaluation of the Uterine Cavity in Patients Undergoing Infertility Studies. J Ultrasound Med. 2018 Jun;37(6):1431\u0026ndash;1437.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLudwin I, Ludwin A, Wiechec M, Nocun A, Banas T, Basta P, Pitynski K. Accuracy of hysterosalpingo-foam sonography in comparison to hysterosalpingo-contrast sonography with air/saline and to laparoscopy with dye. Hum Reprod. 2017 Apr 1;32(4):758\u0026ndash;769.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHandelzalts JE, Levy S, Peled Y, Binyamin L, Wiznitzer A, Goldzweig G, Krissi H. Information seeking and perceptions of anxiety and pain among women undergoing hysterosalpingography. Eur J Obstet Gynecol Reprod Biol. 2016 Jul;202:41\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang N, Liu Y, He Y, Shi J, Zhou M, Liu H. Transvaginal four-dimensional hysterosalpingo-contrast sonography: Pain perception and factors influencing pain severity. J Obstet Gynaecol Res. 2021;47(1):302\u0026ndash;310.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang L, Zhu J, Xu L, Zhang X, Wang H, Luo Z, Zhao Y, Yu Y, Zhang Y, Shi H, Bao H. Efficacy and safety of flurbiprofen axetil in the prevention of pain on propofol injection: a systematic review and meta-analysis. Med Sci Monit. 2014 Jun 17;20:995\u0026ndash;1002.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatrowski R, Babbel B, J\u0026auml;ger C. Uterine rupture after balloon inflation of the intrauterine Foley catheter during laparoscopic chromopertubation. Wien Klin Wochenschr. 2016;128(15\u0026ndash;16):599\u0026ndash;601.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDishuck CF, Perchik JD, Porter KK, Gunn DD. Advanced Imaging in Female Infertility. Curr Urol Rep. 2019;20(11):77. Published 2019 Nov 16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSocolov D, Boian I, Boiculese L, Tamba B, Anghelache-Lupascu I, Socolov R. Comparison of the pain experienced by infertile women undergoing hysterosalpingo contrast sonography or radiographic hysterosalpingography. Int J Gynaecol Obstet. 2010;111(3):256\u0026ndash;259.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLindborg L, Thorburn J, Bergh C, Strandell A. Influence of HyCoSy on spontaneous pregnancy: a randomized controlled trial. Hum Reprod. 2009;24(5):1075\u0026ndash;1079. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/humrep/den485\u003c/span\u003e\u003cspan address=\"10.1093/humrep/den485\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLI Chengwei, SHEN Min, GUO Xuezhen, PENG Liwen, JIANG Kui-Ming, HUANG Huang. Clinical observation of flurbiprofen ester to relieve pain in hysterosalpingography [J]. International Journal of Medicine and Health,2021,27(08):1197\u0026ndash;1199.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGupta N, Ghosh B, Mittal S. Comparison of oral naproxen and intrauterine lignocaine instillation for pain relief during hysterosalpingography. Int J Gynaecol Obstet. 2008;102(3):284\u0026ndash;286.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuzel AI, Kuyumcuoglu U, Erdemoğlu M. The effect of flurbiprofen as prophylactic analgesic before hysterosalpingography. J Int Med Res. 2010;38(5):1780\u0026ndash;1784.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang RD, Sheng XR, Guan WX, Wang M, Peng C, Yang YY, Huang HG, Ning-Li, Jia WD. Flurbiprofen axetil for postoperative analgesia in upper abdominal surgery: a randomized, parallel controlled, double-blind, multicenter clinical study. Surg Today. 2020 Jul;50(7):749\u0026ndash;756.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKotera A. Efficacy of flurbiprofen axetil for preventing postanesthetic shivering in patients undergoing gynecologic laparotomy surgeries. JA Clin Rep. 2020;6(1):96. Published 2020 Dec 7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHao J, Wang K, Shao Y, Cheng X, Yan Z. Intravenous flurbiprofen axetil to relieve cancer-related multiple breakthrough pain: a clinical study. J Palliat Med. 2013;16(2):190\u0026ndash;192.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao X, Ji L. Flurbiprofen axetil: Analgesic effect and adverse reaction. Pak J Pharm Sci. 2018;31(3(Special)):1163\u0026ndash;1167.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Analgesia, Atropine, Flurbiprofen ester, 4-dimensional hysterosalpingography","lastPublishedDoi":"10.21203/rs.3.rs-2875202/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2875202/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e The purpose of this article is to investigate the analgesic effect of flurbiprofen ester injection continuous intravenous drip in transvaginal 4-dimensional hysterosalpingography (TVS 4D-HyCoSy).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eTwo hundred thirty patients who underwent TVS 4D-HyCoSy for infertility from May 2018 to August 2021 at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, were selected. They were grouped according to tubal patency, flurbiprofen ester use, and uterine cannula diameter, i.e., bilateral tubal patency group and nonbilateral tubal patency group, atropine group and atropine + flurbiprofen ester group, and coarse tube group and fine tube group, to compare the analgesic effect during TVS 4D-HyCoSy, pain relief effect between groups, record the incidence of adverse effects, and analyze the factors related to the influence of pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003e1. The atropine + flurbiprofen ester group had significantly fewer adverse effects in the former patients compared with the atropine group; 2. Flurbiprofen ester continuous intravenous infusion was effective for analgesia after ultrasound tubal contrast. Flurbiprofen ester continuous intravenous infusion was effective in relieving pain within 30 minutes after imaging regardless of the patency of the fallopian tubes; 3. The addition of flurbiprofen ester significantly relieved pain in the fine tube group in those with bilateral patency of the fallopian tubes and in the thick tube group and fine tube group in those with nonbilateral patency of the fallopian tubes; 4. Multifactorial analysis of pain relief during imaging suggested that the use of flurbiprofen for bilateral tubal patency had a significant positive effect on pain relief within 30 minutes after the examination, AUC 0.732; 95% CI: 0.665-0.798.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eBilateral tubal patency and flurbiprofen will have a significant positive effect on pain relief. The analgesic effect of flurbiprofen ester injection with continuous drip started before TVS 4D-HyCoSy was good, and the pain relief effect was significant within 30 minutes after examination with few adverse effects, which is worthy of clinical promotion.\u003c/p\u003e","manuscriptTitle":"Use of Flurbiprofen ester in 4-dimensional hysterosalpingography : could it effectively relieve pain during infertility examination?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-10 16:32:51","doi":"10.21203/rs.3.rs-2875202/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c409b12d-3627-4c8f-8185-6d37f11cbeed","owner":[],"postedDate":"May 10th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-08-08T03:14:05+00:00","versionOfRecord":[],"versionCreatedAt":"2023-05-10 16:32:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2875202","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2875202","identity":"rs-2875202","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}