Perioperative Intravenous Esketamine Infusion for Cesarean Section Pain Relief: A Prospective Randomized Controlled Study

Perioperative Intravenous Esketamine Infusion for Cesarean Section Pain Relief: A Prospective Randomized Controlled Study | 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 Perioperative Intravenous Esketamine Infusion for Cesarean Section Pain Relief: A Prospective Randomized Controlled Study Siqi Ma, Hao Guo, Xiaoyan Ran, Xuelian Pan, Xinjun Luo, Yun Xiao, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4006081/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 Purpose: To investigate the safety and efficacy of esketamine combined with butorphanol for postoperative analgesia after cesarean section. Methods: 160 parturients who underwent cesarean section were randomly divided into two groups: Group S received intraoperative esketaimine infusion with 0.15mg/kg/h and postoperative 0.2mg/kg butorphanol+ 2mg/kg esketaimine for patient-controlled intravenous analgesia (PCIA). Group C received the same volume of 5% glucose infusion and postoperative butorphanol 0.2mg/kg for PCIA. The primary outcome was postoperative analgesic effectiveness as reflected by the number of analgesic pumps pressed during 24h postoperative period by patients. The secondary outcomes included the VAS scores of postoperative pain, Edinburgh Postnatal Depression Scale (EPDS) scores, neonatal Apgar scores, the time to first get out of bed, the gut functional recovery time, the rescue analgesic treatments, and adverse effects. Results: There was no statistical difference in analgesic effectiveness during the 24h postoperative period (P>0.05). Both the number of analgesic pump presses and VAS scores during the postoperative period were not significantly different between the two groups (P＞0.05). The EPDS scores of Group S at postoperative 8h, 24h, 96h, and one week were lower than in the C group (P<0.05). The incidence of dizziness was higher in Group S (P<0.05). Conclusion: Supplement of esketamine during the perioperative period can not improve postoperative analgesia after cesarean section, and increases the incidence of adverse effects. Trial registration: The trial was registered with Chinese Clinical Trial website (www.chictr.org.cn/index.aspx ChiCTR2100054435) on December 27, 2021 (27/12/2021). obstetric analgesia patient-controlled intravenous analgesia postpartum depression Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Cesarean section is a highly invasive procedure with moderate/severe pain, and persistent postoperative pain affects parturients' postoperative recovery and is associated with the development of postpartum depression[ 1 ]. Post-cesarean pain mainly includes incisional pain and visceral pain from uterine contractions. Unlike other surgeries, parturients after cesarean section have the extra burden of breastfeeding their newborn. The possible adverse effects of drug secretion through breast milk on the newborn limited the clinical application of many analgesics, such as Non-Steroidal Anti-inflammatory Drugs (NSAIDs) and opioids[ 2 ]. Butorphanol, one of the partial opioid receptor agonists, is recommended by the World Health Organization for pain management after cesarean section. However, our clinical experience and previous studies showed that butorphanol alone is not effective for pain relief and parturients are unwilling to get out of bed[ 3 ]. Multimodal analgesia is a well-known strategy for improving the effectiveness of postoperative analgesia[ 4 – 6 ]. The advantage is to use the combination of drugs with different mechanisms of action, which can achieve more efficient analgesia by reducing the dose of a single drug, thus reducing adverse effects. However, considering the effects of analgesic drugs on postpartum contractions, as well as on the newborn and lactation, the utilization of commonly used analgesic drugs for other types of surgery is not suitable for cesarean section. Esketamine is a new analgesic drug, which produces analgesia and anesthesia by non-competitive antagonism of NMDA receptors, and has higher efficacy and lower side effects in comparison with ketamine[ 7 ]. It was reported that esketamine can be safely used as a single intravenous injection for analgesia during cesarean section[ 8 ]. It has been shown that the use of esketamine in combination with oxycodone for postoperative analgesia in lumbar fusion significantly reduced the consumption of opioids and improved analgesia without serious adverse effects[ 9 ], but studies on the use of esketamine for postoperative analgesia in cesarean section need to be investigated further. In addition to the analgesic effect, esketamine has also shown significant therapeutic effects in the clinical treatment of depression[ 10 ], so it is worth further exploring whether the use of esketamine for postoperative analgesia in cesarean delivery can reduce the occurrence of postpartum depression. Therefore, this study was designed to determine the safety and efficacy of combined esketamine and butorphanol for postoperative analgesia after cesarean section. Methods Subjects This randomized, controlled, double-blind, prospective clinical study was approved by the Shiyan Renmin Hospital Ethics Committee (syrmyy2021-018) and registered on the Chinese Clinical Trial website ( www.chictr.org.cn/index.aspx ChiCTR2100054435) on December 27, 2021 (27/12/2021). 160 patients who received cesarean section at Shiyan Renmin Hospital from January 2022 to August 2022 were recruited. Inclusion criteria included: 1) age 20–40 years, 2) singleton intrauterine pregnancy, 3) BMI 18–25 kg/m2, 4) ASA class Ⅱ-Ⅲ. Exclusion criteria included: 1) patients with major organ diseases such as heart, brain, lung, liver, and kidney; 2) patients with combined severe physical diseases, cognitive dysfunction, psychiatric diseases, and language communication disorders; 3) history of allergy to the study drugs and opioids; 4) long-term use of antipsychotics and opioids. Rejected criteria included: 1) switching to general anesthesia; 2) serious adverse events (malignant arrhythmia, acute hemorrhagic shock) during surgery; 3) follow-up loss. Anesthetic Management Patients were monitored for electrocardiography, heart rate, pulse oximetry, and body temperature upon admission to the operating room, pure oxygen was administered via face mask at 2L/min and peripheral venous cannulation was established. The combined-spinal epidural anesthesia was performed in the L3-4 interval, and 0.5% ropivacaine(Guangdong Jiabo Pharmaceutical Co. Ltd, China) 15mg was given in the subarachnoid space after the outflow of cerebrospinal fluid, and an epidural catheter was then placed 4cm upward. Epidural local anesthetics were added to maintain the block level of T6-S2, and the hemodynamic stability was maintained with intravenous fluids supplemented with vasoactive drugs as necessary. An intravenous analgesic pump(Jiangsu Renxian Medical Technology Co., Ltd, China) started to run when leaving the operating room at the end of surgery. Intervention On the morning of the surgery, 160 patients were randomly allocated to one of the two groups with a 1:1 ratio using computer-generated random numbers: The esketamine + butorphanol group (group S) received an intraoperative infusion of esketamine(Jiangsu Hengrui Pharmaceutical Co., Ltd, China) 0.15mg/kg/h and postoperative butorphanol(Jiangsu Hengrui Pharmaceutical Co., Ltd China) 0.2mg/kg + esketamine 2mg/kg + azasetron(Nanjing Pharmaceutical Factory Co. Ltd, China) 20mg diluted to 150ml with saline for patient-controlled intravenous analgesia (PCIA); The butorphanol group (group C) received equal volume of 5% glucose (Sichuan Kelun Pharmaceutical Co., Ltd, China) solution as the above group and postoperative butorphanol 0.2mg/kg + azasetron 20mg diluted to 150ml with saline for PCIA. Analgesic pump parameters were 3 ml loading volume, 3 ml/h background infusion volume, Patient-Controlled Analgesia 3 ml PCIA, and 15 min lock time. If analgesia was inadequate and patients felt intolerable pain, it was rescued with diclofenac sodium (Hubei Dongxin Pharmaceutical Co. Ltd, China). Outcome assessment The primary outcome was postoperative analgesic effectiveness as reflected by the number of analgesic pumps pressed during 24h postoperative period by patients. Secondary outcomes included the Visual Analog Scale (VAS) scores together with the rescue analgesic treatments, the time to first get out of bed, and gut functional recovery time. The occurrence of adverse reactions such as postoperative nausea and vomiting (PONV), dizziness, nightmares, restlessness, hallucinations, and blurred vision were also recorded. The neonatal Apgar scores were recorded at 1 min and 5 min after birth. The Edinburgh Postnatal Depression Scale (EPDS) scores were evaluated at 8h, 24h, 96h, and one week postoperatively. Statistical Analysis and Sample Size Retrospective analysis of clinical data in Shiyan Renmin Hospital yielded that if patients used the same analgesia methods as group C, the mean analgesic pump pressed times was 12(7). We assumed that our trial strategy improved postoperative analgesia with a reduction of the pump pressed number by 30%, a minimum of 144 patients was required with a two-tailed α = 0.05 and power of 90%, the sample size ratio of 1:1. Considering a loss-to-follow-up rate of 10%, 160 patients (80 patients/arm) would need to be recruited in the study. Continuous variables conforming to the features of normal distribution were represented as mean ± standard deviation and analyzed using the independent t-test. Non-normally distributed measures are expressed as median (M) and interquartile range (IQR) and analyzed with the Mann-Whitney U test. Qualitative variables were presented as numbers (percentages) and analyzed by using the Chi-square test. All analyses were done with SPSS version 26.0 (IBM Corp. Armonk, NY, USA). P values of less than 0.05 were considered to be statistically significant. Results A total of 160 maternities undergoing cesarean section were randomly divided into 2 groups. Three patients were excluded because of excessive blood loss, and two patients were excluded because they switched to general anesthesia. The outcome analysis included the final 155 patients (Group S, n = 78; Group C, n = 77) (Fig. 1 ). The demographic and clinical characteristics of the randomized subjects, and there were no clinically significant differences (Table 1 ). GraphPad Prism 8.0.2 was used to create all the artwork. Table 1 Demographics of the parturients VARIABLES GROUP C GROUP S P VALUE AGE (YEARS) 31.0(4.5) 31.6(4.1) 0.36 BMI (KG/㎡) 22.3(1.9) 21.7(2.0) 0.07 ASA CLASS (Ⅱ/Ⅲ) 73/4 75/3 0.69 NUMBER OF CESAREAN DELIVERIES (1/2) 53/24 53/25 0.91 PREOPERATIVE VAS SCORE 0.8(0.7) 0.8(0.7) 0.67 PREOPERATIVE EPDS SCORE 2.9(0.9) 2.9(1.0) 0.10 Group S: Intraoperative infusion of esketamine and postoperative butorphanol plus esketamine 2mg/kg and azasetron; Group C: Postoperative butorphanol and azasetron. Number of PCA compressions at 24h postoperatively There was no statistical difference in the number of PCA presses in group C [12(6 ~ 18)] and group S [10(5 ~ 22.25)] during 24h after surgery [P > 0.05, 95% CI (-3 to 3)]. (FIG.2) VAS scores at different time points The differences in VAS scores between the two groups were not statistically significant at 8h [P > 0.05, 95% CI (0 to 1)], 24h [P > 0.05, 95% CI (0 to 1)], and 96h [P > 0.05, 95% CI (0 to 0)]. (Fig. 3 ). EPDS scores at different time points Compared with the group C, the group S had significantly lower EPDS scores at postoperative 8h [P < 0.05, 95% CI (1 to 2)], 24h [P < 0.05, 95% CI (1 to 2)], 96h [P < 0.05, 95% CI (1 to 2)], and one week [P 0.05, 95% CI (0 to 0)] and 5min Apgar scores [P > 0.05, 95% CI (0 to 0)] of both groups. The time to first get out of bed and intestinal exhaust time No statistically significant differences were found when comparing the time to first bed [P > 0.05, MD = 0.423, 95% CI (-1.33 to 2.18)] and time to intestinal exhaust [P > 0.05, MD = 0.196, 95% CI (-2.53 to 2.92)] of both groups. Postoperative rescue analgesia and incidence of adverse reactions When comparing the incidence of the postoperative rescue analgesia of the two groups, the difference between them was not statistically significant [P > 0.05, RR = 0.844, 95% CI (0.46 to 1.55)]. The incidence of dizziness in group S (15/78, 19%) was higher than in group C (4/77, 5%) [P < 0.05, RR = 0.270, 95% CI (0.09 to 0.78)]. One patient in group S had hallucination, which was none in group C. The other adverse reactions such as respiratory depression and skin pruritus were no significant difference in both groups after surgery (Table 2 ). Table 2 Postoperative remedial analgesia and incidence of adverse reactions Factors Group C Group S P value Remedial analgesia 19% (15/77) 23% (18/78) 0.58 respiratory depression 0 0 skin pruritus 0 0 PONV 5% (4/77) 6% (5/78) 0.75 Dizziness 5% (4/77) 19% (15/78)* 0.01* Nightmares 1% (1/77) 3% (2/78) 0.57 Restlessness 3% (2/77) 3% (2/78) 0.99 Hallucinations 0 1% (1/78) 0.32 Blurred vision 1% (1/77) 0 0.31 PONV: postoperative nausea and vomiting. Group S: Intraoperative infusion of esketamine and postoperative butorphanol plus esketamine 2mg/kg and azasetron; Group C: Postoperative butorphanol and azasetron. *: Compared with the group C, P < 0.05. Discussion To our knowledge, the rate of excellent postoperative analgesia after the cesarean section was relatively low[ 11 ]. To explore the more effective scheme to control postoperative pain after the cesarean section, we designed this single-center, prospective, double-blind, randomized, placebo-controlled trial. This study did not show the statistical difference in the number of 24h PCA presses in group S compared to group C, and the VAS scores at each postoperative time point. These indicated that esketamine may have no improved effect on the management of maternal pain in the postoperative period. However, Wang Ye et al. showed that 0.004-0.01mg/kg/h esketamine with sufentanil for postoperative PCIA after cesarean delivery significantly reduced the incidence of postoperative pain[ 12 ]. The reason for this difference may be due to the difference between combined drugs and the dosage of esketamine, and it may also be related to the fact that we take the number of PCA presses as the main index. The emotional state of patients may be a factor to impacts the pain sensitivity of the parturients after surgery. In this study, EPDS scores were lower in group S than in group C at all postoperative time points. It inferred that intraoperative esketamine 0.15mg/kg/h combined with postoperative 0.04mg/kg/h continuous intravenous infusion was effective in improving maternal emotional state up to one week after surgery. It has been reported that low-dose esketamine combined with sufentanil can improve postoperative depression after cesarean delivery[ 13 ]. Intravenous administration of 0.5mg/kg of esketamine rapidly relieved suicidal ideation in postpartum depression[ 14 ]. The mechanism of the antidepressant effect of esketamine is not clear, it may be related to a decrease in the release of γ-amino butyric acid (GABA) and an increase in glutamate content in the synaptic gap, leading to enhanced excitatory synaptic activity[ 15 ]. This study has shown that there was no significant difference in the Apgar scores of neonates in group S at 1min, 5mim after birth compared with group C. Therefore, the application of esketamine 0.15mg/kg/h intravenous pumping before fetal delivery did not affect neonatal outcomes. As for the other adverse effects, there was no significant difference between the two groups except that the incidence of dizziness was higher in Group S. The previous study also found that dizziness was the most common adverse effect after intranasal administration of esketamine, but all patients' dizziness resolved spontaneously about 2 hours after surgery when no special treatment was required[ 16 ]. The present study showed no statistical difference in the time to first postoperative bed activity between the two groups. This indicated that dizziness due to esketamine did not affect maternal postoperative activity. Although there was one case of hallucination and two cases of nightmares in group S, there was no statistical difference compared with group C and no serious consequences. Consequently, perioperative esketamine combined with butorphanol infusion was a safe and effective treatment without severe adverse effects. The limitation of this study was the insufficient sample size. The relatively small sample size made this hypothesis-generating study underpowered to show more statistical differences between groups. The other limitation was we did not test the higher dosage of esketamine infusion in consideration of the safety of newborns. Conclusion Supplement of esketamine during the perioperative period can not improve postoperative analgesia after cesarean section and increases the incidence of adverse effects. Abbreviations PCIA: patient-controlled intravenous analgesia EPDS: Edinburgh Postnatal Depression Scale NSAIDs: Non-Steroidal Anti-inflammatory Drugs VAS: Visual Analog Scale PONV: postoperative nausea and vomiting CI: confidence interval IQR: interquartile range GABA: γ-amino butyric acid Declarations Ethics approval and consent to participate The research studies on humans have been performed in accordance with the principles stated in the Declaration of Helsinki. Prior to starting the study, ethical approval was obtained for all protocols from the Shiyan Renmin Hospital Ethics Committee(syrmyy2021-018). All participants signed informed consent prior to inclusion in the study. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding The research was supported by the National Natural Science Foundation of China [grant number 81341111 and 81701891], Youth Foundation of Hubei Provincial Health Committee [grant number WJ2021Q009], Key Research and Development Plan of Hubei Province [grant number 2022BCE007]. Authors’ contributions All authors have given substantial contributions to the conception or the design of the manuscript, including author Siqi Ma, author Hao Guo, and author Xiaoyan Ran to the acquisition, analysis, and interpretation of the data. All authors have participated in drafting the manuscript, and author Siqi Ma revised it critically. All authors read and approved the final version of the manuscript. Acknowledgments The authors acknowledge the Department of Anesthesiology and Pain Medicine of the hospital where the study took place, especially the maternal area and the Department of Obstetrics and Gynecology of the hospital. References Sun KW, Pan PH. Persistent pain after cesarean delivery. 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A systematic review of opioid use and multimodal strategies in solid organ transplant recipients and living donors. Pharmacotherapy. 2023;43(6):514-51. Stormholt ER, Steiness J, Derby CB, Larsen ME, Maagaard M, Mathiesen O. Glucocorticoids added to paracetamol and NSAIDs for post-operative pain: A systematic review with meta-analysis and trial sequential analysis. Acta Anaesthesiol Scand. 2023;67(6):688-702. Zhang X, Wang J, An XH, Chao YC, Bian Y, Xu Z, et al. Optimum dose of spinal ropivacaine with or without single intravenous bolus of S-ketamine during elective cesarean delivery: a randomized, double-blind, sequential dose-finding study. BMC Pregnancy Childbirth. 2021;21(1):746. Shen J, Song C, Lu X, Wen Y, Song S, Yu J, et al. The effect of low-dose esketamine on pain and post-partum depression after cesarean section: A prospective, randomized, double-blind clinical trial. Front Psychiatry. 2022;13:1038379. Brinck ECV, Virtanen T, Makela S, Soini V, Hynninen VV, Mulo J, et al. S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: A randomized, double-blind, placebo-controlled clinical trial. PLoS One. 2021;16(6):e0252626. Fu DJ, Zhang Q, Shi L, Borentain S, Guo S, Mathews M, et al. Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality. BMC Psychiatry. 2023;23(1):587. Usichenko TI, Henkel BJ, Klausenitz C, Hesse T, Pierdant G, Cummings M, et al. Effectiveness of Acupuncture for Pain Control After Cesarean Delivery: A Randomized Clinical Trial. JAMA Netw Open. 2022;5(2):e220517. Wang Y, Zhang Q, Dai X, Xiao G, Luo H. Effect of low-dose esketamine on pain control and postpartum depression after cesarean section: a retrospective cohort study. Ann Palliat Med. 2022;11(1):45-57. Han Y, Li P, Miao M, Tao Y, Kang X, Zhang J. S-ketamine as an adjuvant in patient-controlled intravenous analgesia for preventing postpartum depression: a randomized controlled trial. BMC Anesthesiol. 2022;22(1):49. Machado C, Lacerda ALT, Bressan RA, Noto C. Esketamine for Postpartum Suicidality. Biol Psychiatry. 2021;89(6):e35-e6. Krystal JH, Charney DS, Duman RS. A New Rapid-Acting Antidepressant. Cell. 2020;181(1):7. Morrison RL, Fedgchin M, Singh J, Van Gerven J, Zuiker R, Lim KS, et al. Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. Psychopharmacology (Berl). 2018;235(4):1107-19. 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. 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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-4006081","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":283561492,"identity":"8dc982e1-0d03-4af8-bc39-28063abc1108","order_by":0,"name":"Siqi Ma","email":"","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Siqi","middleName":"","lastName":"Ma","suffix":""},{"id":283561493,"identity":"d3f7869b-6521-42bc-b896-1e0f81678098","order_by":1,"name":"Hao Guo","email":"","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Guo","suffix":""},{"id":283561494,"identity":"9042f2b4-98ec-442f-8545-86b54a988f01","order_by":2,"name":"Xiaoyan Ran","email":"","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyan","middleName":"","lastName":"Ran","suffix":""},{"id":283561495,"identity":"d5dfa4de-7d0a-4de8-a675-540a214a2919","order_by":3,"name":"Xuelian Pan","email":"","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xuelian","middleName":"","lastName":"Pan","suffix":""},{"id":283561496,"identity":"137c81a5-d635-4722-8f22-d2a33b6b5609","order_by":4,"name":"Xinjun Luo","email":"","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xinjun","middleName":"","lastName":"Luo","suffix":""},{"id":283561497,"identity":"3497f1ca-a7f7-4626-a209-3998af370121","order_by":5,"name":"Yun Xiao","email":"","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Xiao","suffix":""},{"id":283561498,"identity":"a763d24d-ab04-4bb4-80d3-cc78bd6cc098","order_by":6,"name":"Rui Xue","email":"","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Xue","suffix":""},{"id":283561499,"identity":"b638b1b7-0f7f-4ac2-b04e-7267d738ae3f","order_by":7,"name":"Ran Ran","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYPACCR7G9uYDBz78IF6LhQxzz7HEgzN7iNdSYcM+w8f4MAcbEWrN288e+/BzhwQP7wyeD4cZeBjk+cUO4NcicyYveWbvGQkeydm9Gw4XWDAYzpydgF+LBEOOMQNvmwSP4ZyzGw7P4GFIMLhNSAv/G2PGv0At9jdyHhzmYSNGi0SOMTPIFsYZOQzEanljzCwL0tJzzAAYyBJE+IU/x5jxbVudPTAqH3/48MNGnl+agBYMI0hTPgpGwSgYBaMAOwAATCtAx+C8aWoAAAAASUVORK5CYII=","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Ran","middleName":"","lastName":"Ran","suffix":""}],"badges":[],"createdAt":"2024-03-02 09:44:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4006081/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4006081/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53669450,"identity":"2643b134-c3d7-4535-9f8d-94f022bb7f49","added_by":"auto","created_at":"2024-03-28 17:38:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":84519,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT flow diagram for the study\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4006081/v1/24cb181728766c3204e38896.png"},{"id":53669448,"identity":"f5d7c7b5-cf2a-4acd-9e5b-d647985f1b62","added_by":"auto","created_at":"2024-03-28 17:38:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26755,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of PCA compressions at 24h postoperatively\u003c/p\u003e\n\u003cp\u003eGroup S: Intraoperative infusion of esketamine and postoperative butorphanol plus esketamine 2mg/kg and azasetron; Group C: Postoperative butorphanol and azasetron.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4006081/v1/799deea0384eb96a06b2c12a.png"},{"id":53669452,"identity":"b960267b-f552-4f57-af33-42580c140aa9","added_by":"auto","created_at":"2024-03-28 17:38:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30437,"visible":true,"origin":"","legend":"\u003cp\u003eVAS scores at each postoperative time point\u003c/p\u003e\n\u003cp\u003eVAS: level of pain scores on a 0 to 10 scale: 0 = no pain to 10 =worst pain imaginable. Group S: Intraoperative infusion of esketamine and postoperative butorphanol plus esketamine 2mg/kg and azasetron; Group C: Postoperative butorphanol and azasetron.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4006081/v1/f2417d51c6c554d4e5feaee5.png"},{"id":53670296,"identity":"4515cc6e-0c4e-4d5c-aca0-0f067cc26561","added_by":"auto","created_at":"2024-03-28 17:46:13","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":35049,"visible":true,"origin":"","legend":"\u003cp\u003eEPDS scores at each postoperative time point\u003c/p\u003e\n\u003cp\u003eEPDS scores: level of depression scores on a 0 to 30 scale: less than 9 = normal, 9~13 = high-risk groups, more than 13 = postpartum depression. Group S: Intraoperative infusion of esketamine and postoperative butorphanol plus esketamine 2mg/kg and azasetron; Group C: Postoperative butorphanol and azasetron. *: Compared with the group C, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4006081/v1/069ad92b013776582c88c54f.png"},{"id":59620524,"identity":"f9d42bcf-23ec-4edf-864d-8a4aa9654dca","added_by":"auto","created_at":"2024-07-04 01:59:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":683517,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4006081/v1/052db2e2-763f-4715-88f9-6c21ccce605c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Perioperative Intravenous Esketamine Infusion for Cesarean Section Pain Relief: A Prospective Randomized Controlled Study","fulltext":[{"header":"Background","content":"\u003cp\u003eCesarean section is a highly invasive procedure with moderate/severe pain, and persistent postoperative pain affects parturients' postoperative recovery and is associated with the development of postpartum depression[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Post-cesarean pain mainly includes incisional pain and visceral pain from uterine contractions. Unlike other surgeries, parturients after cesarean section have the extra burden of breastfeeding their newborn. The possible adverse effects of drug secretion through breast milk on the newborn limited the clinical application of many analgesics, such as Non-Steroidal Anti-inflammatory Drugs (NSAIDs) and opioids[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Butorphanol, one of the partial opioid receptor agonists, is recommended by the World Health Organization for pain management after cesarean section. However, our clinical experience and previous studies showed that butorphanol alone is not effective for pain relief and parturients are unwilling to get out of bed[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMultimodal analgesia is a well-known strategy for improving the effectiveness of postoperative analgesia[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The advantage is to use the combination of drugs with different mechanisms of action, which can achieve more efficient analgesia by reducing the dose of a single drug, thus reducing adverse effects. However, considering the effects of analgesic drugs on postpartum contractions, as well as on the newborn and lactation, the utilization of commonly used analgesic drugs for other types of surgery is not suitable for cesarean section. Esketamine is a new analgesic drug, which produces analgesia and anesthesia by non-competitive antagonism of NMDA receptors, and has higher efficacy and lower side effects in comparison with ketamine[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It was reported that esketamine can be safely used as a single intravenous injection for analgesia during cesarean section[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It has been shown that the use of esketamine in combination with oxycodone for postoperative analgesia in lumbar fusion significantly reduced the consumption of opioids and improved analgesia without serious adverse effects[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], but studies on the use of esketamine for postoperative analgesia in cesarean section need to be investigated further. In addition to the analgesic effect, esketamine has also shown significant therapeutic effects in the clinical treatment of depression[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], so it is worth further exploring whether the use of esketamine for postoperative analgesia in cesarean delivery can reduce the occurrence of postpartum depression.\u003c/p\u003e \u003cp\u003eTherefore, this study was designed to determine the safety and efficacy of combined esketamine and butorphanol for postoperative analgesia after cesarean section.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003eThis randomized, controlled, double-blind, prospective clinical study was approved by the Shiyan Renmin Hospital Ethics Committee (syrmyy2021-018) and registered on the Chinese Clinical Trial website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.chictr.org.cn/index.aspx\" target=\"_blank\"\u003ewww.chictr.org.cn/index.aspx\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn/index.aspx\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e ChiCTR2100054435) on December 27, 2021 (27/12/2021). 160 patients who received cesarean section at Shiyan Renmin Hospital from January 2022 to August 2022 were recruited. Inclusion criteria included: 1) age 20\u0026ndash;40 years, 2) singleton intrauterine pregnancy, 3) BMI 18\u0026ndash;25 kg/m2, 4) ASA class Ⅱ-Ⅲ. Exclusion criteria included: 1) patients with major organ diseases such as heart, brain, lung, liver, and kidney; 2) patients with combined severe physical diseases, cognitive dysfunction, psychiatric diseases, and language communication disorders; 3) history of allergy to the study drugs and opioids; 4) long-term use of antipsychotics and opioids. Rejected criteria included: 1) switching to general anesthesia; 2) serious adverse events (malignant arrhythmia, acute hemorrhagic shock) during surgery; 3) follow-up loss.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAnesthetic Management\u003c/h2\u003e \u003cp\u003ePatients were monitored for electrocardiography, heart rate, pulse oximetry, and body temperature upon admission to the operating room, pure oxygen was administered via face mask at 2L/min and peripheral venous cannulation was established. The combined-spinal epidural anesthesia was performed in the L3-4 interval, and 0.5% ropivacaine(Guangdong Jiabo Pharmaceutical Co. Ltd, China) 15mg was given in the subarachnoid space after the outflow of cerebrospinal fluid, and an epidural catheter was then placed 4cm upward. Epidural local anesthetics were added to maintain the block level of T6-S2, and the hemodynamic stability was maintained with intravenous fluids supplemented with vasoactive drugs as necessary. An intravenous analgesic pump(Jiangsu Renxian Medical Technology Co., Ltd, China) started to run when leaving the operating room at the end of surgery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eIntervention\u003c/h2\u003e \u003cp\u003eOn the morning of the surgery, 160 patients were randomly allocated to one of the two groups with a 1:1 ratio using computer-generated random numbers: The esketamine\u0026thinsp;+\u0026thinsp;butorphanol group (group S) received an intraoperative infusion of esketamine(Jiangsu Hengrui Pharmaceutical Co., Ltd, China) 0.15mg/kg/h and postoperative butorphanol(Jiangsu Hengrui Pharmaceutical Co., Ltd China) 0.2mg/kg\u0026thinsp;+\u0026thinsp;esketamine 2mg/kg\u0026thinsp;+\u0026thinsp;azasetron(Nanjing Pharmaceutical Factory Co. Ltd, China) 20mg diluted to 150ml with saline for patient-controlled intravenous analgesia (PCIA); The butorphanol group (group C) received equal volume of 5% glucose (Sichuan Kelun Pharmaceutical Co., Ltd, China) solution as the above group and postoperative butorphanol 0.2mg/kg\u0026thinsp;+\u0026thinsp;azasetron 20mg diluted to 150ml with saline for PCIA. Analgesic pump parameters were 3 ml loading volume, 3 ml/h background infusion volume, Patient-Controlled Analgesia 3 ml PCIA, and 15 min lock time. If analgesia was inadequate and patients felt intolerable pain, it was rescued with diclofenac sodium (Hubei Dongxin Pharmaceutical Co. Ltd, China).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcome assessment\u003c/h2\u003e \u003cp\u003eThe primary outcome was postoperative analgesic effectiveness as reflected by the number of analgesic pumps pressed during 24h postoperative period by patients. Secondary outcomes included the Visual Analog Scale (VAS) scores together with the rescue analgesic treatments, the time to first get out of bed, and gut functional recovery time. The occurrence of adverse reactions such as postoperative nausea and vomiting (PONV), dizziness, nightmares, restlessness, hallucinations, and blurred vision were also recorded. The neonatal Apgar scores were recorded at 1 min and 5 min after birth. The Edinburgh Postnatal Depression Scale (EPDS) scores were evaluated at 8h, 24h, 96h, and one week postoperatively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis and Sample Size\u003c/h2\u003e \u003cp\u003eRetrospective analysis of clinical data in Shiyan Renmin Hospital yielded that if patients used the same analgesia methods as group C, the mean analgesic pump pressed times was 12(7). We assumed that our trial strategy improved postoperative analgesia with a reduction of the pump pressed number by 30%, a minimum of 144 patients was required with a two-tailed α\u0026thinsp;=\u0026thinsp;0.05 and power of 90%, the sample size ratio of 1:1. Considering a loss-to-follow-up rate of 10%, 160 patients (80 patients/arm) would need to be recruited in the study.\u003c/p\u003e \u003cp\u003eContinuous variables conforming to the features of normal distribution were represented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and analyzed using the independent t-test. Non-normally distributed measures are expressed as median (M) and interquartile range (IQR) and analyzed with the Mann-Whitney U test. Qualitative variables were presented as numbers (percentages) and analyzed by using the Chi-square test. All analyses were done with SPSS version 26.0 (IBM Corp. Armonk, NY, USA). P values of less than 0.05 were considered to be statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 160 maternities undergoing cesarean section were randomly divided into 2 groups. Three patients were excluded because of excessive blood loss, and two patients were excluded because they switched to general anesthesia. The outcome analysis included the final 155 patients (Group S, n\u0026thinsp;=\u0026thinsp;78; Group C, n\u0026thinsp;=\u0026thinsp;77) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The demographic and clinical characteristics of the randomized subjects, and there were no clinically significant differences (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). GraphPad Prism 8.0.2 was used to create all the artwork.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographics of the parturients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVARIABLES\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGROUP C\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGROUP S\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP VALUE\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAGE (YEARS)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.0(4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.6(4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI (KG/㎡)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.3(1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.7(2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eASA CLASS (Ⅱ/Ⅲ)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUMBER OF CESAREAN DELIVERIES (1/2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53/24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53/25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePREOPERATIVE VAS SCORE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8(0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8(0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePREOPERATIVE EPDS SCORE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9(0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9(1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.10\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\u003eGroup S: Intraoperative infusion of esketamine and postoperative butorphanol plus esketamine 2mg/kg and azasetron; Group C: Postoperative butorphanol and azasetron.\u003c/p\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eNumber of PCA compressions at 24h postoperatively\u003c/h2\u003e\n \u003cp\u003eThere was no statistical difference in the number of PCA presses in group C [12(6\u0026thinsp;~\u0026thinsp;18)] and group S [10(5\u0026thinsp;~\u0026thinsp;22.25)] during 24h after surgery [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, 95% CI (-3 to 3)]. (FIG.2)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eVAS scores at different time points\u003c/h2\u003e\n \u003cp\u003eThe differences in VAS scores between the two groups were not statistically significant at 8h [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, 95% CI (0 to 1)], 24h [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, 95% CI (0 to 1)], and 96h [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, 95% CI (0 to 0)]. (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eEPDS scores at different time points\u003c/h2\u003e\n \u003cp\u003eCompared with the group C, the group S had significantly lower EPDS scores at postoperative 8h [P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, 95% CI (1 to 2)], 24h [P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, 95% CI (1 to 2)], 96h [P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, 95% CI (1 to 2)], and one week [P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, 95% CI (1 to 2)] (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eNeonatal Apgar scores\u003c/h2\u003e\n \u003cp\u003eThere was no statistically significant difference between neonatal 1min Apgar scores [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, 95% CI (0 to 0)] and 5min Apgar scores [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, 95% CI (0 to 0)] of both groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eThe time to first get out of bed and intestinal exhaust time\u003c/h2\u003e\n \u003cp\u003eNo statistically significant differences were found when comparing the time to first bed [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, MD\u0026thinsp;=\u0026thinsp;0.423, 95% CI (-1.33 to 2.18)] and time to intestinal exhaust [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, MD\u0026thinsp;=\u0026thinsp;0.196, 95% CI (-2.53 to 2.92)] of both groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003ePostoperative rescue analgesia and incidence of adverse reactions\u003c/h2\u003e\n \u003cp\u003eWhen comparing the incidence of the postoperative rescue analgesia of the two groups, the difference between them was not statistically significant [P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, RR\u0026thinsp;=\u0026thinsp;0.844, 95% CI (0.46 to 1.55)]. The incidence of dizziness in group S (15/78, 19%) was higher than in group C (4/77, 5%) [P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, RR\u0026thinsp;=\u0026thinsp;0.270, 95% CI (0.09 to 0.78)]. One patient in group S had hallucination, which was none in group C. The other adverse reactions such as respiratory depression and skin pruritus were no significant difference in both groups after surgery (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePostoperative remedial analgesia and incidence of adverse reactions\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup C\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup S\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRemedial analgesia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19% (15/77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23% (18/78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003erespiratory depression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eskin pruritus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePONV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5% (4/77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6% (5/78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDizziness\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5% (4/77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19% (15/78)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.01*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNightmares\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1% (1/77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3% (2/78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRestlessness\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3% (2/77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3% (2/78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHallucinations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1% (1/78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBlurred vision\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1% (1/77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.31\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\u003ePONV: postoperative nausea and vomiting. Group S: Intraoperative infusion of esketamine and postoperative butorphanol plus esketamine 2mg/kg and azasetron; Group C: Postoperative butorphanol and azasetron. *: Compared with the group C, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, the rate of excellent postoperative analgesia after the cesarean section was relatively low[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. To explore the more effective scheme to control postoperative pain after the cesarean section, we designed this single-center, prospective, double-blind, randomized, placebo-controlled trial. This study did not show the statistical difference in the number of 24h PCA presses in group S compared to group C, and the VAS scores at each postoperative time point. These indicated that esketamine may have no improved effect on the management of maternal pain in the postoperative period. However, Wang Ye et al. showed that 0.004-0.01mg/kg/h esketamine with sufentanil for postoperative PCIA after cesarean delivery significantly reduced the incidence of postoperative pain[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The reason for this difference may be due to the difference between combined drugs and the dosage of esketamine, and it may also be related to the fact that we take the number of PCA presses as the main index.\u003c/p\u003e \u003cp\u003eThe emotional state of patients may be a factor to impacts the pain sensitivity of the parturients after surgery. In this study, EPDS scores were lower in group S than in group C at all postoperative time points. It inferred that intraoperative esketamine 0.15mg/kg/h combined with postoperative 0.04mg/kg/h continuous intravenous infusion was effective in improving maternal emotional state up to one week after surgery. It has been reported that low-dose esketamine combined with sufentanil can improve postoperative depression after cesarean delivery[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Intravenous administration of 0.5mg/kg of esketamine rapidly relieved suicidal ideation in postpartum depression[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The mechanism of the antidepressant effect of esketamine is not clear, it may be related to a decrease in the release of γ-amino butyric acid (GABA) and an increase in glutamate content in the synaptic gap, leading to enhanced excitatory synaptic activity[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has shown that there was no significant difference in the Apgar scores of neonates in group S at 1min, 5mim after birth compared with group C. Therefore, the application of esketamine 0.15mg/kg/h intravenous pumping before fetal delivery did not affect neonatal outcomes. As for the other adverse effects, there was no significant difference between the two groups except that the incidence of dizziness was higher in Group S. The previous study also found that dizziness was the most common adverse effect after intranasal administration of esketamine, but all patients' dizziness resolved spontaneously about 2 hours after surgery when no special treatment was required[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The present study showed no statistical difference in the time to first postoperative bed activity between the two groups. This indicated that dizziness due to esketamine did not affect maternal postoperative activity. Although there was one case of hallucination and two cases of nightmares in group S, there was no statistical difference compared with group C and no serious consequences. Consequently, perioperative esketamine combined with butorphanol infusion was a safe and effective treatment without severe adverse effects.\u003c/p\u003e \u003cp\u003eThe limitation of this study was the insufficient sample size. The relatively small sample size made this hypothesis-generating study underpowered to show more statistical differences between groups. The other limitation was we did not test the higher dosage of esketamine infusion in consideration of the safety of newborns.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSupplement of esketamine during the perioperative period can not improve postoperative analgesia after cesarean section and increases the incidence of adverse effects.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePCIA: patient-controlled intravenous analgesia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEPDS:\u0026nbsp;Edinburgh Postnatal Depression Scale\u003c/p\u003e\n\u003cp\u003eNSAIDs:\u0026nbsp;Non-Steroidal Anti-inflammatory Drugs\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVAS:\u0026nbsp;Visual Analog Scale\u003c/p\u003e\n\u003cp\u003ePONV:\u0026nbsp;postoperative nausea and vomiting\u003c/p\u003e\n\u003cp\u003eCI: confidence interval\u003c/p\u003e\n\u003cp\u003eIQR: interquartile range\u003c/p\u003e\n\u003cp\u003eGABA: \u0026gamma;-amino butyric acid\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research studies on humans have been performed in accordance with the principles stated in the Declaration of Helsinki. Prior to starting the study, ethical approval\u0026nbsp;was\u0026nbsp;obtained for all protocols from the Shiyan Renmin Hospital Ethics Committee(syrmyy2021-018). All participants signed informed consent prior to inclusion in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author\u0026nbsp;upon reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe research was supported by the National Natural Science Foundation of China [grant number 81341111 and 81701891], Youth Foundation of Hubei Provincial Health Committee [grant number WJ2021Q009], Key Research and Development Plan of Hubei Province [grant\u0026nbsp;number\u0026nbsp;2022BCE007].\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions\u003c/p\u003e\n\u003cp\u003eAll authors have given substantial contributions to the conception or the design of the manuscript,\u0026nbsp;including\u0026nbsp;author Siqi Ma, author Hao Guo, and author Xiaoyan Ran to\u0026nbsp;the\u0026nbsp;acquisition, analysis,\u0026nbsp;and interpretation of the data.\u0026nbsp;All authors have participated\u0026nbsp;in\u0026nbsp;drafting the manuscript,\u0026nbsp;and\u0026nbsp;author Siqi Ma revised it critically. All authors read and approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the Department of Anesthesiology and Pain Medicine of the hospital where the study took place, especially the maternal area and the Department of Obstetrics and Gynecology of the hospital.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSun KW, Pan PH. Persistent pain after cesarean delivery. Int J Obstet Anesth. 2019;40:78-90.\u003c/li\u003e\n \u003cli\u003eDuan G, Bao X, Yang G, Peng J, Wu Z, Zhao P, et al. Patient-controlled intravenous tramadol versus patient-controlled intravenous hydromorphone for analgesia after secondary cesarean delivery: a randomized controlled trial to compare analgesic, anti-anxiety and anti-depression effects. J Pain Res. 2019;12:49-59.\u003c/li\u003e\n \u003cli\u003eLiu S, Peng P, Hu Y, Liu C, Cao X, Yang C, et al. The Effectiveness and Safety of Intravenous Dexmedetomidine of Different Concentrations Combined with Butorphanol for Post-Caesarean Section Analgesia: A Randomized Controlled Trial. Drug Des Devel Ther. 2021;15:689-98.\u003c/li\u003e\n \u003cli\u003eGe Z, Li M, Chen Y, Sun Y, Zhang R, Zhang J, et al. The Efficacy and Safety of Parecoxib Multimodal Preemptive Analgesia in Artificial Joint Replacement: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Ther. 2023;12(4):1065-78.\u003c/li\u003e\n \u003cli\u003eKutzler HL, Lichvar AB, Quan D, Bowman LJ, Diamond A, Doligalski C, et al. A systematic review of opioid use and multimodal strategies in solid organ transplant recipients and living donors. Pharmacotherapy. 2023;43(6):514-51.\u003c/li\u003e\n \u003cli\u003eStormholt ER, Steiness J, Derby CB, Larsen ME, Maagaard M, Mathiesen O. Glucocorticoids added to paracetamol and NSAIDs for post-operative pain: A systematic review with meta-analysis and trial sequential analysis. Acta Anaesthesiol Scand. 2023;67(6):688-702.\u003c/li\u003e\n \u003cli\u003eZhang X, Wang J, An XH, Chao YC, Bian Y, Xu Z, et al. Optimum dose of spinal ropivacaine with or without single intravenous bolus of S-ketamine during elective cesarean delivery: a randomized, double-blind, sequential dose-finding study. BMC Pregnancy Childbirth. 2021;21(1):746.\u003c/li\u003e\n \u003cli\u003eShen J, Song C, Lu X, Wen Y, Song S, Yu J, et al. The effect of low-dose esketamine on pain and post-partum depression after cesarean section: A prospective, randomized, double-blind clinical trial. Front Psychiatry. 2022;13:1038379.\u003c/li\u003e\n \u003cli\u003eBrinck ECV, Virtanen T, Makela S, Soini V, Hynninen VV, Mulo J, et al. S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: A randomized, double-blind, placebo-controlled clinical trial. PLoS One. 2021;16(6):e0252626.\u003c/li\u003e\n \u003cli\u003eFu DJ, Zhang Q, Shi L, Borentain S, Guo S, Mathews M, et al. Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality. BMC Psychiatry. 2023;23(1):587.\u003c/li\u003e\n \u003cli\u003eUsichenko TI, Henkel BJ, Klausenitz C, Hesse T, Pierdant G, Cummings M, et al. Effectiveness of Acupuncture for Pain Control After Cesarean Delivery: A Randomized Clinical Trial. JAMA Netw Open. 2022;5(2):e220517.\u003c/li\u003e\n \u003cli\u003eWang Y, Zhang Q, Dai X, Xiao G, Luo H. Effect of low-dose esketamine on pain control and postpartum depression after cesarean section: a retrospective cohort study. Ann Palliat Med. 2022;11(1):45-57.\u003c/li\u003e\n \u003cli\u003eHan Y, Li P, Miao M, Tao Y, Kang X, Zhang J. S-ketamine as an adjuvant in patient-controlled intravenous analgesia for preventing postpartum depression: a randomized controlled trial. BMC Anesthesiol. 2022;22(1):49.\u003c/li\u003e\n \u003cli\u003eMachado C, Lacerda ALT, Bressan RA, Noto C. Esketamine for Postpartum Suicidality. Biol Psychiatry. 2021;89(6):e35-e6.\u003c/li\u003e\n \u003cli\u003eKrystal JH, Charney DS, Duman RS. A New Rapid-Acting Antidepressant. Cell. 2020;181(1):7.\u003c/li\u003e\n \u003cli\u003eMorrison RL, Fedgchin M, Singh J, Van Gerven J, Zuiker R, Lim KS, et al. Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. Psychopharmacology (Berl). 2018;235(4):1107-19.\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":"obstetric analgesia, patient-controlled intravenous analgesia, postpartum depression ","lastPublishedDoi":"10.21203/rs.3.rs-4006081/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4006081/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTo investigate the safety and efficacy of esketamine combined with butorphanol for postoperative analgesia after cesarean section.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003e160 parturients who underwent cesarean section were randomly divided into two groups: Group S received intraoperative esketaimine infusion with 0.15mg/kg/h and postoperative 0.2mg/kg butorphanol+ 2mg/kg esketaimine for patient-controlled intravenous analgesia (PCIA). Group C received the same volume of 5% glucose infusion and postoperative butorphanol 0.2mg/kg for PCIA. The primary outcome was postoperative analgesic effectiveness as reflected by the number of analgesic pumps pressed during 24h postoperative period by patients. The secondary outcomes included the VAS scores of postoperative pain, Edinburgh Postnatal Depression Scale (EPDS) scores, neonatal Apgar scores, the time to first get out of bed, the gut functional recovery time, the rescue analgesic treatments, and adverse effects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThere was no statistical difference in analgesic effectiveness during the 24h postoperative period (P\u0026gt;0.05). Both the number of analgesic pump presses and VAS scores during the postoperative period were not significantly different between the two groups (P＞0.05). The EPDS scores of Group S at postoperative 8h, 24h, 96h, and one week were lower than in the C group (P\u0026lt;0.05). The incidence of dizziness was higher in Group S (P\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eSupplement of esketamine during the perioperative period can not improve postoperative analgesia after cesarean section, and increases the incidence of adverse effects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eThe trial was registered with Chinese Clinical Trial website (www.chictr.org.cn/index.aspx ChiCTR2100054435) on December 27, 2021 (27/12/2021).\u003c/p\u003e","manuscriptTitle":"Perioperative Intravenous Esketamine Infusion for Cesarean Section Pain Relief: A Prospective Randomized Controlled Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-28 17:38:08","doi":"10.21203/rs.3.rs-4006081/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":"e7e44f86-7ca5-4486-adf2-a99008b9ebb2","owner":[],"postedDate":"March 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-04T01:51:44+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-28 17:38:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4006081","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4006081","identity":"rs-4006081","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}