Addition of lidocaine to prophylactic ondansetron and dexamethasone in high-risk children for postoperative vomiting: A randomised, controlled, double-blinded study

Addition of lidocaine to prophylactic ondansetron and dexamethasone in high-risk children for postoperative vomiting: A randomised, controlled, double-blinded 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 Article Addition of lidocaine to prophylactic ondansetron and dexamethasone in high-risk children for postoperative vomiting: A randomised, controlled, double-blinded study Jin-fei Xu, Ming-cheng Du, Yi Chen, Yang Hu, Xiang Long, Jing-jing Jiang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4526807/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Aug, 2025 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract A combination of dexamethasone, ondansetron, and total intravenous anaesthesia (TIVA) is recommended as prophylaxis to prevent postoperative vomiting (POV) in high-risk children. Implementing TIVA in paediatric anaesthesia presents challenges due to its widespread ease of use. Regarding lidocaine’s antiemetic effect in paediatric patients, incorporating lidocaine can mitigate POV in high-risk children. Among 204 children undergoing elective tonsillectomy (with/without adenoidectomy), those with a postoperative vomiting score ≥ 4 were randomised into Group C (saline) and Group L (lidocaine). The primary outcome was the incidence of POV at 24 hours postoperatively. The secondary outcome was the number of coughs at 30 minutes postoperatively. The POV incidence differed with 15 patients in Group C (14.7%) and 5 in Group L (4.9%) presenting with one or more episodes of POV (P = 0.019). The number of coughs at 30 minutes postoperatively differed between Group L (1[0–2]) and Group C (1[0–2]) (P = 0.007). A lower percentage of patients experienced adverse events in Group C (2.2%) compared with Group L (1.1%) (P = 0.567); no severe events occurred. Adding lidocaine to ondansetron and dexamethasone is effective in reducing the POV incidence and extubation coughs in high-risk children following volatile anaesthesia for tonsillectomy. Antiemetics Lidocaine Paediatric Anaesthesia Postoperative Vomiting Tonsillectomy Figures Figure 1 Introduction Postoperative nausea and vomiting (PONV) is one of the most common complications in paediatric patients; it prolongs hospitalisation and is the most common cause of dissatisfaction in children and their parents [ 1 , 2 ]. PONV frequently delays discharge from post-anaesthesia care units (PACU) and is the leading cause of unexpected hospital admission after planned ambulatory surgery [ 3 ]. To address concerns about the hazards and discomfort of PONV, the combination of a 5HT3 antagonist and dexamethasone is recommended by Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting [ 1 ]. Despite combining two antiemetic agents, the residual incidence of POV remains high, approximately 30%, in high-risk patients [ 4 – 6 ]. In terms of the worldwide prevalence of volatile anaesthesia in paediatric patients and limited treatment efficacy with the bi-combination of antiemetics, the multimodal combination prophylactic therapy using different drug classes is more suitable for children at high risk for POV [ 7 ]. Although effective in high-risk adults, adding droperidol to a combination of ondansetron and dexamethasone did not further reduce POV frequency in high-risk children [ 8 ]. Lidocaine is an amino-amide local anaesthetic possessing analgesic, anti-hyperalgesic, and anti-inflammatory properties, making it suitable as a general anaesthetic adjuvant [ 9 ]. Studies have demonstrated that intravenous lidocaine has antiemetic properties in pediatric patients [ 10 , 11 ]. We hypothesised that a combination of three drugs (ondansetron, dexamethasone, and lidocaine) reduces the incidence of POV in paediatric patients who are at a high risk of POV. Because of the difficulty in assessing nausea in paediatric patients, we limited our trial to evaluating POV. The selection of POV as the primary outcome was guided by the need for clinically meaningful outcomes with potential benefits. Materials and Methods Study Design This was a single-centre, parallel-group, randomised, double-blinded controlled trial conducted in accordance with the Declaration of Helsinki and its later amendments. The study protocol was approved by the Institutional Review Board of Yichang Central People’s Hospital (HEC-KYJJ-2023-053-02). The trial was registered at www.chictr.org.cn (ChiCTR2300072362) on 12 June 2023. The study was conducted from 15 June 2023 to 31 August 2023 at Yichang Central People’s Hospital. Written informed consent was obtained from the parents of each child. The patients were randomised in a 1:1 ratio to each group. Randomisation was computer-generated, and each patient was assigned a code. Patients Patients aged 3–15 years (American Society of Anesthesiologists grade I–II) scheduled for elective tonsillectomy (with or without adenoidectomy) were included. Concerning the risk factors for POV, we utilised the vomiting in the postoperative period [ 12 ] score for assessing and enrolling patients with a score exceeding 4, indicating a high risk for POV [ 8 ]. The induction protocol included opioid administration, which conforms to the score requirement of multiple opioid doses. The enrollment criteria included the following: age 3–6 years or > 13 years with a confirmed personal history of POV, motion sickness, or familial history of POV and age 6–13 years, each contributing 2 points in the scoring system [ 12 ]. Children were randomised into two groups: saline (Group C) and lidocaine (Group L). The exclusion criteria included chronic cough, history of steroid or bronchodilator use, reactive respiratory tract disease, upper airway infection within the past 2 weeks, gastroesophageal reflux, morbid obesity, allergy to any study drugs, and the use of medications or nutraceuticals influencing blood pressure (BP) and heart rate. Cases with surgeries exceeding 2 hours, unexpected bleeding, or more than two intubation attempts were also excluded. Perioperative Anaesthetic Care Preoperatively, each child underwent a fasting period of 6 h and abstained from clear fluid intake for 2 h. Accompanied by their parents, the children were brought into the operating room, a measure aimed at reducing their separation anxiety. Vital signs, including non-invasive BP, heart rate, electrocardiography, and pulse oxygen saturation, were monitored using a multifunction monitor (GE Healthcare, Helsinki, Finland). The BP cuff, sized at approximately two-thirds of the upper arm length, was used for each patient. A 22-gauge intravenous catheter was placed in the dorsal veins of the hand. During the first hour, patients received 10 ml/kg/h intravenous fluids, followed by an infusion rate using the 4-2-1 rule [ 13 ]. Prior to the administration of general anaesthesia, patients underwent preoxygenation. The anaesthesia induction protocol included sufentanil at 0.25 µg/kg, propofol at 2.0 mg/kg, and rocuronium at 0.6 mg/kg. Ventilation through a facemask with 100% oxygen was initiated once the eyelash reflex was no longer present. A cuffed endotracheal tube was used, the size of which was selected based on a widely used formula ([3.5 + age in years]/4). Patients were excluded from the study if any difficulty was encountered during facemask ventilation. Anaesthesia was maintained with 2–3% sevoflurane, 0.1µg/kg/min remifentanyl, and 50% medical air in oxygen. Ondansetron (0.1 mg/kg) and dexamethasone (0.125 mg/kg) were injected immediately after the induction of anaesthesia. After the injection of the combination of drugs, 1.5 mg kg − 1 lidocaine or 0.9% saline was injected intravenously over 5 min with activation of the pump, followed by either 2 mg kg − 1 h − 1 lidocaine or 0.9% saline, respectively, at the same rate and volume. The anaesthesia nurse who prepared the research treatment solutions and activated the pump was blinded to the study groups, strictly followed the trial protocol and was forbidden from discussing and informing others about the trial. An experienced surgeon (Xiao-bo Zhang) performed the surgery with the same surgical technique (bipolar diathermy). At the end of the operation, sevoflurane, remifetanyl, and the study treatment were discontinued. Neostigmine 0.04 mg/kg and atropine 0.02 mg/kg were administered to antagonise any residual neuromuscular blockade. Extubation was performed by an experienced anaesthetist, who was blinded to the study after confirming adequate tidal volume, regular spontaneous respiratory patterns, and purposeful behaviour (eyes open upon request). After extubation, the children were monitored for at least 5 min to resume regular spontaneous respiration and were subsequently transferred to the PACU. Electrocardiography, peripheral pulse oximetry, and non-invasive BP measurements were performed. An experienced investigator (Ming-cheng Du) who was blinded to the study began tracking POV throughout the 24 h after surgery. When their Steward recovery score was higher than 4, patients were discharged from the PACU to the ward, where they remained overnight. Other perioperative care was provided according to the practices of the local clinicians. Primary Outcomes The primary outcome was the incidence of any emetic episodes (retching or vomiting per the parent’s report) within 24 h postoperatively. The rescue methods for POV were intravenous ondansetron 50 µg/kg and dexamethasone 0.1 mg/kg. Secondary Outcomes Secondary outcomes were extubation time and the number of extubation coughs in the 30 minutes following surgery. Adverse events such as drowsiness, headache, tongue numbness, tinnitus, dizziness, skin erythema, sinus arrest, hives, and tracheospasm were also recorded. Statistical Analysis The required sample size was determined based on a preliminary experiment. To achieve 90% power (with a two-sided α risk of 0.05) for detecting a 10% absolute risk reduction in POV incidence in Group L, we calculated a necessary sample size of 204 randomised patients. Between-group comparisons utilised the Student’s t -test or Wilcoxon rank-sum test, chosen according to the Shapiro–Wilk test results. For proportional inferences, we applied the χ2 test and Fisher’s exact test. Descriptive statistics were presented as mean ± standard deviation, median (interquartile range), or odds ratio (95% confidence interval). The significance threshold was set at P < 0.05. All analyses were conducted using STATA v26.0 (StataCorp LP, College Station, TX, USA). Results Patients Between 15 June 12 2023, and 31 August 2023, 204 patients were included in the analysis and divided into two groups; the characteristics and operative data did not differ between the groups (Table 1 ). Table 1 Baseline, anaesthetic characteristics, and postoperative care data. Group C (n = 102) Group L (n = 102) P value Male/female 65/37 54/48 0.118 Age (year) 7 [6 to 8] 7 [5 to 8] 0.411 Weight (kg) 26.3 [21.0 to 33.3] 24.0 [20.0 to 31.5] 0.144 Tonsillectomy/adenotonsillectomy, n 1/101 0/102 0.316 Height (cm) 127 [120 to 135] 125 [115 to 135] 0.271 Duration of surgery (min) 22 [15.8 to 30] 23 [17.8 to 30.3] 0.359 Time to extubation (min) 14.6 ± 3.0 17.5 ± 3.3 < 0.001 VPOP score 4 [4 to 5] 4 [4 to 5] 0.547 Values are number, number (%), mean ± standard deviation , or median [interquartile range] . VPOP, vomiting in the postoperative period. * P values were performed using the Wilcoxon rank-sum test based on the Shapiro–Wilk test results. Primary Outcomes The incidence of POV was 14.7% and 4.9% in Groups C (15/102) and L (5/102), respectively. A significant difference between Groups C and L (P = 0.019) (Fig. 1 ) was observed. Secondary Outcomes Statistically significant differences were also observed in the time to extubation, where Group L exhibited an extubation time 3 min longer than that of Group C (Table 1 ). The number of extubation coughs, which may pose risks for children post-tonsillectomy, differed significantly between the groups (P = 0.007) (Table 2 ). Furthermore, no severe complications were reported in either group (Table 3 ). Table 2 Number of extubation coughs during 30 min postoperatively. Group C (n = 102) Group L (n = 102) P value Number of extubation coughs 1 [0 to 2] 0 [0 to 1.25] 0.007 Values are median (interquartile range) . Table 3 Postoperative adverse events in Groups C and L. Group C (n = 102) Group L (n = 102) P value Drowsiness 1 (1.0) 0 (0) 0.316 Headache 1 (1.0) 1 (1.0) 1.0 Tongue numbness 0 (0) 0 (0) 1.0 Tinnitus 0 (0) 0 (0) 1.0 Dizziness 5 (4.9) 6 (5.9) 0.757 Skin erythema 1 (1.0) 0 (0) 0.316 Sinus arrest 0 (0) 0 (0) 1.0 Hives 0 (0) 0 (0) 1.0 Tracheospasm 0 (0) 0 (0) 1.0 Data presented are the number of cases (%). Discussion A key finding of our study is that adding lidocaine to the prophylactic mixture of ondansetron and dexamethasone decreased POV incidence in high-risk children. Additionally, incorporating lidocaine reduced the number of coughs within 30 min post-surgery. Notably, the extubation time was 3 min longer in Group L, which was deemed clinically insignificant. Previous studies have attempted to assess the relative benefits of triple-combined prophylaxis in children; however, they were unsuccessful [ 8 , 14 ]. Different mechanisms may account for the efficacy of lidocaine and other drugs. Another possible explanation for the low incidence of POV in our trial would be the analgesic effect and opioid-sparing properties of lidocaine, as postoperative long-acting opioid administration is another risk factor [ 1 ]. Tonsillectomy (with/without adenoidectomy) remains one of the most common surgical procedures performed in children worldwide and is a high-risk surgery for POV [ 1 ]. With the combination of a 5-HT3 antagonist and dexamethasone, the incidence of PONV/POV in high-risk children decreased to 30% [ 1 ]. However, we observed a lower incidence of POV (14.7%) with the antiemetic prophylaxis of ondansetron and dexamethasone. Different anaesthetic techniques (intravenous induction and parental accompaniment to treat anxiety in children) might have partly accounted for the efficacy of our trial. In children, coughing during emergence following tonsillectomy may cause bleeding and laryngospasm [ 15 ]. A meta-analysis indicated that a single intravenous bolus of lidocaine decreased the incidence of cough in children dose-dependently [ 16 ]. Our trial found that intraoperative lidocaine reduced the incidence of cough in children. At the time of extubation, the duration for Group L exceeded that of Group C by 3 min, was deemed clinically insignificant, and no substantial difference (P < 0.001) was observed in the baseline characteristics of patients (Table 1 ). Our trial reported no severe adverse events, aligning with the findings of similar studies [ 12 ]. The limitations of this study include the lack of testing for lidocaine plasma concentration. While lidocaine application was advised, and its safety and plasma concentration correlation was confirmed in prior studies [ 9 , 11 , 17 ], direct measurements were not conducted in this trial. Secondly, the children who underwent tonsillectomy needed hospitalisation in China, which was different from patients in the United States, who were inpatients and ambulatory patients. In our trial, we maintained the minimum alveolar concentration value between 0.7 and 1.2 as the anaesthesia depth. Despite the study’s randomised design and similar baseline characteristics among enrollees, we acknowledge the potential variability in anaesthesia depth across groups. As a single-centre study, the generalisability of the results might be limited. In conclusion, adding lidocaine to ondansetron and dexamethasone reduced the incidence of POV following volatile anaesthesia in high-risk children undergoing a tonsillectomy and lowered the incidence of extubation cough during the first 30 min postoperatively. however, further research is needed to establish lidocaine’s efficacy in high-risk adult populations. Declarations Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Acknowledgements: None Author Contributions ： Jin-fei Xu and Ming-cheng Du helped with the data curation. Jin-fei Xu and Yi Chen helped with the software and formal analysis. Yang Hu, Ming-cheng Du, and Yi Chen helped with project administration. Xiang Long and Jing-jing Jiang helped with resources and investigation. Yuan Gong helped with the methodology, supervision, and validation. All authors have contributed equally to the manuscript and have read and approved the final version of the manuscript. Competing Interests Statement: None Funding Statement: Support was provided solely from institutional and/or departmental sources. References Gan, T. J., et al . Fourth consensus guidelines for the management of postoperative nausea and vomiting. Anesth. Analg. 131, 411-448 (2020). Kermode, J., Walker, S., & Webb, I. Postoperative vomiting in children. Anaesth. Intensive Care. 23, 196-199 (1995). Gold, B. S., Kitz, D. S., Lecky, J. H., & Neuhaus, J. M. Unanticipated admission to the hospital following ambulatory surgery. JAMA. 262, 3008-3010 (1989). Bharti, N. & Shende, D. Comparison of anti-emetic effects of ondansetron and low-dose droperidol in pediatric strabismus surgery. J. Pediatr. Ophthalmol. Strabismus. 40, 23-26 (2003). Bolton, C. M., Myles, P. S., Carlin, J. B., & Nolan, T. Randomized, double-blind study comparing the efficacy of moderate-dose metoclopramide and ondansetron for the prophylactic control of postoperative vomiting in children after tonsillectomy. Br. J. Anaesth. 99, 699-703 (2007). Klockgether-Radke, A., Neumann, S., Neumann, P., Braun, U., & Mühlendyck, H. Ondansetron, droperidol and their combination for the prevention of post-operative vomiting in children. Eur. J. Anaesthesiol. 14, 362-367 (1997). Kovac, A. L. Postoperative nausea and vomiting in pediatric patients. Paediatr. Drugs. 23, 11-37 (2021). Bourdaud, N., et al . Addition of droperidol to prophylactic ondansetron and dexamethasone in children at high risk for postoperative vomiting. A randomized, controlled, double-blind study. Br. J. Anaesth. 118, 918-923 (2017). Estebe, J. P. Intravenous lidocaine. Best Pract. Res. Clin. Anaesthesiol. 31, 513-521 (2017). Nakajima, D., Kawakami, H., Mihara, T., Sato, H., & Goto, T. Effectiveness of intravenous lidocaine in preventing postoperative nausea and vomiting in pediatric patients: a systematic review and meta-analysis. PLoS One. 15, e0227904 (2020). Echevarría, G. C., et al . Intra-operative lidocaine in the prevention of vomiting after elective tonsillectomy in children: a randomised controlled trial. Eur. J. Anaesthesiol. 35, 343-348 (2018). Bourdaud, N., et al . Development and validation of a risk score to predict the probability of postoperative vomiting in pediatric patients: the VPOP score. Paediatr. Anaesth. 24, 945-952 (2014). Vallet, B., et al . Guidelines for perioperative haemodynamic optimization. Ann. Fr. Anesth. Reanim. 32, e151-158 (2013). Gunter, J. B., McAuliffe, J. J., Beckman, E. C., Wittkugel, E. P., Spaeth, J. P., & Varughese, A. M. A factorial study of ondansetron, metoclopramide, and dexamethasone for emesis prophylaxis after adenotonsillectomy in children. Paediatr. Anaesth. 16, 1153-1165 (2006). Afshan, G., Chohan, U., Qamar-Ul-Hoda, M., & Kamal, R. S. Is there a role of a small dose of propofol in the treatment of laryngeal spasm? Paediatr. Anaesth. 12, 625-628 (2002). Clivio, S., Putzu, A., & Tramèr, M. R. Intravenous lidocaine for the prevention of cough: systematic review and meta-analysis of randomized controlled trials. Anesth. Analg. 129, 1249-1255 (2019). Beaussier, M., Delbos, A., Maurice-Szamburski, A., Ecoffey, C., & Mercadal, L. Perioperative use of intravenous lidocaine. Drugs. 78, 1229-1246 (2018). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 18 Aug, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 13 Mar, 2025 Reviews received at journal 06 Mar, 2025 Reviewers agreed at journal 24 Jan, 2025 Reviewers agreed at journal 23 Jan, 2025 Reviews received at journal 06 Aug, 2024 Reviewers agreed at journal 04 Aug, 2024 Reviewers invited by journal 01 Aug, 2024 Editor assigned by journal 30 Jul, 2024 Editor invited by journal 12 Jun, 2024 Submission checks completed at journal 12 Jun, 2024 First submitted to journal 04 Jun, 2024 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. 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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-4526807","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":319238888,"identity":"353141bb-d3a7-4a5f-9fa3-00cb0a9bfc3c","order_by":0,"name":"Jin-fei Xu","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jin-fei","middleName":"","lastName":"Xu","suffix":""},{"id":319238889,"identity":"49c14a5c-7b22-4d83-8138-2d929aa2d951","order_by":1,"name":"Ming-cheng Du","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ming-cheng","middleName":"","lastName":"Du","suffix":""},{"id":319238890,"identity":"9f696488-c70f-49d7-8a98-bf4d7af83f0e","order_by":2,"name":"Yi Chen","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Chen","suffix":""},{"id":319238891,"identity":"40be0d91-2f7c-423e-ac65-9d9a8d216f0d","order_by":3,"name":"Yang Hu","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Hu","suffix":""},{"id":319238892,"identity":"639032e3-3801-447b-a36b-1a385c756112","order_by":4,"name":"Xiang Long","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Long","suffix":""},{"id":319238893,"identity":"ba16948a-b980-474d-aa3d-ece27ccc96de","order_by":5,"name":"Jing-jing Jiang","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jing-jing","middleName":"","lastName":"Jiang","suffix":""},{"id":319238894,"identity":"2914cc87-63df-4f8a-8dfc-b204dd48f67f","order_by":6,"name":"Yuan Gong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApklEQVRIiWNgGAWjYNCCCgk5eRK1nLEwNmwgSQdjW0UiwwFiVctHJLBJ/JwnkcDYwPzw0Q1itBjeSGCT7N0mkcfOwGZsnEOUlhn536QZt0kUMzbwsEkTqSWBTZpxjkRiwwFitchLgLQ0kKLFgOcBs2XPMQljw2Zi/SLfnsB440dNnZw8e/PDx8TZciGBRQLMYiZGOdiW/gPMH4hVPApGwSgYBSMUAAA0cyq7mlObQwAAAABJRU5ErkJggg==","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Gong","suffix":""}],"badges":[],"createdAt":"2024-06-04 09:21:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4526807/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4526807/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-16367-w","type":"published","date":"2025-08-18T16:29:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":59870909,"identity":"d17fe54a-a3fc-417e-9809-f15de4b554bf","added_by":"auto","created_at":"2024-07-08 17:02:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38981,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence of postoperative vomiting among the study groups\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4526807/v1/8b3829c5760630aacda67d66.png"},{"id":89847253,"identity":"d382f889-5b5b-4950-aec2-9a25b1334390","added_by":"auto","created_at":"2025-08-25 16:42:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":624608,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4526807/v1/80d9924c-d2b2-4d32-a29a-5e75c3e6efdd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Addition of lidocaine to prophylactic ondansetron and dexamethasone in high-risk children for postoperative vomiting: A randomised, controlled, double-blinded study","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePostoperative nausea and vomiting (PONV) is one of the most common complications in paediatric patients; it prolongs hospitalisation and is the most common cause of dissatisfaction in children and their parents [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. PONV frequently delays discharge from post-anaesthesia care units (PACU) and is the leading cause of unexpected hospital admission after planned ambulatory surgery [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. To address concerns about the hazards and discomfort of PONV, the combination of a 5HT3 antagonist and dexamethasone is recommended by Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite combining two antiemetic agents, the residual incidence of POV remains high, approximately 30%, in high-risk patients [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In terms of the worldwide prevalence of volatile anaesthesia in paediatric patients and limited treatment efficacy with the bi-combination of antiemetics, the multimodal combination prophylactic therapy using different drug classes is more suitable for children at high risk for POV [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Although effective in high-risk adults, adding droperidol to a combination of ondansetron and dexamethasone did not further reduce POV frequency in high-risk children [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLidocaine is an amino-amide local anaesthetic possessing analgesic, anti-hyperalgesic, and anti-inflammatory properties, making it suitable as a general anaesthetic adjuvant [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Studies have demonstrated that intravenous lidocaine has antiemetic properties in pediatric patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. We hypothesised that a combination of three drugs (ondansetron, dexamethasone, and lidocaine) reduces the incidence of POV in paediatric patients who are at a high risk of POV. Because of the difficulty in assessing nausea in paediatric patients, we limited our trial to evaluating POV. The selection of POV as the primary outcome was guided by the need for clinically meaningful outcomes with potential benefits.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Design\u003c/h2\u003e\n \u003cp\u003eThis was a single-centre, parallel-group, randomised, double-blinded controlled trial conducted in accordance with the Declaration of Helsinki and its later amendments. The study protocol was approved by the Institutional Review Board of Yichang Central People\u0026rsquo;s Hospital (HEC-KYJJ-2023-053-02). The trial was registered at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.chictr.org.cn\u003c/span\u003e\u003c/span\u003e (ChiCTR2300072362) on 12 June 2023. The study was conducted from 15 June 2023 to 31 August 2023 at Yichang Central People\u0026rsquo;s Hospital. Written informed consent was obtained from the parents of each child.\u003c/p\u003e\n \u003cp\u003eThe patients were randomised in a 1:1 ratio to each group. Randomisation was computer-generated, and each patient was assigned a code.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003ePatients\u003c/h2\u003e\n \u003cp\u003ePatients aged 3\u0026ndash;15 years (American Society of Anesthesiologists grade I\u0026ndash;II) scheduled for elective tonsillectomy (with or without adenoidectomy) were included. Concerning the risk factors for POV, we utilised the vomiting in the postoperative period [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e] score for assessing and enrolling patients with a score exceeding 4, indicating a high risk for POV [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. The induction protocol included opioid administration, which conforms to the score requirement of multiple opioid doses. The enrollment criteria included the following: age 3\u0026ndash;6 years or \u0026gt;\u0026thinsp;13 years with a confirmed personal history of POV, motion sickness, or familial history of POV and age 6\u0026ndash;13 years, each contributing 2 points in the scoring system [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. Children were randomised into two groups: saline (Group C) and lidocaine (Group L). The exclusion criteria included chronic cough, history of steroid or bronchodilator use, reactive respiratory tract disease, upper airway infection within the past 2 weeks, gastroesophageal reflux, morbid obesity, allergy to any study drugs, and the use of medications or nutraceuticals influencing blood pressure (BP) and heart rate. Cases with surgeries exceeding 2 hours, unexpected bleeding, or more than two intubation attempts were also excluded.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003ePerioperative Anaesthetic Care\u003c/h2\u003e\n \u003cp\u003ePreoperatively, each child underwent a fasting period of 6 h and abstained from clear fluid intake for 2 h. Accompanied by their parents, the children were brought into the operating room, a measure aimed at reducing their separation anxiety. Vital signs, including non-invasive BP, heart rate, electrocardiography, and pulse oxygen saturation, were monitored using a multifunction monitor (GE Healthcare, Helsinki, Finland). The BP cuff, sized at approximately two-thirds of the upper arm length, was used for each patient. A 22-gauge intravenous catheter was placed in the dorsal veins of the hand. During the first hour, patients received 10 ml/kg/h intravenous fluids, followed by an infusion rate using the 4-2-1 rule [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003ePrior to the administration of general anaesthesia, patients underwent preoxygenation. The anaesthesia induction protocol included sufentanil at 0.25 \u0026micro;g/kg, propofol at 2.0 mg/kg, and rocuronium at 0.6 mg/kg. Ventilation through a facemask with 100% oxygen was initiated once the eyelash reflex was no longer present. A cuffed endotracheal tube was used, the size of which was selected based on a widely used formula ([3.5\u0026thinsp;+\u0026thinsp;age in years]/4). Patients were excluded from the study if any difficulty was encountered during facemask ventilation.\u003c/p\u003e\n \u003cp\u003eAnaesthesia was maintained with 2\u0026ndash;3% sevoflurane, 0.1\u0026micro;g/kg/min remifentanyl, and 50% medical air in oxygen. Ondansetron (0.1 mg/kg) and dexamethasone (0.125 mg/kg) were injected immediately after the induction of anaesthesia. After the injection of the combination of drugs, 1.5 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e lidocaine or 0.9% saline was injected intravenously over 5 min with activation of the pump, followed by either 2 mg kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e lidocaine or 0.9% saline, respectively, at the same rate and volume. The anaesthesia nurse who prepared the research treatment solutions and activated the pump was blinded to the study groups, strictly followed the trial protocol and was forbidden from discussing and informing others about the trial.\u003c/p\u003e\n \u003cp\u003eAn experienced surgeon (Xiao-bo Zhang) performed the surgery with the same surgical technique (bipolar diathermy). At the end of the operation, sevoflurane, remifetanyl, and the study treatment were discontinued. Neostigmine 0.04 mg/kg and atropine 0.02 mg/kg were administered to antagonise any residual neuromuscular blockade. Extubation was performed by an experienced anaesthetist, who was blinded to the study after confirming adequate tidal volume, regular spontaneous respiratory patterns, and purposeful behaviour (eyes open upon request). After extubation, the children were monitored for at least 5 min to resume regular spontaneous respiration and were subsequently transferred to the PACU. Electrocardiography, peripheral pulse oximetry, and non-invasive BP measurements were performed. An experienced investigator (Ming-cheng Du) who was blinded to the study began tracking POV throughout the 24 h after surgery.\u003c/p\u003e\n \u003cp\u003eWhen their Steward recovery score was higher than 4, patients were discharged from the PACU to the ward, where they remained overnight. Other perioperative care was provided according to the practices of the local clinicians.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary Outcomes\u003c/h2\u003e\n \u003cp\u003eThe primary outcome was the incidence of any emetic episodes (retching or vomiting per the parent\u0026rsquo;s report) within 24 h postoperatively. The rescue methods for POV were intravenous ondansetron 50 \u0026micro;g/kg and dexamethasone 0.1 mg/kg.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eSecondary Outcomes\u003c/h2\u003e\n \u003cp\u003eSecondary outcomes were extubation time and the number of extubation coughs in the 30 minutes following surgery. Adverse events such as drowsiness, headache, tongue numbness, tinnitus, dizziness, skin erythema, sinus arrest, hives, and tracheospasm were also recorded.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eThe required sample size was determined based on a preliminary experiment. To achieve 90% power (with a two-sided \u0026alpha; risk of 0.05) for detecting a 10% absolute risk reduction in POV incidence in Group L, we calculated a necessary sample size of 204 randomised patients. Between-group comparisons utilised the Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test or Wilcoxon rank-sum test, chosen according to the Shapiro\u0026ndash;Wilk test results. For proportional inferences, we applied the \u0026chi;2 test and Fisher\u0026rsquo;s exact test. Descriptive statistics were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, median (interquartile range), or odds ratio (95% confidence interval). The significance threshold was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All analyses were conducted using STATA v26.0 (StataCorp LP, College Station, TX, USA).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eBetween 15 June 12 2023, and 31 August 2023, 204 patients were included in the analysis and divided into two groups; the characteristics and operative data did not differ between the groups (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\u003eBaseline, anaesthetic characteristics, and postoperative care data.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup C (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup L (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale/female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65/37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54/48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 [6 to 8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 [5 to 8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.411\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.3 [21.0 to 33.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.0 [20.0 to 31.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.144\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTonsillectomy/adenotonsillectomy, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127 [120 to 135]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125 [115 to 135]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.271\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of surgery (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 [15.8 to 30]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 [17.8 to 30.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.359\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to extubation (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eVPOP score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 [4 to 5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 [4 to 5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.547\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eValues are number, number (%), \u003cem\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation\u003c/em\u003e, or \u003cem\u003emedian [interquartile range]\u003c/em\u003e. VPOP, vomiting in the postoperative period. *\u003cem\u003eP\u003c/em\u003e values were performed using the Wilcoxon rank-sum test based on the Shapiro\u0026ndash;Wilk test results.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcomes\u003c/h2\u003e \u003cp\u003eThe incidence of POV was 14.7% and 4.9% in Groups C (15/102) and L (5/102), respectively. A significant difference between Groups C and L (P\u0026thinsp;=\u0026thinsp;0.019) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) was observed.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcomes\u003c/h2\u003e \u003cp\u003eStatistically significant differences were also observed in the time to extubation, where Group L exhibited an extubation time 3 min longer than that of Group C (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The number of extubation coughs, which may pose risks for children post-tonsillectomy, differed significantly between the groups (P\u0026thinsp;=\u0026thinsp;0.007) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Furthermore, no severe complications were reported in either group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eNumber of extubation coughs during 30 min postoperatively.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroup C (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup L (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of extubation coughs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 [0 to 2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0 [0 to 1.25]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eValues are \u003cem\u003emedian (interquartile range)\u003c/em\u003e.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostoperative adverse events in Groups C and L.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup C (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup L (n\u0026thinsp;=\u0026thinsp;102)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrowsiness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTongue numbness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTinnitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDizziness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.757\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin erythema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSinus arrest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHives\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTracheospasm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData presented are the number of cases (%).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eA key finding of our study is that adding lidocaine to the prophylactic mixture of ondansetron and dexamethasone decreased POV incidence in high-risk children. Additionally, incorporating lidocaine reduced the number of coughs within 30 min post-surgery. Notably, the extubation time was 3 min longer in Group L, which was deemed clinically insignificant.\u003c/p\u003e \u003cp\u003ePrevious studies have attempted to assess the relative benefits of triple-combined prophylaxis in children; however, they were unsuccessful [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Different mechanisms may account for the efficacy of lidocaine and other drugs. Another possible explanation for the low incidence of POV in our trial would be the analgesic effect and opioid-sparing properties of lidocaine, as postoperative long-acting opioid administration is another risk factor [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTonsillectomy (with/without adenoidectomy) remains one of the most common surgical procedures performed in children worldwide and is a high-risk surgery for POV [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. With the combination of a 5-HT3 antagonist and dexamethasone, the incidence of PONV/POV in high-risk children decreased to 30% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, we observed a lower incidence of POV (14.7%) with the antiemetic prophylaxis of ondansetron and dexamethasone. Different anaesthetic techniques (intravenous induction and parental accompaniment to treat anxiety in children) might have partly accounted for the efficacy of our trial.\u003c/p\u003e \u003cp\u003eIn children, coughing during emergence following tonsillectomy may cause bleeding and laryngospasm [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A meta-analysis indicated that a single intravenous bolus of lidocaine decreased the incidence of cough in children dose-dependently [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Our trial found that intraoperative lidocaine reduced the incidence of cough in children. At the time of extubation, the duration for Group L exceeded that of Group C by 3 min, was deemed clinically insignificant, and no substantial difference (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was observed in the baseline characteristics of patients (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Our trial reported no severe adverse events, aligning with the findings of similar studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe limitations of this study include the lack of testing for lidocaine plasma concentration. While lidocaine application was advised, and its safety and plasma concentration correlation was confirmed in prior studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], direct measurements were not conducted in this trial. Secondly, the children who underwent tonsillectomy needed hospitalisation in China, which was different from patients in the United States, who were inpatients and ambulatory patients. In our trial, we maintained the minimum alveolar concentration value between 0.7 and 1.2 as the anaesthesia depth. Despite the study\u0026rsquo;s randomised design and similar baseline characteristics among enrollees, we acknowledge the potential variability in anaesthesia depth across groups. As a single-centre study, the generalisability of the results might be limited.\u003c/p\u003e \u003cp\u003eIn conclusion, adding lidocaine to ondansetron and dexamethasone reduced the incidence of POV following volatile anaesthesia in high-risk children undergoing a tonsillectomy and lowered the incidence of extubation cough during the first 30 min postoperatively. however, further research is needed to establish lidocaine\u0026rsquo;s efficacy in high-risk adult populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eJin-fei Xu and Ming-cheng Du helped with the data curation. Jin-fei Xu and Yi Chen helped with the software and formal analysis. Yang Hu, Ming-cheng Du, and Yi Chen helped with project administration. Xiang Long and Jing-jing Jiang helped with resources and investigation. Yuan Gong helped with the methodology, supervision, and validation. All authors have contributed equally to the manuscript and have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests Statement:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement:\u003c/strong\u003e Support was provided solely from institutional and/or departmental sources.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGan, T. J., \u003cem\u003eet al\u003c/em\u003e. Fourth consensus guidelines for the management of postoperative nausea and vomiting. \u003cem\u003eAnesth. Analg.\u003c/em\u003e \u003cstrong\u003e131,\u003c/strong\u003e 411-448 (2020). \u003c/li\u003e\n\u003cli\u003eKermode, J., Walker, S., \u0026amp; Webb, I. Postoperative vomiting in children. \u003cem\u003eAnaesth. Intensive Care.\u003c/em\u003e \u003cstrong\u003e23, \u003c/strong\u003e196-199 (1995). \u003c/li\u003e\n\u003cli\u003eGold, B. S., Kitz, D. S., Lecky, J. H., \u0026amp; Neuhaus, J. M. Unanticipated admission to the hospital following ambulatory surgery. \u003cem\u003eJAMA.\u003c/em\u003e \u003cstrong\u003e262,\u003c/strong\u003e 3008-3010 (1989).\u003c/li\u003e\n\u003cli\u003eBharti, N. \u0026amp; Shende, D. Comparison of anti-emetic effects of ondansetron and low-dose droperidol in pediatric strabismus surgery. \u003cem\u003eJ. Pediatr. Ophthalmol. Strabismus.\u003c/em\u003e \u003cstrong\u003e40,\u003c/strong\u003e 23-26 (2003). \u003c/li\u003e\n\u003cli\u003eBolton, C. M., Myles, P. S., Carlin, J. B., \u0026amp; Nolan, T. Randomized, double-blind study comparing the efficacy of moderate-dose metoclopramide and ondansetron for the prophylactic control of postoperative vomiting in children after tonsillectomy. \u003cem\u003eBr. J. Anaesth.\u003c/em\u003e \u003cstrong\u003e99,\u003c/strong\u003e 699-703 (2007). \u003c/li\u003e\n\u003cli\u003eKlockgether-Radke, A., Neumann, S., Neumann, P., Braun, U., \u0026amp; M\u0026uuml;hlendyck, H. Ondansetron, droperidol and their combination for the prevention of post-operative vomiting in children. \u003cem\u003eEur. J. Anaesthesiol.\u003c/em\u003e \u003cstrong\u003e14,\u003c/strong\u003e 362-367 (1997). \u003c/li\u003e\n\u003cli\u003eKovac, A. L. Postoperative nausea and vomiting in pediatric patients. \u003cem\u003ePaediatr. Drugs.\u003c/em\u003e \u003cstrong\u003e23,\u003c/strong\u003e 11-37 (2021). \u003c/li\u003e\n\u003cli\u003eBourdaud, N., \u003cem\u003eet al\u003c/em\u003e. Addition of droperidol to prophylactic ondansetron and dexamethasone in children at high risk for postoperative vomiting. A randomized, controlled, double-blind study. \u003cem\u003eBr. J. Anaesth.\u003c/em\u003e \u003cstrong\u003e118,\u003c/strong\u003e 918-923 (2017). \u003c/li\u003e\n\u003cli\u003eEstebe, J. P. Intravenous lidocaine. \u003cem\u003eBest Pract. Res. Clin. Anaesthesiol.\u003c/em\u003e \u003cstrong\u003e31,\u003c/strong\u003e 513-521 (2017). \u003c/li\u003e\n\u003cli\u003eNakajima, D., Kawakami, H., Mihara, T., Sato, H., \u0026amp; Goto, T. Effectiveness of intravenous lidocaine in preventing postoperative nausea and vomiting in pediatric patients: a systematic review and meta-analysis. \u003cem\u003ePLoS One.\u003c/em\u003e \u003cstrong\u003e15,\u003c/strong\u003e e0227904 (2020). \u003c/li\u003e\n\u003cli\u003eEchevarr\u0026iacute;a, G. C., \u003cem\u003eet al\u003c/em\u003e. Intra-operative lidocaine in the prevention of vomiting after elective tonsillectomy in children: a randomised controlled trial. \u003cem\u003eEur. J. Anaesthesiol.\u003c/em\u003e \u003cstrong\u003e35,\u003c/strong\u003e 343-348 (2018). \u003c/li\u003e\n\u003cli\u003eBourdaud, N., \u003cem\u003eet al\u003c/em\u003e. Development and validation of a risk score to predict the probability of postoperative vomiting in pediatric patients: the VPOP score. \u003cem\u003ePaediatr. Anaesth.\u003c/em\u003e \u003cstrong\u003e24,\u003c/strong\u003e 945-952 (2014). \u003c/li\u003e\n\u003cli\u003eVallet, B., \u003cem\u003eet al\u003c/em\u003e. Guidelines for perioperative haemodynamic optimization. \u003cem\u003eAnn. Fr. Anesth. Reanim.\u003c/em\u003e \u003cstrong\u003e32,\u003c/strong\u003e e151-158 (2013). \u003c/li\u003e\n\u003cli\u003eGunter, J. B., McAuliffe, J. J., Beckman, E. C., Wittkugel, E. P., Spaeth, J. P., \u0026amp; Varughese, A. M. A factorial study of ondansetron, metoclopramide, and dexamethasone for emesis prophylaxis after adenotonsillectomy in children. \u003cem\u003ePaediatr. Anaesth.\u003c/em\u003e \u003cstrong\u003e16,\u003c/strong\u003e 1153-1165 (2006). \u003c/li\u003e\n\u003cli\u003eAfshan, G., Chohan, U., Qamar-Ul-Hoda, M., \u0026amp; Kamal, R. S. Is there a role of a small dose of propofol in the treatment of laryngeal spasm? \u003cem\u003ePaediatr. Anaesth.\u003c/em\u003e \u003cstrong\u003e12,\u003c/strong\u003e 625-628 (2002). \u003c/li\u003e\n\u003cli\u003eClivio, S., Putzu, A., \u0026amp; Tram\u0026egrave;r, M. R. Intravenous lidocaine for the prevention of cough: systematic review and meta-analysis of randomized controlled trials. \u003cem\u003eAnesth. Analg. \u003c/em\u003e\u003cstrong\u003e129,\u003c/strong\u003e 1249-1255 (2019). \u003c/li\u003e\n\u003cli\u003eBeaussier, M., Delbos, A., Maurice-Szamburski, A., Ecoffey, C., \u0026amp; Mercadal, L. Perioperative use of intravenous lidocaine. \u003cem\u003eDrugs.\u003c/em\u003e \u003cstrong\u003e78,\u003c/strong\u003e 1229-1246 (2018).\u003c/li\u003e\n\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Antiemetics, Lidocaine, Paediatric Anaesthesia, Postoperative Vomiting, Tonsillectomy","lastPublishedDoi":"10.21203/rs.3.rs-4526807/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4526807/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA combination of dexamethasone, ondansetron, and total intravenous anaesthesia (TIVA) is recommended as prophylaxis to prevent postoperative vomiting (POV) in high-risk children. Implementing TIVA in paediatric anaesthesia presents challenges due to its widespread ease of use. Regarding lidocaine\u0026rsquo;s antiemetic effect in paediatric patients, incorporating lidocaine can mitigate POV in high-risk children. Among 204 children undergoing elective tonsillectomy (with/without adenoidectomy), those with a postoperative vomiting score\u0026thinsp;\u0026ge;\u0026thinsp;4 were randomised into Group C (saline) and Group L (lidocaine). The primary outcome was the incidence of POV at 24 hours postoperatively. The secondary outcome was the number of coughs at 30 minutes postoperatively. The POV incidence differed with 15 patients in Group C (14.7%) and 5 in Group L (4.9%) presenting with one or more episodes of POV (P\u0026thinsp;=\u0026thinsp;0.019). The number of coughs at 30 minutes postoperatively differed between Group L (1[0\u0026ndash;2]) and Group C (1[0\u0026ndash;2]) (P\u0026thinsp;=\u0026thinsp;0.007). A lower percentage of patients experienced adverse events in Group C (2.2%) compared with Group L (1.1%) (P\u0026thinsp;=\u0026thinsp;0.567); no severe events occurred. Adding lidocaine to ondansetron and dexamethasone is effective in reducing the POV incidence and extubation coughs in high-risk children following volatile anaesthesia for tonsillectomy.\u003c/p\u003e","manuscriptTitle":"Addition of lidocaine to prophylactic ondansetron and dexamethasone in high-risk children for postoperative vomiting: A randomised, controlled, double-blinded study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-08 17:01:58","doi":"10.21203/rs.3.rs-4526807/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-13T04:18:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-06T06:27:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"46703441987876477031515780537509833124","date":"2025-01-24T12:15:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"193915034434767325320613404792385037749","date":"2025-01-23T12:37:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-06T21:23:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"139386095572495931681312948666549853583","date":"2024-08-04T11:25:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-01T15:30:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-31T03:49:18+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-12T09:20:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-12T05:00:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-04T09:17:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cca56e05-fb19-4f8f-bf87-828f3bbb5202","owner":[],"postedDate":"July 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:35:30+00:00","versionOfRecord":{"articleIdentity":"rs-4526807","link":"https://doi.org/10.1038/s41598-025-16367-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-08-18 16:29:27","publishedOnDateReadable":"August 18th, 2025"},"versionCreatedAt":"2024-07-08 17:01:58","video":"","vorDoi":"10.1038/s41598-025-16367-w","vorDoiUrl":"https://doi.org/10.1038/s41598-025-16367-w","workflowStages":[]},"version":"v1","identity":"rs-4526807","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4526807","identity":"rs-4526807","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}