The ED 50 /ED 95 of esketamine in inhibiting body movement when patients undergoing hysteroscopy

The ED 50 /ED 95 of esketamine in inhibiting body movement when patients undergoing hysteroscopy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The ED 50 /ED 95 of esketamine in inhibiting body movement when patients undergoing hysteroscopy Dan Wang, Shuangfeng Li, Jun Wang, Shuai Chen, Zhenzhen Li, Ying Zhong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3942407/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 Background Patients would have a strong discomfort feeling and pain in hysteroscopic surgery because of expanding the cervical canal and tissue stretching. Nowadays, propofol has no analgesic effect, it is necessary to combine other analgesic drugs to inhibit intraoperative body movement and eliminate discomfortable feeling. This study was to explore the half effective dose (ED 50 ) and 95% effective dose (ED 95 ) of esketamine combined with propofol in inhibiting body movement when patients underwent hysteroscopy. Methods 26 patients who needed hysteroscopy were recruited in Haikou Maternal and Child Health Hospital of China. All patients received intravenous esketamine and propofol. The plasma concentration of propofol was set to 3 µg/mL for target-controlled infusion. The dose of esketamine was determined by the Dixon up-and-down sequential method. The ED 50 /ED 95 of esketamine were detected by binary regression (probit). The respiration, circulation and body movement of patients were observed. The operating time, the awakening time and the analgesic effect were recorded. Results The ED 50 /ED 95 of esketamine combined with propofol plasma concetration 3 µg/mL inhibiting body movement in patients with hysteroscopy were 0.391 mg/kg and 0.476 mg/kg, respectively (95% confidence intervals were 0.34–0.431 mg/kg and 0.434–0.778 mg/kg). There are not respiratory and circulatory depression in all patients. Conclusions Esketamine at 0.476 mg/kg which combined with propofol plasma concetration 3 µg/mL showed a good analgesic effect in hysteroscopy. Esketamine Propofol Hysteroscopy Sequential method Half effective dose Figures Figure 1 Figure 2 Introduction Patients would have a strong discomfort feeling and pain in hysteroscopic surgery because of expanding the cervical canal and tissue stretching. Therefore, a safe and effective anesthetic scheme is very important to carry out hysteroscopy smoothly [ 1 ]. Propofol is a short-acting intravenous sedative anesthetic which has an extensive inhibitory effect on the central nervous system, so that patients can quickly fall asleep and recover [ 2 ]. Because propofol has no analgesic effect, it is necessary to combine other analgesic drugs to inhibit intraoperative body movement and eliminate discomfortable feeling. At present, esketamine is a new type of intravenous anesthetic with faster-acting, mild respiratory inhibition and rapid recovery[ 3 ]. Esketamine is not only a sedative, but also shows a strong analgesic effect. Its analgesic effect is twice as much as ketamine [ 4 ]. Its sympathetic properties counteract the hemodynamic inhibition of propofol, thus esketamine when combined with propofol can not only provide effective sedative and analgesic effect for patients, but also reduce the using dosage of propofol and reduce the incidence of adverse events in the respiratory and circulatory system [ 5 ]. In this study, we evaluated the 50% effective dose (ED 50) and 95% effective dose (ED 95 ) of esketamine which combined with propofol 3 µg/mL in target-controlled infusion during hysteroscopy, so as to provide more reference for guiding clinical medication. Materials and Methods This experiment has been approved by the Medical Ethics Committee of Haikou Maternal and Child Health Hospital (China, Reference No. [2021] 03002). Informed consent forms were signed by patients. Patients 26 patients who volunteered to perform hysteroscopic surgery with general anesthesia in Haikou Maternal and Child Health Hospital were selected. The inclusion criteria were as follows: ASA classification I to II, female, age 18 to 60 years old, and no history of vaginal delivery. The exclusion criteria included hepatitis and renal failure, habitual sedative or analgesic use, mental illness, and allergy to esketamine or propofol. Clinical protocol The patients fasted from solids for 6 h and from liquids for 2 h, then entered the operating room with standard monitoring and inhaled oxygen (3 L/min) by nasal catheter. Before the operation, esketamine (batch number: 210827BL, Jiangsu Hengrui Pharmaceutical Co., Ltd.) was injected intravenously, then propofol (batch number: 10PK7760, Beijing Freseniusscapi Pharmaceutical Co., Ltd.) was continuously given by target-controlled infusion with a plasma concentration of 3 µg/ml. The dose of esketamine was determined by the Dixon up-and-down sequential method[ 6 ]. the initial dose of esketamine was set to be 0.5 mg/kg. If the patients showed negative reaction (with no body movement during hysteroscopy), the dose of esketamine in the next patient was 0.9 times dose of the previous patient, but if the patient had positive reaction (with body movement during hysteroscopy), the dose of esketamine in the next patient was 1.1 times dose of the previous patient. The hysteroscopy began to be performed when patients lost consciousness, as reflected by a bispectral index (BIS) (BIS Complete Monitoring System, Covidien) value between 50 and 75. If patients showed body movement during the operation, propofol 0.5-1 mg/kg was added intravenously to complete the operation. The study was terminated when the seventh crossing inflection point appeared. All patients were performed by a gynecologist who had worked clinically for more than 5 years, and all patients were anesthetized by a same anesthesiologist. The heart rate (HR), mean arterial pressure ( MAP) and blood oxygen saturation (SpO 2 ) were recorded at baseline before the beginning of anesthesia (T 1 ), at the beginning of hysteroscopy (T 2 ), at when the cervix was dilated (T 3 ), at the end of hysteroscopy (T 4 ), and at when patients to awake (T 5 ), respectively. The dody movement during hysteroscopy, the operation time (the time of hysteroscopy), and the awakening time (the time between the end of the hysteroscopy and when patients to awake) were recorded. Additionally, the score of the visual analogue scale (VAS) was evaluated and recorded at 10 min. after awakening. The number of patients with dizziness, nausea/vomiting or agitation after awakening was also recorded. Respiratory depression (SpO 2 < 90% during inhaling oxygen) and circulatory depression (MAP < 50 mmHg or HR < 50 beats/min.) during surgery and other complications were recorded. Ephedrine 6 mg was injected intravenously when patients developed hypotension (MAP < 50 mmHg); atropine 0.5 mg was injected intravenously when patients developed bradycardia (heart rate < 50 beats/min.); pressurized mask ventilation or mechanical ventilation with laryngeal mask was used when patients had respiratory depression (SpO 2 < 90%); and tropisetron 2 mg was injected intravenously when patients developed nausea/vomiting. Statistical processing methods IBM SPSS Statistics 23.0 (IBM Corporation, version 19; Armonk, NY, USA) was used for statistical analyses of data. The ED 50 /ED 95 as well as the 95% CIs of esketamine were calculated by binary regression (probit) [ 7 ]. Normally distributed statistics were analyzed as the mean ± standard deviation and by repeated measurement analysis of variance. The nonparametric data were analysed using the median (Q1, Q3). Microsoft Excel was used to make the charts of sequence diagram and dose-effect curve. Finally, a P value of < 0.05 was accepted to be statistically significant. Results Included patients general information and vital signs A total of 26 female patients were included in this study, including 22 cases of ASA classification I and 4 cases of ASA classification Ⅱ. The mean ± standard deviation of the age was 34.04 ± 10.75 (y) and the BMI was 22.83 ± 3.39 (kg/m 2 ). The MAP of patients at when the cervix was dilated (T 3 ) was significantly higher than that at other four time points (T 1 , T 2 , T 4 , T 5 ) (P < 0.05). There were no significant differences in HR and SpO 2 at five time points of T 1 -T 5 . Results are shown in Table 1 . Table 1 Comparison of vital signs in patients during hysteroscopy (n = 26, ‾x ± s) Index Before the beginning of anesthesia (T 1 ) At the beginning of hysteroscopy (T 2 ) When the cervix was dilated (T 3 ) At the end of hysteroscopy (T 4 ) When patients to awake (T 5 ) F P MAP (mmHg) 88.04 ± 10.32 87.88 ± 9.00 96.92 ± 10.82* 91.08 ± 9.57 88.38 ± 10.46 16.591 < 0.001 HR (bpm) 79.46 ± 11.83 75.19 ± 8.61 77.65 ± 9.12 74.42 ± 9.45 75.04 ± 7.00 2.836 0.049 SPO 2 (%) 99.62 ± 0.57 99.46 ± 0.51 99.23 ± 0.59 99.42 ± 0.50 99.42 ± 0.58 1.881 0.150 *Significant differences (P < 0.05) The ED 50 and ED 95 of esketamine In this study, the individual responses to esketamine using Dixon’s up-and-down method are shown in Fig. 1 . The initial dose of esketamine was 0.5mg/kg, and the fourth patient started to show positive reaction. The trial was terminated when a seventh fold was formed in the 26th patient. 12 patients were positive and 14 patients were negative. The dose-response curve of esketamine is shown in Fig. 2 . With infusing propofol (in plasma concentration 3 µg/ml), the ED 50 /ED 95 of esketamine in inhibiting body movement during hysteroscopy was 0.391 mg/kg (95% CI = 0.34 ~ 0.431 mg/kg) and 0.476 mg/kg (95% CI = 0.434 ~ 0.778 mg/kg), respectively. The operation time, recovery time, pain score and adverse reaction The mean ± standard deviation of the operation time was 24.85 ± 8.09 (min.), and of the recovery time was 7.23 ± 3.22 (min.). The median VAS pain score (10 min. after awakening) was 1 (0, 2). Two cases showed vomiting, three cases occurred dizziness and one cases had agitation after awakening. No respiratory depression, hypotension and nightmares occurred in all cases. Discussion ED 50 /ED 95 is a common sensitive index in clinical study of drug dose-effect relationship [ 8 ]. Sequential method [ 6 , 7 ] is a classical method for calculating the ED 50 /ED 95 of drugs with fewer cases and less experimental period, and it is used normally in the anaesthetic drugs study. In our study, we measured the ED 50 /ED 95 and 95% CI of esketamine by using the sequential method, and the main criterion was whether the body movement was inhibited during hysteroscopy. Esketamine is a sedative and analgesic anesthetic. It is a dextral structure of ketamine and acts through antagonizing NMDA receptors. When combined with propofol, esketamine could produce a good clinical anesthetic effect [ 9 – 12 ]. Eberl et al [ 9 ]. reported that the synergistic effect of ketamine and propofol could improve the safety and satisfaction of patients and reduce the using dose of drugs during ERCP,. Zhang Zhongqi et al [ 10 ]. repoerted that esketamine at 0.3 mg/kg when combined with propofol in gastroscopy not only reduced the risk of cardiovascular and respiratory adverse events, but also provided sedation and analgesia. Zhan Yongtong et al [ 11 ]. also reported that esketamine at 0.2 mg/kg when combined with propofol in gastroscopy had shorter anesthesia induction time, lower incidence of cough and body movement, and less consumption of propofol per minute than propofol alone, and there was no effect on recovery time, hemodynamic stability, postoperative cognitive function, and incidence of adverse events. Chen Jiejuan et al [ 12 ]. reported that the anesthesia effect of intravenous esketamine at 0.25mg/kg combined with propofol for painless abortion was better than that of fentanyl combined with propofol. In this study, we also found that the combination of esketamine and propofol also produced a good clinical anesthetic effect during hysteroscopy. None of the patients developed hypotension, bradycardia and respiratory inhibition, which was explained by the sympathomimetic activity of esketamine to antagonize the inhibitory effect of propofol on the respiratory and to counteract the vagal reflex effect during surgery [ 13 , 14 ]. The mean arterial pressure (MAP) of patients during cervical dilatation (T 3 ) was significantly higher than that of other four monitoring points (T 1 , T 2 , T 4 , T 5 ), which indicated that cervical dilatation was a great stimulus in patients, but all MAP fluctuated within 20% range of preoperative blood pressure. The BIS value of intraoperative anesthetic depth was maintained between 65 and 75. 2 patients showed postoperative nausea and vomiting, and 3 patients experienced postoperative dizziness, which all of them relieved about 2 hours after operation. All patients did not experience psychiatric adverse effects such as nightmares and cognitive impairment, which correlated with the reduced use of esketamine and possibly also related with the reduced incidence of adverse effects by propofol through activating GABA receptors. The median VAS pain score (10 min, after awakening) of the patients was 1 (0, 2), which indicated that esketamine had a good analgesic effect. Its related mechanism may be through inhibiting NMDA receptor which linked nociceptive stimulus conduction at the central and peripheral system, and may also through activating the pain inhibitory system. In this study, target-controlled infusion of propofol using a plasma concentration of 3 µg/mL was applied to maintain the whole procedure from anesthesia induction, anesthesia maintenance to awakening as a continuous procedure with less impact on the respiratory and circulatory system of patients, less medication consumption, and easier regulation of intraoperative anesthetic depth. This study was limited to patients with no history of vaginal delivery. which had greater stimulation intensity during cervical dilatation than in those with a history of vaginal delivery. Therefore, patients with a history of vaginal delivery to undergo hysteroscopy may require a smaller dose of esketamine. The specific effective dose of esketamine requires further study. In conclusion, combined with target-controlled infusion of propofol (3 µg/mL in plasma concentration) during hysteroscopy, the ED 50 and ED 95 of esketamine were 0.391 mg/kg and 0.476 mg/kg, respectively, without significant adverse effects. Conclusion The ED 50 /ED 95 of esketamine combined with propofol at plasma concetration 3 µg/mL inhibiting body movement in patients with hysteroscopy were 0.391 mg/kg and 0.476 mg/kg, respectively. So, esketamine at 0.476 mg/kg which combined with propofol at plasma concetration 3 µg/mL showed a good analgesic effect in hysteroscopy. Declarations Acknowledgements Thanks are due to all those who assisted in recruitment and program delivery of this study—notably, to the families, doctors, anesthesiologist, and nurses. Thanks to the experts and professors of the ethics committee for participating in the review of this study. Author contributions Shuangfeng Li and Dan Wang conceived and designed the experiments; Jun Wang and Shuai Chen performed the experiments;Zhenzhen Li, Ying Zhong ,Jun Wang, Wang Dan, Shuai Chen analyzed the data and wrote the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work. Funding This work was supported by the Hainan Health Science and Education Project of China (grant number: 820QN393). Data availability statement The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors. Competing interests The authors declare no competing interests. Ethics statement The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Haikou Maternal and Child Health Hospital. And this study was passed by the Chinese Clinical Trial Registry (Registration date: January 13 th ,2024; Registration number: ChiCTR2400079831). The patients/participants provided their written informed consent to participate in this study. Consent for publication Not applicable. References Okohue JE. Overview of hysteroscopy. West Afr J Med, 2020, 37(2): 178-182. Yu J, Xiang B, Song Y, Chen H, Li Y, Liu C. ED50 of propofol in combination with low‐dose sufentanil for intravenous anaesthesia in hysteroscopy. Basic Clin Pharmacol Toxicol, 2019;125(5):460-465. Wang J, Huang J, Yang S, Cui C, Ye L, Wang SY, Yang GP, Pei Q. Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine:A Randomized, Open-Label Clinical. Drug Des Devel Ther. 2019;13:4135-4144. Lei Y, Liu H, Xia F, Gan S, Wang Y, Huo W, Wang Q, Ji F. Effects of Esketamine on Acute and Chronic Pain After Thoracoscopy Pulmonary Surgery Under General Anesthesia: A Multicenter-Prospective, Randomized, Double-Blind, and Controlled Trial. Front Med (Lausanne). 2021;8:693594. Xin N, Yan W, Jin S. Efficacy of Analgesic Propofol/Esketamine and Propofol/Fentanyl for Painless Induced Abortion: A Randomized Clinical Trial. Biomed Res Int. 2022;2022:5095282. Dixon WJ. Staircase bioassay: the up-and-down method. Neurosci Biobehav Rev. 1991;15(1):47–50. Gorges M, Zhou G, Brant R, Ansermino JM. Sequential allocation trial design in anesthesia: an introduction to methods, modeling, and clinical applications. Paediatr Anaesth. 2017;27(3):240–7. Dixon WJ. The up-and-Down method for small samples. Journal of the American Statistical Association. 1965;312:967-978. Eberl S, Koers L, van Hooft JE, de Jong E, Schneider T, Hollmann MW, Preckel B. Sedation with propofol during ERCP: is the combination with esketamine more effective and safer than with alfentanil? Study protocol for a randomized controlled trial. Trials. 2017;18(1):472. Zheng Y, Xu Y, Huang B, Mai Y, Zhang Y, Zhang Z. Effective dose of propofol combined with a low-dose esketamine for gastroscopy in elderly patients: A dose finding study using dixon's up-and-down method. Front Pharmacol. 2022;13:956392. Zhan Y, Liang S, Yang Z, Luo Q, Li S, Li J, Liang Z, Li Y. Efficacy and safety of subanesthetic doses of esketamine combined with propofol in painless gastrointestinal endoscopy: a prospective, double-blind, randomized controlled trial. BMC Gastroenterol. 2022;22(1):391. Chen J, Zou X, Hu B, Yang Y, Wang F, Zhou Q, Shen M. Effect of different doses of esketamine compared with fentanyl combined with propofol on hypotension in patients undergoing painless abortion surgery: a prospective, randomized, double-blind controlled clinical trial. BMC Anesthesiol. 2022;22(1):305. Jonkman K, van Rijnsoever E, Olofsen E, Aarts L, Sarton E, van Velzen M, Niesters M, Dahan A. Esketamine counters opioid-induced respiratory depression. Br J Anaesth. 2018;120(5):1117-1127. Trimmel H, Helbok R, Staudinger T, Jaksch W, Messerer B, Schöchl H, Likar R. S(+)-ketamine : Current trends in emergency and intensive care medicine. Wien Klin Wochenschr. 2018;130(9-10):356-366. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3942407","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":272464725,"identity":"f876f75b-2f95-42ba-9151-7d76eb552a21","order_by":0,"name":"Dan Wang","email":"","orcid":"","institution":"The Second Xiangya Hospital of Central South University","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Wang","suffix":""},{"id":272464726,"identity":"a68e7122-9c8c-4b0b-a30f-d6880d8a3555","order_by":1,"name":"Shuangfeng Li","email":"","orcid":"","institution":"Haikou Maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuangfeng","middleName":"","lastName":"Li","suffix":""},{"id":272464727,"identity":"6ebda672-02ae-456c-b17c-316d16ebf410","order_by":2,"name":"Jun Wang","email":"","orcid":"","institution":"The Second Xiangya Hospital of Central South University","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Wang","suffix":""},{"id":272464728,"identity":"3354eaed-e6f3-4ddb-aa16-607c5cd47086","order_by":3,"name":"Shuai Chen","email":"","orcid":"","institution":"Haikou Maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuai","middleName":"","lastName":"Chen","suffix":""},{"id":272464729,"identity":"228788b0-5965-4cb4-8b78-a6f8230fc135","order_by":4,"name":"Zhenzhen Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYBACPjBZwMDAz8x88AFRWtjApAEDg2Q7W7IBaVoMzvOYCRCnhf/4M8kfBoftjQ8zmDEw1NhEE2HLgTRpHoPDidsOM6Q9YDiWlttAUAtjw2FjBoPDCWaHGY4bADlEaGFmbDYEO6yZsU2COC1APQ+ADmPcwMzMRqQWHjbGxzwG6YkzDrMxGyQQ4xd+/uMPDv6osLbn7z//8cGHGhvCWqCgGUIlEKkcBOpIUDsKRsEoGAUjDgAAjz0281qVwyEAAAAASUVORK5CYII=","orcid":"","institution":"Haikou Maternal and Child Health Hospital","correspondingAuthor":true,"prefix":"","firstName":"Zhenzhen","middleName":"","lastName":"Li","suffix":""},{"id":272464730,"identity":"ade7eeb6-ebe9-4c27-945c-5036948de43c","order_by":5,"name":"Ying Zhong","email":"","orcid":"","institution":"Haikou Maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Zhong","suffix":""}],"badges":[],"createdAt":"2024-02-09 08:15:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3942407/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3942407/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51081972,"identity":"7dc7a046-3907-48df-81ac-7a93293e1360","added_by":"auto","created_at":"2024-02-13 19:20:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":119806,"visible":true,"origin":"","legend":"\u003cp\u003eResponses (inhibiting body movement) of consecutive patients who received esketamine combined with propofol during hysteroscopy\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3942407/v1/5061e18bae84331f2c843686.png"},{"id":51081973,"identity":"112ed22d-df45-451f-b363-86370628d8eb","added_by":"auto","created_at":"2024-02-13 19:20:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":70550,"visible":true,"origin":"","legend":"\u003cp\u003eEffective dose of esketamine combined with propofol in inhibiting body movement of patients during hysteroscopy\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3942407/v1/af8403be71c75346037c18e9.png"},{"id":74286967,"identity":"28efd412-4224-4447-9219-feeeabb8eb0c","added_by":"auto","created_at":"2025-01-20 16:16:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":752738,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3942407/v1/911a651b-4428-4715-be4f-433180a65068.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The ED 50 /ED 95 of esketamine in inhibiting body movement when patients undergoing hysteroscopy","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePatients would have a strong discomfort feeling and pain in hysteroscopic surgery because of expanding the cervical canal and tissue stretching. Therefore, a safe and effective anesthetic scheme is very important to carry out hysteroscopy smoothly [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Propofol is a short-acting intravenous sedative anesthetic which has an extensive inhibitory effect on the central nervous system, so that patients can quickly fall asleep and recover [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Because propofol has no analgesic effect, it is necessary to combine other analgesic drugs to inhibit intraoperative body movement and eliminate discomfortable feeling. At present, esketamine is a new type of intravenous anesthetic with faster-acting, mild respiratory inhibition and rapid recovery[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Esketamine is not only a sedative, but also shows a strong analgesic effect. Its analgesic effect is twice as much as ketamine [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Its sympathetic properties counteract the hemodynamic inhibition of propofol, thus esketamine when combined with propofol can not only provide effective sedative and analgesic effect for patients, but also reduce the using dosage of propofol and reduce the incidence of adverse events in the respiratory and circulatory system [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we evaluated the 50% effective dose (ED\u003csub\u003e50)\u003c/sub\u003e and 95% effective dose (ED\u003csub\u003e95\u003c/sub\u003e) of esketamine which combined with propofol 3 \u0026micro;g/mL in target-controlled infusion during hysteroscopy, so as to provide more reference for guiding clinical medication.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e This experiment has been approved by the Medical Ethics Committee of Haikou Maternal and Child Health Hospital (China, Reference No. [2021] 03002). Informed consent forms were signed by patients.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e26 patients who volunteered to perform hysteroscopic surgery with general anesthesia in Haikou Maternal and Child Health Hospital were selected. The inclusion criteria were as follows: ASA classification I to II, female, age 18 to 60 years old, and no history of vaginal delivery. The exclusion criteria included hepatitis and renal failure, habitual sedative or analgesic use, mental illness, and allergy to esketamine or propofol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinical protocol\u003c/h2\u003e \u003cp\u003eThe patients fasted from solids for 6 h and from liquids for 2 h, then entered the operating room with standard monitoring and inhaled oxygen (3 L/min) by nasal catheter. Before the operation, esketamine (batch number: 210827BL, Jiangsu Hengrui Pharmaceutical Co., Ltd.) was injected intravenously, then propofol (batch number: 10PK7760, Beijing Freseniusscapi Pharmaceutical Co., Ltd.) was continuously given by target-controlled infusion with a plasma concentration of 3 \u0026micro;g/ml. The dose of esketamine was determined by the Dixon up-and-down sequential method[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. the initial dose of esketamine was set to be 0.5 mg/kg. If the patients showed negative reaction (with no body movement during hysteroscopy), the dose of esketamine in the next patient was 0.9 times dose of the previous patient, but if the patient had positive reaction (with body movement during hysteroscopy), the dose of esketamine in the next patient was 1.1 times dose of the previous patient.\u003c/p\u003e \u003cp\u003eThe hysteroscopy began to be performed when patients lost consciousness, as reflected by a bispectral index (BIS) (BIS Complete Monitoring System, Covidien) value between 50 and 75. If patients showed body movement during the operation, propofol 0.5-1 mg/kg was added intravenously to complete the operation. The study was terminated when the seventh crossing inflection point appeared. All patients were performed by a gynecologist who had worked clinically for more than 5 years, and all patients were anesthetized by a same anesthesiologist.\u003c/p\u003e \u003cp\u003eThe heart rate (HR), mean arterial pressure ( MAP) and blood oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e) were recorded at baseline before the beginning of anesthesia (T\u003csub\u003e1\u003c/sub\u003e), at the beginning of hysteroscopy (T\u003csub\u003e2\u003c/sub\u003e), at when the cervix was dilated (T\u003csub\u003e3\u003c/sub\u003e), at the end of hysteroscopy (T\u003csub\u003e4\u003c/sub\u003e), and at when patients to awake (T\u003csub\u003e5\u003c/sub\u003e), respectively. The dody movement during hysteroscopy, the operation time (the time of hysteroscopy), and the awakening time (the time between the end of the hysteroscopy and when patients to awake) were recorded. Additionally, the score of the visual analogue scale (VAS) was evaluated and recorded at 10 min. after awakening. The number of patients with dizziness, nausea/vomiting or agitation after awakening was also recorded. Respiratory depression (SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;90% during inhaling oxygen) and circulatory depression (MAP\u0026thinsp;\u0026lt;\u0026thinsp;50 mmHg or HR\u0026thinsp;\u0026lt;\u0026thinsp;50 beats/min.) during surgery and other complications were recorded.\u003c/p\u003e \u003cp\u003eEphedrine 6 mg was injected intravenously when patients developed hypotension (MAP\u0026thinsp;\u0026lt;\u0026thinsp;50 mmHg); atropine 0.5 mg was injected intravenously when patients developed bradycardia (heart rate\u0026thinsp;\u0026lt;\u0026thinsp;50 beats/min.); pressurized mask ventilation or mechanical ventilation with laryngeal mask was used when patients had respiratory depression (SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;90%); and tropisetron 2 mg was injected intravenously when patients developed nausea/vomiting.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical processing methods\u003c/h2\u003e \u003cp\u003eIBM SPSS Statistics 23.0 (IBM Corporation, version 19; Armonk, NY, USA) was used for statistical analyses of data. The ED\u003csub\u003e50\u003c/sub\u003e/ED\u003csub\u003e95\u003c/sub\u003e as well as the 95% CIs of esketamine were calculated by binary regression (probit) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNormally distributed statistics were analyzed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and by repeated measurement analysis of variance. The nonparametric data were analysed using the median (Q1, Q3).\u003c/p\u003e \u003cp\u003eMicrosoft Excel was used to make the charts of sequence diagram and dose-effect curve. Finally, a \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;0.05 was accepted to be statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eIncluded patients general information and vital signs\u003c/h2\u003e \u003cp\u003eA total of 26 female patients were included in this study, including 22 cases of ASA classification I and 4 cases of ASA classification Ⅱ. The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation of the age was 34.04\u0026thinsp;\u0026plusmn;\u0026thinsp;10.75 (y) and the BMI was 22.83\u0026thinsp;\u0026plusmn;\u0026thinsp;3.39 (kg/m\u003csup\u003e2\u003c/sup\u003e). The MAP of patients at when the cervix was dilated (T\u003csub\u003e3\u003c/sub\u003e) was significantly higher than that at other four time points (T\u003csub\u003e1\u003c/sub\u003e, T\u003csub\u003e2\u003c/sub\u003e, T\u003csub\u003e4\u003c/sub\u003e, T\u003csub\u003e5\u003c/sub\u003e) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There were no significant differences in HR and SpO\u003csub\u003e2\u003c/sub\u003e at five time points of T\u003csub\u003e1\u003c/sub\u003e-T\u003csub\u003e5\u003c/sub\u003e. Results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of vital signs in patients during hysteroscopy (n\u0026thinsp;=\u0026thinsp;26, \u0026oline;x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore the beginning of anesthesia (T\u003csub\u003e1\u003c/sub\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the beginning of hysteroscopy (T\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWhen the cervix was dilated (T\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAt the end of hysteroscopy (T\u003csub\u003e4\u003c/sub\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eWhen patients to awake (T\u003csub\u003e5\u003c/sub\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAP (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88.04\u0026thinsp;\u0026plusmn;\u0026thinsp;10.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87.88\u0026thinsp;\u0026plusmn;\u0026thinsp;9.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e96.92\u0026thinsp;\u0026plusmn;\u0026thinsp;10.82*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e91.08\u0026thinsp;\u0026plusmn;\u0026thinsp;9.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e88.38\u0026thinsp;\u0026plusmn;\u0026thinsp;10.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16.591\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR (bpm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79.46\u0026thinsp;\u0026plusmn;\u0026thinsp;11.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.19\u0026thinsp;\u0026plusmn;\u0026thinsp;8.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77.65\u0026thinsp;\u0026plusmn;\u0026thinsp;9.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e74.42\u0026thinsp;\u0026plusmn;\u0026thinsp;9.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e75.04\u0026thinsp;\u0026plusmn;\u0026thinsp;7.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSPO\u003csub\u003e2\u003c/sub\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e99.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e99.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.881\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.150\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e*Significant differences (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eThe ED\u003csub\u003e50\u003c/sub\u003e and ED\u003csub\u003e95\u003c/sub\u003e of esketamine\u003c/h2\u003e \u003cp\u003eIn this study, the individual responses to esketamine using Dixon\u0026rsquo;s up-and-down method are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The initial dose of esketamine was 0.5mg/kg, and the fourth patient started to show positive reaction. The trial was terminated when a seventh fold was formed in the 26th patient. 12 patients were positive and 14 patients were negative.\u003c/p\u003e \u003cp\u003eThe dose-response curve of esketamine is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. With infusing propofol (in plasma concentration 3 \u0026micro;g/ml), the ED\u003csub\u003e50\u003c/sub\u003e/ED\u003csub\u003e95\u003c/sub\u003e of esketamine in inhibiting body movement during hysteroscopy was 0.391 mg/kg (95% CI\u0026thinsp;=\u0026thinsp;0.34\u0026thinsp;~\u0026thinsp;0.431 mg/kg) and 0.476 mg/kg (95% CI\u0026thinsp;=\u0026thinsp;0.434\u0026thinsp;~\u0026thinsp;0.778 mg/kg), respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eThe operation time, recovery time, pain score and adverse reaction\u003c/h2\u003e \u003cp\u003eThe mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation of the operation time was 24.85\u0026thinsp;\u0026plusmn;\u0026thinsp;8.09 (min.), and of the recovery time was 7.23\u0026thinsp;\u0026plusmn;\u0026thinsp;3.22 (min.). The median VAS pain score (10 min. after awakening) was 1 (0, 2). Two cases showed vomiting, three cases occurred dizziness and one cases had agitation after awakening. No respiratory depression, hypotension and nightmares occurred in all cases.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eED\u003csub\u003e50\u003c/sub\u003e/ED\u003csub\u003e95\u003c/sub\u003e is a common sensitive index in clinical study of drug dose-effect relationship [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Sequential method [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] is a classical method for calculating the ED\u003csub\u003e50\u003c/sub\u003e/ED\u003csub\u003e95\u003c/sub\u003e of drugs with fewer cases and less experimental period, and it is used normally in the anaesthetic drugs study. In our study, we measured the ED\u003csub\u003e50\u003c/sub\u003e/ED\u003csub\u003e95\u003c/sub\u003e and 95% CI of esketamine by using the sequential method, and the main criterion was whether the body movement was inhibited during hysteroscopy.\u003c/p\u003e \u003cp\u003eEsketamine is a sedative and analgesic anesthetic. It is a dextral structure of ketamine and acts through antagonizing NMDA receptors. When combined with propofol, esketamine could produce a good clinical anesthetic effect [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Eberl et al [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. reported that the synergistic effect of ketamine and propofol could improve the safety and satisfaction of patients and reduce the using dose of drugs during ERCP,. Zhang Zhongqi et al [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. repoerted that esketamine at 0.3 mg/kg when combined with propofol in gastroscopy not only reduced the risk of cardiovascular and respiratory adverse events, but also provided sedation and analgesia. Zhan Yongtong et al [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. also reported that esketamine at 0.2 mg/kg when combined with propofol in gastroscopy had shorter anesthesia induction time, lower incidence of cough and body movement, and less consumption of propofol per minute than propofol alone, and there was no effect on recovery time, hemodynamic stability, postoperative cognitive function, and incidence of adverse events. Chen Jiejuan et al [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. reported that the anesthesia effect of intravenous esketamine at 0.25mg/kg combined with propofol for painless abortion was better than that of fentanyl combined with propofol.\u003c/p\u003e \u003cp\u003eIn this study, we also found that the combination of esketamine and propofol also produced a good clinical anesthetic effect during hysteroscopy. None of the patients developed hypotension, bradycardia and respiratory inhibition, which was explained by the sympathomimetic activity of esketamine to antagonize the inhibitory effect of propofol on the respiratory and to counteract the vagal reflex effect during surgery [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The mean arterial pressure (MAP) of patients during cervical dilatation (T\u003csub\u003e3\u003c/sub\u003e ) was significantly higher than that of other four monitoring points (T\u003csub\u003e1\u003c/sub\u003e, T\u003csub\u003e2\u003c/sub\u003e, T\u003csub\u003e4\u003c/sub\u003e, T\u003csub\u003e5\u003c/sub\u003e), which indicated that cervical dilatation was a great stimulus in patients, but all MAP fluctuated within 20% range of preoperative blood pressure. The BIS value of intraoperative anesthetic depth was maintained between 65 and 75.\u003c/p\u003e \u003cp\u003e2 patients showed postoperative nausea and vomiting, and 3 patients experienced postoperative dizziness, which all of them relieved about 2 hours after operation. All patients did not experience psychiatric adverse effects such as nightmares and cognitive impairment, which correlated with the reduced use of esketamine and possibly also related with the reduced incidence of adverse effects by propofol through activating GABA receptors. The median VAS pain score (10 min, after awakening) of the patients was 1 (0, 2), which indicated that esketamine had a good analgesic effect. Its related mechanism may be through inhibiting NMDA receptor which linked nociceptive stimulus conduction at the central and peripheral system, and may also through activating the pain inhibitory system.\u003c/p\u003e \u003cp\u003eIn this study, target-controlled infusion of propofol using a plasma concentration of 3 \u0026micro;g/mL was applied to maintain the whole procedure from anesthesia induction, anesthesia maintenance to awakening as a continuous procedure with less impact on the respiratory and circulatory system of patients, less medication consumption, and easier regulation of intraoperative anesthetic depth.\u003c/p\u003e \u003cp\u003eThis study was limited to patients with no history of vaginal delivery. which had greater stimulation intensity during cervical dilatation than in those with a history of vaginal delivery. Therefore, patients with a history of vaginal delivery to undergo hysteroscopy may require a smaller dose of esketamine. The specific effective dose of esketamine requires further study.\u003c/p\u003e \u003cp\u003eIn conclusion, combined with target-controlled infusion of propofol (3 \u0026micro;g/mL in plasma concentration) during hysteroscopy, the ED\u003csub\u003e50\u003c/sub\u003e and ED\u003csub\u003e95\u003c/sub\u003e of esketamine were 0.391 mg/kg and 0.476 mg/kg, respectively, without significant adverse effects.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe ED\u003csub\u003e50\u003c/sub\u003e/ED\u003csub\u003e95\u003c/sub\u003e of esketamine combined with propofol at plasma concetration 3 \u0026micro;g/mL inhibiting body movement in patients with hysteroscopy were 0.391 mg/kg and 0.476 mg/kg, respectively. So, esketamine at 0.476 mg/kg which combined with propofol at plasma concetration 3 \u0026micro;g/mL showed a good analgesic effect in hysteroscopy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThanks are due to all those who assisted in recruitment and program delivery of this study\u0026mdash;notably, to the families, doctors, anesthesiologist, and nurses. Thanks to the experts and professors of the ethics committee for participating in the review of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShuangfeng Li and Dan Wang conceived and designed the experiments; Jun Wang and Shuai Chen performed the experiments;Zhenzhen Li, Ying Zhong ,Jun Wang, Wang Dan, Shuai Chen analyzed the data and wrote the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Hainan Health Science and Education Project of China (grant number: 820QN393).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\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\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the Medical Ethics Committee of Haikou Maternal and Child Health Hospital. And this study was passed by the Chinese Clinical Trial Registry (Registration date: January 13\u003csup\u003eth\u003c/sup\u003e,2024; Registration number: ChiCTR2400079831). The patients/participants provided their written informed consent to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOkohue JE. Overview of hysteroscopy. West Afr J Med, 2020, 37(2): 178-182.\u003c/li\u003e\n\u003cli\u003eYu J, Xiang B, Song Y, Chen H, Li Y, Liu C. ED50 of propofol in combination with low‐dose sufentanil for intravenous anaesthesia in hysteroscopy. Basic Clin Pharmacol Toxicol, 2019;125(5):460-465. \u003c/li\u003e\n\u003cli\u003eWang J, Huang J, Yang S, Cui C, Ye L, Wang SY, Yang GP, Pei Q. Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine:A Randomized, Open-Label Clinical. Drug Des Devel Ther. 2019;13:4135-4144. \u003c/li\u003e\n\u003cli\u003eLei Y, Liu H, Xia F, Gan S, Wang Y, Huo W, Wang Q, Ji F. Effects of Esketamine on Acute and Chronic Pain After Thoracoscopy Pulmonary Surgery Under General Anesthesia: A Multicenter-Prospective, Randomized, Double-Blind, and Controlled Trial. Front Med (Lausanne). 2021;8:693594.\u003c/li\u003e\n\u003cli\u003eXin N, Yan W, Jin S. Efficacy of Analgesic Propofol/Esketamine and Propofol/Fentanyl for Painless Induced Abortion: A Randomized Clinical Trial. Biomed Res Int. 2022;2022:5095282. \u003c/li\u003e\n\u003cli\u003eDixon WJ. Staircase bioassay: the up-and-down method. Neurosci Biobehav Rev. 1991;15(1):47\u0026ndash;50.\u003c/li\u003e\n\u003cli\u003eGorges M, Zhou G, Brant R, Ansermino JM. Sequential allocation trial design in anesthesia: an introduction to methods, modeling, and clinical applications. Paediatr Anaesth. 2017;27(3):240\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eDixon WJ. The up-and-Down method for small samples. Journal of the American Statistical Association. 1965;312:967-978. \u003c/li\u003e\n\u003cli\u003eEberl S, Koers L, van Hooft JE, de Jong E, Schneider T, Hollmann MW, Preckel B. Sedation with propofol during ERCP: is the combination with esketamine more effective and safer than with alfentanil? Study protocol for a randomized controlled trial. Trials. 2017;18(1):472.\u003c/li\u003e\n\u003cli\u003eZheng Y, Xu Y, Huang B, Mai Y, Zhang Y, Zhang Z. Effective dose of propofol combined with a low-dose esketamine for gastroscopy in elderly patients: A dose finding study using dixon\u0026apos;s up-and-down method. Front Pharmacol. 2022;13:956392. \u003c/li\u003e\n\u003cli\u003eZhan Y, Liang S, Yang Z, Luo Q, Li S, Li J, Liang Z, Li Y. Efficacy and safety of subanesthetic doses of esketamine combined with propofol in painless gastrointestinal endoscopy: a prospective, double-blind, randomized controlled trial. BMC Gastroenterol. 2022;22(1):391. \u003c/li\u003e\n\u003cli\u003eChen J, Zou X, Hu B, Yang Y, Wang F, Zhou Q, Shen M. Effect of different doses of esketamine compared with fentanyl combined with propofol on hypotension in patients undergoing painless abortion surgery: a prospective, randomized, double-blind controlled clinical trial. BMC Anesthesiol. 2022;22(1):305.\u003c/li\u003e\n\u003cli\u003eJonkman K, van Rijnsoever E, Olofsen E, Aarts L, Sarton E, van Velzen M, Niesters M, Dahan A. Esketamine counters opioid-induced respiratory depression. Br J Anaesth. 2018;120(5):1117-1127.\u003c/li\u003e\n\u003cli\u003eTrimmel H, Helbok R, Staudinger T, Jaksch W, Messerer B, Sch\u0026ouml;chl H, Likar R. S(+)-ketamine : Current trends in emergency and intensive care medicine. Wien Klin Wochenschr. 2018;130(9-10):356-366. \u003c/li\u003e\n\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":"Esketamine, Propofol, Hysteroscopy, Sequential method, Half effective dose","lastPublishedDoi":"10.21203/rs.3.rs-3942407/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3942407/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePatients would have a strong discomfort feeling and pain in hysteroscopic surgery because of expanding the cervical canal and tissue stretching. Nowadays, propofol has no analgesic effect, it is necessary to combine other analgesic drugs to inhibit intraoperative body movement and eliminate discomfortable feeling. This study was to explore the half effective dose (ED\u003csub\u003e50\u003c/sub\u003e) and 95% effective dose (ED\u003csub\u003e95\u003c/sub\u003e) of esketamine combined with propofol in inhibiting body movement when patients underwent hysteroscopy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e26 patients who needed hysteroscopy were recruited in Haikou Maternal and Child Health Hospital of China. All patients received intravenous esketamine and propofol. The plasma concentration of propofol was set to 3 \u0026micro;g/mL for target-controlled infusion. The dose of esketamine was determined by the Dixon up-and-down sequential method. The ED\u003csub\u003e50\u003c/sub\u003e/ED\u003csub\u003e95\u003c/sub\u003e of esketamine were detected by binary regression (probit). The respiration, circulation and body movement of patients were observed. The operating time, the awakening time and the analgesic effect were recorded.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe ED\u003csub\u003e50\u003c/sub\u003e/ED\u003csub\u003e95\u003c/sub\u003e of esketamine combined with propofol plasma concetration 3 \u0026micro;g/mL inhibiting body movement in patients with hysteroscopy were 0.391 mg/kg and 0.476 mg/kg, respectively (95% confidence intervals were 0.34\u0026ndash;0.431 mg/kg and 0.434\u0026ndash;0.778 mg/kg). There are not respiratory and circulatory depression in all patients.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eEsketamine at 0.476 mg/kg which combined with propofol plasma concetration 3 \u0026micro;g/mL showed a good analgesic effect in hysteroscopy.\u003c/p\u003e","manuscriptTitle":"The ED 50 /ED 95 of esketamine in inhibiting body movement when patients undergoing hysteroscopy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-13 19:20:08","doi":"10.21203/rs.3.rs-3942407/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":"91af8275-d2fd-4fff-a9f4-3073b3a1e63b","owner":[],"postedDate":"February 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-20T16:15:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-13 19:20:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3942407","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3942407","identity":"rs-3942407","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}