Determination of the ED 50 of intravenous lidocaine for pain on awakening after pediatric tonsillectomy: A randomized controlled trial

Determination of the ED 50 of intravenous lidocaine for pain on awakening after pediatric tonsillectomy: A randomized controlled trial | 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 Determination of the ED 50 of intravenous lidocaine for pain on awakening after pediatric tonsillectomy: A randomized controlled trial Yang Hu, Ming-Cheng Du, Yi Chen, Xiang Long, Jing-Jing Jiang, and 1 more This is a preprint; it has not been peer reviewed by a journal.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-5156340/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: We investigated the potential of intravenous lidocaine to reduce pain on awakening in a dose-dependent manner and aimed to determine the median effective dose (ED 50 ) of lidocaine in 200 children aged 3–12 years (American Society of Anesthesiologists physical status I–II) who underwent elective tonsillectomy with or without adenoidectomy at Yichang Central People’s Hospital. Methods: The patients were randomized into four dose groups (A–D: 0.0, 1.0, 1.5, and 2.0 mg/kg, respectively) and underwent the same anesthetic induction and maintenance protocols. The primary outcome was pain on awakening, whereas secondary outcomes included pain scores at 1, 4, 12, and 24 h after awakening; incidences of laryngospasm, bronchospasm, or perioperative stridor; and time to extubation. Intraoperative cardiac events were classified as safety events. Results: Our findings indicated that intravenous lidocaine dose-dependently reduced pain on awakening. The ED 50 of intravenous lidocaine for pain on awakening was 1.75 mg/kg. Significant differences were observed between groups A and D (P ≤ 0.001). No incidents of laryngospasm, bronchospasm, or perioperative stridor were observed. Furthermore, there were significant between-group differences in time to extubation (P ≤ 0.05). Conclusion: In conclusion, our study demonstrated that lidocaine dose-dependently reduced pain on awakening in children undergoing tonsillectomy with or without adenoidectomy (ED 50 = 1.75 mg/kg), with no severe adverse events. Trial registration: This study was approved by the Institutional Review Board of Yichang Central People’s Hospital (HEC-KYJJ-2020-038-02), The trial was registered at www.chictr.org.cn (ChiCTR2100053006). lidocaine pediatric patient tonsillectomy pain on awakening Figures Figure 1 Figure 2 Background Tonsillectomy, with or without adenoidectomy, is one of the most common surgical procedures performed in children wherein children receive general anesthesia via a tracheal tube [ 1 , 2 ]. Although this surgery is a common and safe procedure in children, severe pain on awakening is frequently observed following pediatric adenotonsillectomy [ 3 ]. It can easily turn into persistent pain without appropriate treatment and drastically limits patients’ oral intake of fluids and pain medication, potentially extending postoperative length of stay [ 4 , 5 ]. Lidocaine is a local anesthetic that is used as a general anesthetic adjunct because of its analgesic, anti-hyperalgesic, anti-inflammatory, and immunomodulatory properties related to stress [ 6 – 8 ]. Intravenous lidocaine reduces pain after elective surgery under general anesthesia [ 9 ]. However, it is unclear whether lidocaine reduces pain on awakening in a dose-dependent manner, and the median effective dose (ED 50 ) of intravenous lidocaine in children remains unknown. We hypothesized that intravenous lidocaine reduces pain on awakening in a dose-dependent manner and determined the ED 50 of lidocaine in children undergoing tonsillectomy with or without adenoidectomy. The choice of pain on awakening as the primary outcome was guided by the need for clinically meaningful outcomes with potential benefits. Methods Ethical Considerations All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study design was approved by the Institutional Review Board (president: Ke-Jun Yan) of Yichang Central People’s Hospital (approval number: HEC-KYJJ-2020-038-02; approval date: September 17, 2021). Written informed consent was obtained from the parents or guardians of all children enrolled in the study. Study Design This single-center, parallel-group, double-blind, randomized controlled trial (principal investigator: Yuan Gong) was registered in the Chinese Clinical Trial Registry ( http://chictr.org.cn/showproj.aspx?proj=136605 ) (registration number: ChiCTR2100053006; registration date: November 8, 2021). The trial was conducted from December 1, 2021, to May 30, 2022, at Yichang Central People’s Hospital, Hubei Province, China, in accordance with the CONSORT guidelines. Randomization was computer-generated, and each patient was assigned a code. The random numbers were generated using SPSS software (IBM Statistics 26.0.0.0; IBM Corp, Armonk, NY, USA). The 200 random numbers were arranged in ascending order. Finally, the patients were divided into four groups: group A, 1–50; group B, 51–100; group C, 101–150; and group D, 151–200. Patients were randomized to receive anesthesia with saline or three additional doses of lidocaine in a ratio of 1:1:1. On the day of the study, a nurse anesthetist who was blinded to the study opened the sealed envelope containing the sequential number, prepared the study drug, and assigned a randomization code that only the participants knew. Patients and investigators who were collecting the clinical information were blinded to the experimental groups until data analysis was complete. Patients The inclusion criteria were patients aged 3–12 years (American Society of Anesthesiologists physical status I–II) who were scheduled for elective tonsillectomy with or without adenoidectomy. Children were divided into the following four groups, according to the dose of lidocaine administered: A (0.0 mg/kg), B (1.0 mg/kg), C (1.5 mg/kg), and D (2.0 mg/kg). The exclusion criteria were chronic cough, a history of steroid or bronchodilator treatment, reactive airway disease, upper airway infection 2 weeks before the procedure, angiotensin-converting enzyme inhibitor therapy, gastroesophageal reflux, morbid obesity, known allergy to any of the study drugs, use of medications or nutraceuticals known to affect blood pressure (BP) and heart rate (HR), surgery lasting > 2 h, unexpected bleeding, and the need for > 2 intubation attempts. Perioperative Anesthetic Care Preoperatively, all children fasted for 6 h and were restricted from oral intake of clear fluids for 1 h. The children entered the operating room accompanied by their parents to curb separation anxiety. Non-invasive BP, HR, and pulse oxygen saturation were measured, and electrocardiography was performed using a multifunction monitor (GE Healthcare, Chicago, IL, USA). The width of the BP cuff for each patient was approximately two-thirds of the length of the upper arm. After stabilization for 5 min, baseline HR, systolic BP, diastolic BP, and mean arterial pressure values were obtained from the average of three measurements taken 2 min apart. A 22-gauge intravenous catheter was subsequently inserted into a vein on the back of the hand. After preoxygenation, the drug of interest (lidocaine [Anhui Changjiang Pharmaceutical Co. Ltd., Wuhu City, China] or 0.9% saline) was administered intravenously for 10 minutes. A nurse anesthetist who was blinded to the study prepared the drug of interest to be administered through an infusion pump. General anesthesia was induced 2 min after administration, using the following induction protocol: sufentanil (0.25 µg/kg [Yichang Renfu Pharmaceutical Co. Ltd., Yichang City, China]), propofol (2.0 mg/kg [Fresenius Kabi Deutschland GmbH, Homburg, Germany]), and rocuronium (0.6 mg/kg [Zhejiang Xianju Pharmaceutical Co. Ltd., Taizhou City, Zhejiang Province, China]). An anesthetist who was blinded to the study graded the cough response during injection. When the eyelash reflex disappeared, the lungs were ventilated via a face mask with 100% oxygen. A cuffed tracheal tube was used, the size of which was selected based on a widely used formula (3.5 + [age (years)] / 4). The patient was excluded from the study if any difficulty was encountered while performing face mask ventilation. Anesthesia was maintained with 2–3% sevoflurane (Maruishi Pharmaceutical Co. Ltd., Osaka, Japan) and 50% oxygen. All children were administered ibuprofen (10 mg/kg), acetaminophen (15 mg/kg), and tramadol (1 mg/kg) during the surgical procedure. At the end of the procedure, sevoflurane was discontinued, and neostigmine (0.04 mg/kg [Zhejiang Xianju Pharmaceutical Co. Ltd.]) and atropine (0.02 mg/kg [Suicheng Pharmaceutical Co. Ltd., Xinzheng City, China]) were administered to antagonize any residual neuromuscular blockade after confirming the cessation of the relaxant effect with neuromuscular monitoring. Following surgery, oral suction was immediately performed while the patient was still under anesthesia. After confirming adequate tidal volume, regular spontaneous respiratory pattern, and purposeful behavior (eyes opened on request), extubation was performed by an experienced anesthetist who was blinded to the study while the patient was recovering. After extubation, an anesthetist who was not involved in the study assessed recovery from anesthesia, scored the throat pain, and graded the cough response. Patients were monitored for ≥ 5 min, with 100% oxygen via a face mask, to allow regular spontaneous respiration. Patients were transferred to a post-anesthesia care unit (PACU) after extubation. The time to extubation (from sevoflurane discontinuation to tracheal extubation) was recorded. Electrocardiography, peripheral pulse oximetry, and non-invasive BP measurements were also performed. Patients were discharged from the PACU when their Steward score was > 4. Other postoperative care was performed according to the practices of local clinicians. If the pain (Face, Legs, Activity, Cry, and Consolability scale [children aged 3–4 years], Wong-Baker scale [children aged 4–7 years], or visual analog scale [children aged ≥ 8 years]) 3 score was ≥ 3 at rest, the attending PACU nurse administered intravenous propacetamol (30 mg/kg) as treatment. The pain scales ranged from 0 to 10. The use of other medications was restricted. Primary Outcome The primary outcome was pain on awakening after pediatric tonsillectomy [ 10 ]. Secondary Outcomes The secondary outcomes were pain scores at 1, 4, 12, and 24 h after awakening; incidences of laryngospasm, bronchospasm, and perioperative stridor; and time to extubation. Safety events included intraoperative cardiac events (arrhythmia, hypotension [mean arterial pressure 90 mmHg]), and rescue treatment. Statistical Analyses The sample size was calculated using G* Power (version 3.1.9.2; Heinrich Heine University, Düsseldorf, Germany) with a one-way ANOVA based on an expected pain on awakening score difference of 1 (clinically significant), with 80% power (α = 0.05, β = 0.2), which indicated that 50 patients were required per group. Patient characteristics (including age, height, and weight); pain on awakening scores; incidences of laryngospasm, bronchospasm, and perioperative stridor; duration of surgery; and time to extubation were expressed as mean ± SD and analyzed using ANOVA, with a P-value < 0.05 indicating a significant difference. Statistical significance was set at P < 0.01. All statistical analyses were conducted using GraphPad Prism (version 8.0.2; GraphPad Software Inc., San Diego, CA, USA). Results Patients Between December 1, 2021, and May 30, 2022, a total of 200 patients were enrolled and divided into four groups based on the dose of lidocaine administered (Fig. 1 ). There were significant differences in the time to extubation between groups A and B (P = 0.014), A and C (P = 0.015), and A and D (P = 0.017). Patient characteristics and other operative data were not significantly different between the groups (Table 1 ). Table 1 Patient characteristics and clinical data Group A a (n = 50) Group B b (n = 50) Group C c (n = 50) Group D d (n = 50) Age (years) 5.55 ± 2.02 6.02 ± 2.35 5.77 ± 1.91 5.98 ± 1.67 Height (cm) 118.34 ± 14.21 120.60 ± 16.02 117.81 ± 13.65 120.49 ± 12.02 Weight (kg) 22.88 ± 7.60 23.57 ± 8.57 22.57 ± 6.65 25.03 ± 7.22 Body mass index (kg/m 2 ) 15.96 ± 2.65 15.75 ± 2.22 16.04 ± 2.27 16.97 ± 2.75 Sex (M/F) 26/24 27/23 29/21 29/21 ASA physical status (I/II) 50/0 50/0 50/0 50/0 Duration of surgery (min) 29.74 ± 11.14 29.40 ± 11.10 29.43 ± 13.68 27.34 ± 11.95 Time of extubation (min) 11.55 ± 3.32 13.72 ± 3.30 * 13.70 ± 3.59 * 13.68 ± 3.58 * Incidence of laryngospasm 0 0 0 0 Incidence of bronchospasm 0 0 0 0 Incidence of perioperative stridor 0 0 0 0 Tonsillectomy with or without adenoidectomy 48/2 50/0 50/0 49/1 a Group A: lidocaine (0.0 mg/kg) intravenously; b group B: lidocaine (1.0 mg/kg) intravenously; c group C: lidocaine (1.5 mg/kg) intravenously; d group D: lidocaine (2.0 mg/kg) intravenously Values are expressed as n or mean ± SD. *P < 0.05 (compared with group A). ASA, American Society of Anesthesiologists; F, female; M, male [Table 1 near here] Primary Outcomes The ED 50 of intravenous lidocaine for pain on awakening was 1.75 mg/kg (Fig. 2 a). All 50 patients in each group were assessed for the primary outcome. The score for pain on awakening was significantly different between the groups, in a dose-dependent manner, with significant differences between groups C and D (P = 0.037), A and B (P = 0.007), B and D (P = 0.003), and A and C (P ≤ 0.001) (Table 2 ). There was also a significant difference between groups A and D (P ≤ 0.001) (Fig. 2 b). Table 2 Pain on awakening scores Group A a (n = 50) Group B b (n = 50) Group C c (n = 50) Group D d (n = 50) P-value Score 4.30 ± 2.09 ** 2.90 ± 2.28 *,** 2.57 ± 2.11 * 1.45 ± 1.52 * < 0.001 a Group A: lidocaine (0.0 mg/kg) intravenously; b group B: lidocaine (1.0 mg/kg) intravenously; c group C: lidocaine (1.5 mg/kg) intravenously; d group D: lidocaine (2.0 mg/kg) intravenously Values are expressed as mean ± SD. *P < 0.05 (compared with group A); **P < 0.05 (compared with group D). Secondary outcomes The pain score at 1 h after awakening was significantly different between groups A and B (P ≤ 0.001); A, C, and D (P ≤ 0.001); and B and D (P = 0.010). The pain score at 4 h after awakening was significantly different between groups A and B (P ≤ 0.001); A, C, and D (P ≤ 0.001); and B and D (P = 0.015); however, there were no significant differences in the pain scores at 12 and 24 h after awakening (Table 3 ). No cases of laryngospasm, bronchospasm, or perioperative stridor were observed in any group. However, significant differences in the time to extubation were observed between groups A and B (P = 0.014), A and C (P = 0.015), and A and D (P = 0.017) (Table 1 ). No severe complications, such as arrhythmia, were observed in any group. Table 3 Pain on awakening scores at different time points Score at different time points Group A a (n = 50) Group B b (n = 50) Group C c (n = 50) Group D d (n = 50) P-value *** 1 h 2.34 ± 0.79 1.66 ± 0.96 * 1.45 ± 0.95 * 1.15 ± 0.72 *,** < 0.001 4 h 2.19 ± 0.77 1.55 ± 0.75 * 1.34 ± 0.87 * 1.06 ± 0.92 *,** 0.05 24 h 1.49 ± 0.55 1.23 ± 0.63 1.13 ± 0.74 1.09 ± 0.62 > 0.05 a Group A: lidocaine (0.0 mg/kg) intravenously; b group B: lidocaine (1.0 mg/kg) intravenously; c group C: lidocaine (1.5 mg/kg) intravenously; d group D: lidocaine (2.0 mg/kg) intravenously Values are expressed as mean ± SD. *P < 0.05 (compared with group A); **P < 0.05 (compared with group B); ***P-values of group A compared with groups B, C, and D. Discussion Tonsillectomy is one of the most painful surgical procedures. The relief of pain after tonsillectomy remains challenging and controversial. Several interventions have been recommended to control pain after tonsillectomy in children [ 11 ]. Opioids are an important treatment strategy for postoperative pain. However, there is a tendency to avoid using narcotics for respiratory depression in children. Large studies of non-steroidal anti-inflammatory drugs have demonstrated effective pain management [ 11 ]. However, their potential for treatment of more severe bleeding events has been debated. Lidocaine is recommended for its analgesic effects and ability to improve postoperative outcomes with high patient satisfaction. The recommended dose of lidocaine is an initial bolus of 1–2 mg/kg followed by a continuous infusion of 1–2 mg/kg/h [ 9 ]. However, the ED 50 of intravenous lidocaine for pain on awakening is not known. In the current study, intravenous lidocaine resulted in a dose-dependent reduction in pain on awakening, with an ED 50 of 1.75 mg/kg. Even 1 and 4 h after surgery, there was a considerable reduction in pain scores for those who received lidocaine compared with those who did not receive lidocaine. Only after 12 h did the pain scores exhibit no difference between groups. This seems feasible as the duration of surgery was < 1 h and the half-life of intravenous lidocaine was approximately 2 h [ 12 ]. For the same reason, a single bolus of lidocaine was given without infusion. The exact inhibitory mechanism of lidocaine is unclear. It may involve its analgesic, anti-hyperalgesic, anti-inflammatory, and immunomodulatory properties related to stress [ 6 – 8 ]. No cases of laryngospasm, bronchospasm, perioperative stridor, or other serious complications were observed during anesthesia. Intravenous lidocaine appears safe and does not result in serious adverse events in children. Substantial differences in the time to extubation were observed between the study (B, C, and D) groups and the control (A) group; the time in the control group was 2 min longer to meet extubation requirements. Prolonged time to extubation following general anesthesia is defined as a time of ≥ 15 min [ 13 ]. The mean extubation time was < 15 min in all three study groups, which is considered safe. This study has several limitations. First, it was a single-center study, which reduced its power and reliability. Second, we used the sevoflurane concentration in end-expiratory gas to monitor the depth of anesthesia, potentially leading to an increase in the ED 50 . Conclusions ED 50 of intravenous lidocaine for pain on awakening was 1.75 mg/kg. Intravenous lidocaine reduced pain on awakening in children undergoing tonsillectomy with or without adenoidectomy in a dose-dependent manner without causing serious adverse events. Abbreviations ED 50 Median effective dose BP Blood pressure HR Heart rate PACU Post-anesthesia care unit ASA American Society of Anesthesiologists Declarations Ethics Approval and Consent to Participate This study was approved by the Institutional Review Board (president: Ke-Jun Yan) of Yichang Central People’s Hospital (approval number: HEC-KYJJ-2020-038-02; approval date: September 17, 2021). Written informed consent was obtained from the parents or guardians of all children enrolled in the study. Consent for Publication Not applicable. Availability of Data and Materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing Interests: The authors declare no competing interests. Funding: Support was provided solely from institutional sources. Authors’ Contributions: Data Curation, YH, and MD; Software and Formal Analysis, YH, and YC; Resources and Investigation, YC, and JJ; Project Administration, XL and JJ; Methodology, Supervision, and Validation, YG. All authors read and approved the final version of the manuscript. Acknowledgments We would like to thank Editage (www.editage.com) for the English language editing. References Lerman J. Pediatric ambulatory anesthesia: an update. Curr Opin Anaesthesiol. 2019;32:708-13. Bhattacharyya N, Lin HW. Changes and consistencies in the epidemiology of pediatric adenotonsillar surgery, 1996–2006. Otolaryngol Head Neck Surg. 2010;143:680-4. Muzzi E, Ronfani L, Bossini B, Lezcano C, Orzan E, Barbi E. Effects of intraoperative auditory stimulation on pain and agitation on awakening after pediatric adenotonsillectomy: a randomized clinical trial. JAMA Otolaryngol Head Neck Surg. 2021;147:638-45. Aldamluji N, Burgess A, Pogatzki-Zahn E, Raeder J, Beloeil H, PROSPECT Working Group collaborators*, et al. PROSPECT guideline for tonsillectomy: systematic review and procedure-specific postoperative pain management recommendations. Anaesthesia. 2021;76:947-61. Constant I, Khalfallah SA, Brunaud A, Deramoudt V, Fayoux P, Giovanni A, et al. How to replace codeine after tonsillectomy in children under 12 years of age? Guidelines of the French Oto-Rhino-Laryngology–Head and Neck Surgery Society (SFORL). Eur Ann Otorhinolaryngol Head Neck Dis. 2014;131:233-8. Hermanns H, Hollmann MW, Stevens MF, Lirk P, Brandenburger T, Piegeler T, et al. Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review. Br J Anaesth. 2019;123:335-49. Beaussier M, Delbos A, Maurice-Szamburski A, Ecoffey C, Mercadal L. Perioperative use of intravenous lidocaine. Drugs. 2018;78:1229-46. Foo I, Macfarlane AJR, Srivastava D, Bhaskar A, Barker H, Knaggs R, et al. The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety. Anaesthesia. 2021;76:238-50. Estebe JP. Intravenous lidocaine. Best Pract Res Clin Anaesthesiol. 2017;31:513-21. Muzzi E, Ronfani L, Bossini B, Lezcano C, Orzan E, Barbi E. Effects of intraoperative auditory stimulation on pain and agitation on awakening after pediatric adenotonsillectomy: A randomized clinical trial. JAMA Otolaryngol Head Neck Surg. 2021;147(7):638-45. Barrette LX, Harris J, De Ravin E, Balar E, Moreira AG, Rajasekaran K. Clinical practice guidelines for pain management after tonsillectomy: Systematic quality appraisal using the AGREE II instrument. Int J Pediatr Otorhinolaryngol. 2022;156:111091. Ochs HR, Knüchel M, Abernethy DR, Greenblatt DJ. Dose-independent pharmacokinetics of intravenous lidocaine in humans. J Clin Pharmacol. 1983;23:186-8. Vannucci A, Riordan IR, Prifti K, Sebastiani A, Helsten DL, Lander DP, et al. Prolonged time to extubation after general anaesthesia is associated with early escalation of care: A retrospective observational study. Eur J Anaesthesiol. 2021;38(5):494-504. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5156340","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":388088124,"identity":"18dfd74a-dde5-4453-9bab-7ebe92556949","order_by":0,"name":"Yang Hu","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Hu","suffix":""},{"id":388088125,"identity":"fca84914-06ff-49b2-b79a-3b651abad00e","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":388088126,"identity":"ba8fd1b8-2c1d-4bc1-acbe-04349246f855","order_by":2,"name":"Yi Chen","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Chen","suffix":""},{"id":388088127,"identity":"7af29364-6a8d-4d0a-b9b6-a05f695ac3ee","order_by":3,"name":"Xiang Long","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Long","suffix":""},{"id":388088128,"identity":"3227bdd5-bc3b-4593-8f97-30fa27a28f2d","order_by":4,"name":"Jing-Jing Jiang","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jing-Jing","middleName":"","lastName":"Jiang","suffix":""},{"id":388088129,"identity":"6fb43982-6cb2-4675-b624-be2df309baf9","order_by":5,"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":"2024-09-26 07:08:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5156340/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5156340/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":72206605,"identity":"94419504-3a59-4a63-b8e9-0277a042c59d","added_by":"auto","created_at":"2024-12-23 16:45:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":186008,"visible":true,"origin":"","legend":"\u003cp\u003eFlow Diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5156340/v1/1d52d1e89df3ade3bd76facf.png"},{"id":72206604,"identity":"fd530dca-31fa-4814-9b70-b485d00109e2","added_by":"auto","created_at":"2024-12-23 16:45:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46388,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIntravenous lidocaine for pain on awakening.\u003c/strong\u003e (a) Concentration–response curve. (b)\u003cstrong\u003e \u003c/strong\u003ePain on awakening scores. *P \u0026lt; 0.05; **P \u0026lt; 0.01; ***P \u0026lt; 0.001; ****P \u0026lt; 0.0001. ED\u003csub\u003e50\u003c/sub\u003e, median effective dose.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5156340/v1/2da5b957e75c901fa4787ee5.png"},{"id":73072062,"identity":"2a0e4990-0e2c-4694-9ce1-cdc5695bd1e5","added_by":"auto","created_at":"2025-01-06 12:47:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":649586,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5156340/v1/397fc201-c7d7-443e-bcdc-836909a8f85d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Determination of the ED 50 of intravenous lidocaine for pain on awakening after pediatric tonsillectomy: A randomized controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eTonsillectomy, with or without adenoidectomy, is one of the most common surgical procedures performed in children wherein children receive general anesthesia via a tracheal tube [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although this surgery is a common and safe procedure in children, severe pain on awakening is frequently observed following pediatric adenotonsillectomy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It can easily turn into persistent pain without appropriate treatment and drastically limits patients\u0026rsquo; oral intake of fluids and pain medication, potentially extending postoperative length of stay [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eLidocaine is a local anesthetic that is used as a general anesthetic adjunct because of its analgesic, anti-hyperalgesic, anti-inflammatory, and immunomodulatory properties related to stress [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Intravenous lidocaine reduces pain after elective surgery under general anesthesia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, it is unclear whether lidocaine reduces pain on awakening in a dose-dependent manner, and the median effective dose (ED\u003csub\u003e50\u003c/sub\u003e) of intravenous lidocaine in children remains unknown.\u003c/p\u003e\u003cp\u003eWe hypothesized that intravenous lidocaine reduces pain on awakening in a dose-dependent manner and determined the ED\u003csub\u003e50\u003c/sub\u003e of lidocaine in children undergoing tonsillectomy with or without adenoidectomy. The choice of pain on awakening as the primary outcome was guided by the need for clinically meaningful outcomes with potential benefits.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthical Considerations\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study design was approved by the Institutional Review Board (president: Ke-Jun Yan) of Yichang Central People\u0026rsquo;s Hospital (approval number: HEC-KYJJ-2020-038-02; approval date: September 17, 2021). Written informed consent was obtained from the parents or guardians of all children enrolled in the study.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Design\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThis single-center, parallel-group, double-blind, randomized controlled trial (principal investigator: Yuan Gong) was registered in the Chinese Clinical Trial Registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://chictr.org.cn/showproj.aspx?proj=136605\u003c/span\u003e\u003cspan address=\"http://chictr.org.cn/showproj.aspx?proj=136605\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) (registration number: ChiCTR2100053006; registration date: November 8, 2021). The trial was conducted from December 1, 2021, to May 30, 2022, at Yichang Central People\u0026rsquo;s Hospital, Hubei Province, China, in accordance with the CONSORT guidelines. Randomization was computer-generated, and each patient was assigned a code. The random numbers were generated using SPSS software (IBM Statistics 26.0.0.0; IBM Corp, Armonk, NY, USA). The 200 random numbers were arranged in ascending order. Finally, the patients were divided into four groups: group A, 1\u0026ndash;50; group B, 51\u0026ndash;100; group C, 101\u0026ndash;150; and group D, 151\u0026ndash;200. Patients were randomized to receive anesthesia with saline or three additional doses of lidocaine in a ratio of 1:1:1. On the day of the study, a nurse anesthetist who was blinded to the study opened the sealed envelope containing the sequential number, prepared the study drug, and assigned a randomization code that only the participants knew. Patients and investigators who were collecting the clinical information were blinded to the experimental groups until data analysis was complete.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003ePatients\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe inclusion criteria were patients aged 3\u0026ndash;12 years (American Society of Anesthesiologists physical status I\u0026ndash;II) who were scheduled for elective tonsillectomy with or without adenoidectomy. Children were divided into the following four groups, according to the dose of lidocaine administered: A (0.0 mg/kg), B (1.0 mg/kg), C (1.5 mg/kg), and D (2.0 mg/kg). The exclusion criteria were chronic cough, a history of steroid or bronchodilator treatment, reactive airway disease, upper airway infection 2 weeks before the procedure, angiotensin-converting enzyme inhibitor therapy, gastroesophageal reflux, morbid obesity, known allergy to any of the study drugs, use of medications or nutraceuticals known to affect blood pressure (BP) and heart rate (HR), surgery lasting\u0026thinsp;\u0026gt;\u0026thinsp;2 h, unexpected bleeding, and the need for \u0026gt;\u0026thinsp;2 intubation attempts.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003ePerioperative Anesthetic Care\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePreoperatively, all children fasted for 6 h and were restricted from oral intake of clear fluids for 1 h. The children entered the operating room accompanied by their parents to curb separation anxiety. Non-invasive BP, HR, and pulse oxygen saturation were measured, and electrocardiography was performed using a multifunction monitor (GE Healthcare, Chicago, IL, USA). The width of the BP cuff for each patient was approximately two-thirds of the length of the upper arm. After stabilization for 5 min, baseline HR, systolic BP, diastolic BP, and mean arterial pressure values were obtained from the average of three measurements taken 2 min apart. A 22-gauge intravenous catheter was subsequently inserted into a vein on the back of the hand.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eAfter preoxygenation, the drug of interest (lidocaine [Anhui Changjiang Pharmaceutical Co. Ltd., Wuhu City, China] or 0.9% saline) was administered intravenously for 10 minutes. A nurse anesthetist who was blinded to the study prepared the drug of interest to be administered through an infusion pump. General anesthesia was induced 2 min after administration, using the following induction protocol: sufentanil (0.25 \u0026micro;g/kg [Yichang Renfu Pharmaceutical Co. Ltd., Yichang City, China]), propofol (2.0 mg/kg [Fresenius Kabi Deutschland GmbH, Homburg, Germany]), and rocuronium (0.6 mg/kg [Zhejiang Xianju Pharmaceutical Co. Ltd., Taizhou City, Zhejiang Province, China]). An anesthetist who was blinded to the study graded the cough response during injection. When the eyelash reflex disappeared, the lungs were ventilated via a face mask with 100% oxygen. A cuffed tracheal tube was used, the size of which was selected based on a widely used formula (3.5 + [age (years)] / 4). The patient was excluded from the study if any difficulty was encountered while performing face mask ventilation. Anesthesia was maintained with 2\u0026ndash;3% sevoflurane (Maruishi Pharmaceutical Co. Ltd., Osaka, Japan) and 50% oxygen. All children were administered ibuprofen (10 mg/kg), acetaminophen (15 mg/kg), and tramadol (1 mg/kg) during the surgical procedure.\u003c/p\u003e \u003cp\u003eAt the end of the procedure, sevoflurane was discontinued, and neostigmine (0.04 mg/kg [Zhejiang Xianju Pharmaceutical Co. Ltd.]) and atropine (0.02 mg/kg [Suicheng Pharmaceutical Co. Ltd., Xinzheng City, China]) were administered to antagonize any residual neuromuscular blockade after confirming the cessation of the relaxant effect with neuromuscular monitoring. Following surgery, oral suction was immediately performed while the patient was still under anesthesia. After confirming adequate tidal volume, regular spontaneous respiratory pattern, and purposeful behavior (eyes opened on request), extubation was performed by an experienced anesthetist who was blinded to the study while the patient was recovering. After extubation, an anesthetist who was not involved in the study assessed recovery from anesthesia, scored the throat pain, and graded the cough response. Patients were monitored for \u0026ge;\u0026thinsp;5 min, with 100% oxygen via a face mask, to allow regular spontaneous respiration. Patients were transferred to a post-anesthesia care unit (PACU) after extubation. The time to extubation (from sevoflurane discontinuation to tracheal extubation) was recorded. Electrocardiography, peripheral pulse oximetry, and non-invasive BP measurements were also performed.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003ePatients were discharged from the PACU when their Steward score was \u0026gt;\u0026thinsp;4. Other postoperative care was performed according to the practices of local clinicians. If the pain (Face, Legs, Activity, Cry, and Consolability scale [children aged 3\u0026ndash;4 years], Wong-Baker scale [children aged 4\u0026ndash;7 years], or visual analog scale [children aged\u0026thinsp;\u0026ge;\u0026thinsp;8 years])\u003csup\u003e3\u003c/sup\u003e score was \u0026ge;\u0026thinsp;3 at rest, the attending PACU nurse administered intravenous propacetamol (30 mg/kg) as treatment. The pain scales ranged from 0 to 10. The use of other medications was restricted.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003ePrimary Outcome\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe primary outcome was pain on awakening after pediatric tonsillectomy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcomes\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe secondary outcomes were pain scores at 1, 4, 12, and 24 h after awakening; incidences of laryngospasm, bronchospasm, and perioperative stridor; and time to extubation. Safety events included intraoperative cardiac events (arrhythmia, hypotension [mean arterial pressure\u0026thinsp;\u0026lt;\u0026thinsp;65 mmHg], hypertension [mean arterial pressure\u0026thinsp;\u0026gt;\u0026thinsp;90 mmHg]), and rescue treatment.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical Analyses\u003c/h3\u003e\n\u003cp\u003eThe sample size was calculated using G* Power (version 3.1.9.2; Heinrich Heine University, D\u0026uuml;sseldorf, Germany) with a one-way ANOVA based on an expected pain on awakening score difference of 1 (clinically significant), with 80% power (α\u0026thinsp;=\u0026thinsp;0.05, β\u0026thinsp;=\u0026thinsp;0.2), which indicated that 50 patients were required per group. Patient characteristics (including age, height, and weight); pain on awakening scores; incidences of laryngospasm, bronchospasm, and perioperative stridor; duration of surgery; and time to extubation were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD and analyzed using ANOVA, with a P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicating a significant difference. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.01. All statistical analyses were conducted using GraphPad Prism (version 8.0.2; GraphPad Software Inc., San Diego, CA, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eBetween December 1, 2021, and May 30, 2022, a total of 200 patients were enrolled and divided into four groups based on the dose of lidocaine administered (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There were significant differences in the time to extubation between groups A and B (P\u0026thinsp;=\u0026thinsp;0.014), A and C (P\u0026thinsp;=\u0026thinsp;0.015), and A and D (P\u0026thinsp;=\u0026thinsp;0.017). Patient characteristics and other operative data were not significantly different 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\u003ePatient characteristics and clinical data\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\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup C\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup D\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.55\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.02\u0026thinsp;\u0026plusmn;\u0026thinsp;2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.77\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.67\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\u003e118.34\u0026thinsp;\u0026plusmn;\u0026thinsp;14.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120.60\u0026thinsp;\u0026plusmn;\u0026thinsp;16.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e117.81\u0026thinsp;\u0026plusmn;\u0026thinsp;13.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e120.49\u0026thinsp;\u0026plusmn;\u0026thinsp;12.02\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\u003e22.88\u0026thinsp;\u0026plusmn;\u0026thinsp;7.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.57\u0026thinsp;\u0026plusmn;\u0026thinsp;8.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.57\u0026thinsp;\u0026plusmn;\u0026thinsp;6.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.03\u0026thinsp;\u0026plusmn;\u0026thinsp;7.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.96\u0026thinsp;\u0026plusmn;\u0026thinsp;2.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.04\u0026thinsp;\u0026plusmn;\u0026thinsp;2.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.97\u0026thinsp;\u0026plusmn;\u0026thinsp;2.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (M/F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26/24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27/23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29/21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29/21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASA physical status (I/II)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50/0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration\u0026nbsp;of surgery (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.74\u0026thinsp;\u0026plusmn;\u0026thinsp;11.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.40\u0026thinsp;\u0026plusmn;\u0026thinsp;11.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.43\u0026thinsp;\u0026plusmn;\u0026thinsp;13.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27.34\u0026thinsp;\u0026plusmn;\u0026thinsp;11.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime of extubation (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.55\u0026thinsp;\u0026plusmn;\u0026thinsp;3.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.72\u0026thinsp;\u0026plusmn;\u0026thinsp;3.30\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.70\u0026thinsp;\u0026plusmn;\u0026thinsp;3.59\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.68\u0026thinsp;\u0026plusmn;\u0026thinsp;3.58\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence of laryngospasm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence of bronchospasm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence of perioperative stridor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTonsillectomy with or without adenoidectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49/1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003eGroup A: lidocaine (0.0 mg/kg) intravenously; \u003csup\u003eb\u003c/sup\u003egroup B: lidocaine (1.0 mg/kg) intravenously; \u003csup\u003ec\u003c/sup\u003egroup C: lidocaine (1.5 mg/kg) intravenously; \u003csup\u003ed\u003c/sup\u003egroup D: lidocaine (2.0 mg/kg) intravenously\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eValues are expressed as n or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. *P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (compared with group A). ASA, American Society of Anesthesiologists; F, female; M, male\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e[Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e near here]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcomes\u003c/h2\u003e \u003cp\u003eThe ED\u003csub\u003e50\u003c/sub\u003e of intravenous lidocaine for pain on awakening was 1.75 mg/kg (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). All 50 patients in each group were assessed for the primary outcome. The score for pain on awakening was significantly different between the groups, in a dose-dependent manner, with significant differences between groups C and D (P\u0026thinsp;=\u0026thinsp;0.037), A and B (P\u0026thinsp;=\u0026thinsp;0.007), B and D (P\u0026thinsp;=\u0026thinsp;0.003), and A and C (P\u0026thinsp;\u0026le;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was also a significant difference between groups A and D (P\u0026thinsp;\u0026le;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\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\u003ePain on awakening scores\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup C\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup D\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.09\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.90\u0026thinsp;\u0026plusmn;\u0026thinsp;2.28\u003csup\u003e*,**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.45\u0026thinsp;\u0026plusmn;\u0026thinsp;1.52\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003ea\u003c/sup\u003eGroup A: lidocaine (0.0 mg/kg) intravenously; \u003csup\u003eb\u003c/sup\u003egroup B: lidocaine (1.0 mg/kg) intravenously; \u003csup\u003ec\u003c/sup\u003egroup C: lidocaine (1.5 mg/kg) intravenously; \u003csup\u003ed\u003c/sup\u003egroup D: lidocaine (2.0 mg/kg) intravenously\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eValues are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. *P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (compared with group A); **P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (compared with group D).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eThe pain score at 1 h after awakening was significantly different between groups A and B (P\u0026thinsp;\u0026le;\u0026thinsp;0.001); A, C, and D (P\u0026thinsp;\u0026le;\u0026thinsp;0.001); and B and D (P\u0026thinsp;=\u0026thinsp;0.010). The pain score at 4 h after awakening was significantly different between groups A and B (P\u0026thinsp;\u0026le;\u0026thinsp;0.001); A, C, and D (P\u0026thinsp;\u0026le;\u0026thinsp;0.001); and B and D (P\u0026thinsp;=\u0026thinsp;0.015); however, there were no significant differences in the pain scores at 12 and 24 h after awakening (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No cases of laryngospasm, bronchospasm, or perioperative stridor were observed in any group. However, significant differences in the time to extubation were observed between groups A and B (P\u0026thinsp;=\u0026thinsp;0.014), A and C (P\u0026thinsp;=\u0026thinsp;0.015), and A and D (P\u0026thinsp;=\u0026thinsp;0.017) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). No severe complications, such as arrhythmia, were observed in any group.\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\u003ePain on awakening scores at different time points\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScore at different time points\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup C\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup D\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.96\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e1.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72\u003csup\u003e*,**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\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\u003e4 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e1.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003csup\u003e*,**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\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\u003e12 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.85\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e1.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e1.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003ea\u003c/sup\u003eGroup A: lidocaine (0.0 mg/kg) intravenously; \u003csup\u003eb\u003c/sup\u003egroup B: lidocaine (1.0 mg/kg) intravenously; \u003csup\u003ec\u003c/sup\u003egroup C: lidocaine (1.5 mg/kg) intravenously; \u003csup\u003ed\u003c/sup\u003egroup D: lidocaine (2.0 mg/kg) intravenously\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eValues are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. *P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (compared with group A); **P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (compared with group B); ***P-values of group A compared with groups B, C, and D.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eTonsillectomy is one of the most painful surgical procedures. The relief of pain after tonsillectomy remains challenging and controversial. Several interventions have been recommended to control pain after tonsillectomy in children [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Opioids are an important treatment strategy for postoperative pain. However, there is a tendency to avoid using narcotics for respiratory depression in children. Large studies of non-steroidal anti-inflammatory drugs have demonstrated effective pain management [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, their potential for treatment of more severe bleeding events has been debated.\u003c/p\u003e \u003cp\u003eLidocaine is recommended for its analgesic effects and ability to improve postoperative outcomes with high patient satisfaction. The recommended dose of lidocaine is an initial bolus of 1\u0026ndash;2 mg/kg followed by a continuous infusion of 1\u0026ndash;2 mg/kg/h [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the ED\u003csub\u003e50\u003c/sub\u003e of intravenous lidocaine for pain on awakening is not known. In the current study, intravenous lidocaine resulted in a dose-dependent reduction in pain on awakening, with an ED\u003csub\u003e50\u003c/sub\u003e of 1.75 mg/kg. Even 1 and 4 h after surgery, there was a considerable reduction in pain scores for those who received lidocaine compared with those who did not receive lidocaine. Only after 12 h did the pain scores exhibit no difference between groups. This seems feasible as the duration of surgery was \u0026lt;\u0026thinsp;1 h and the half-life of intravenous lidocaine was approximately 2 h [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. For the same reason, a single bolus of lidocaine was given without infusion. The exact inhibitory mechanism of lidocaine is unclear. It may involve its analgesic, anti-hyperalgesic, anti-inflammatory, and immunomodulatory properties related to stress [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNo cases of laryngospasm, bronchospasm, perioperative stridor, or other serious complications were observed during anesthesia. Intravenous lidocaine appears safe and does not result in serious adverse events in children. Substantial differences in the time to extubation were observed between the study (B, C, and D) groups and the control (A) group; the time in the control group was 2 min longer to meet extubation requirements. Prolonged time to extubation following general anesthesia is defined as a time of \u0026ge;\u0026thinsp;15 min [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The mean extubation time was \u0026lt;\u0026thinsp;15 min in all three study groups, which is considered safe.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, it was a single-center study, which reduced its power and reliability. Second, we used the sevoflurane concentration in end-expiratory gas to monitor the depth of anesthesia, potentially leading to an increase in the ED\u003csub\u003e50\u003c/sub\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eED\u003csub\u003e50\u003c/sub\u003e of intravenous lidocaine for pain on awakening was 1.75 mg/kg. Intravenous lidocaine reduced pain on awakening in children undergoing tonsillectomy with or without adenoidectomy in a dose-dependent manner without causing serious adverse events.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eED\u003csub\u003e50\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMedian effective dose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBlood pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHeart rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePACU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePost-anesthesia care unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Society of Anesthesiologists\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics Approval and Consent to Participate\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board (president: Ke-Jun Yan) of Yichang Central People\u0026rsquo;s Hospital (approval number: HEC-KYJJ-2020-038-02;\u0026nbsp;approval date: September 17, 2021). Written informed consent was obtained from the parents or guardians of all children enrolled in the study.\u003c/p\u003e\n\u003cp\u003eConsent for Publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of Data and Materials:\u0026nbsp;The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting Interests:\u0026nbsp;The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding:\u0026nbsp;Support was provided solely from institutional sources.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; Contributions:\u0026nbsp;Data Curation, YH, and MD; Software and Formal Analysis, YH, and YC; Resources and Investigation, YC, and JJ; Project Administration, XL and JJ; Methodology, Supervision, and Validation, YG. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.com) for the English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLerman J. Pediatric ambulatory anesthesia: an update. Curr Opin Anaesthesiol. 2019;32:708-13. \u003c/li\u003e\n\u003cli\u003eBhattacharyya N, Lin HW. Changes and consistencies in the epidemiology of pediatric adenotonsillar surgery, 1996\u0026ndash;2006. Otolaryngol Head Neck Surg. 2010;143:680-4. \u003c/li\u003e\n\u003cli\u003eMuzzi E, Ronfani L, Bossini B, Lezcano C, Orzan E, Barbi E. Effects of intraoperative auditory stimulation on pain and agitation on awakening after pediatric adenotonsillectomy: a randomized clinical trial. JAMA Otolaryngol Head Neck Surg. 2021;147:638-45. \u003c/li\u003e\n\u003cli\u003eAldamluji N, Burgess A, Pogatzki-Zahn E, Raeder J, Beloeil H, PROSPECT Working Group collaborators*, et al. PROSPECT guideline for tonsillectomy: systematic review and procedure-specific postoperative pain management recommendations. Anaesthesia. 2021;76:947-61. \u003c/li\u003e\n\u003cli\u003eConstant I, Khalfallah SA, Brunaud A, Deramoudt V, Fayoux P, Giovanni A, et al. How to replace codeine after tonsillectomy in children under 12 years of age? Guidelines of the French Oto-Rhino-Laryngology\u0026ndash;Head and Neck Surgery Society (SFORL). Eur Ann Otorhinolaryngol Head Neck Dis. 2014;131:233-8.\u003c/li\u003e\n\u003cli\u003eHermanns H, Hollmann MW, Stevens MF, Lirk P, Brandenburger T, Piegeler T, et al. Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review. Br J Anaesth. 2019;123:335-49.\u003c/li\u003e\n\u003cli\u003eBeaussier M, Delbos A, Maurice-Szamburski A, Ecoffey C, Mercadal L. Perioperative use of intravenous lidocaine. Drugs. 2018;78:1229-46. \u003c/li\u003e\n\u003cli\u003eFoo I, Macfarlane AJR, Srivastava D, Bhaskar A, Barker H, Knaggs R, et al. The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety. Anaesthesia. 2021;76:238-50. \u003c/li\u003e\n\u003cli\u003eEstebe JP. Intravenous lidocaine. Best Pract Res Clin Anaesthesiol. 2017;31:513-21. \u003c/li\u003e\n\u003cli\u003eMuzzi E, Ronfani L, Bossini B, Lezcano C, Orzan E, Barbi E. Effects of intraoperative auditory stimulation on pain and agitation on awakening after pediatric adenotonsillectomy: A randomized clinical trial. JAMA Otolaryngol Head Neck Surg. 2021;147(7):638-45. \u003c/li\u003e\n\u003cli\u003eBarrette LX, Harris J, De Ravin E, Balar E, Moreira AG, Rajasekaran K. Clinical practice guidelines for pain management after tonsillectomy: Systematic quality appraisal using the AGREE II instrument. Int J Pediatr Otorhinolaryngol. 2022;156:111091. \u003c/li\u003e\n\u003cli\u003eOchs HR, Kn\u0026uuml;chel M, Abernethy DR, Greenblatt DJ. Dose-independent pharmacokinetics of intravenous lidocaine in humans. J Clin Pharmacol. 1983;23:186-8.\u003c/li\u003e\n\u003cli\u003eVannucci A, Riordan IR, Prifti K, Sebastiani A, Helsten DL, Lander DP, et al. Prolonged time to extubation after general anaesthesia is associated with early escalation of care: A retrospective observational study. Eur J Anaesthesiol. 2021;38(5):494-504.\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":"lidocaine, pediatric patient, tonsillectomy, pain on awakening","lastPublishedDoi":"10.21203/rs.3.rs-5156340/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5156340/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e We investigated the potential of intravenous lidocaine to reduce pain on awakening in a dose-dependent manner and aimed to determine the median effective dose (ED\u003csub\u003e50\u003c/sub\u003e) of lidocaine in 200 children aged 3–12 years (American Society of Anesthesiologists physical status I–II) who underwent elective tonsillectomy with or without adenoidectomy at Yichang Central People’s Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e The patients were randomized into four dose groups (A–D: 0.0, 1.0, 1.5, and 2.0 mg/kg, respectively) and underwent the same anesthetic induction and maintenance protocols. The primary outcome was pain on awakening, whereas secondary outcomes included pain scores at 1, 4, 12, and 24 h after awakening; incidences of laryngospasm, bronchospasm, or perioperative stridor; and time to extubation. Intraoperative cardiac events were classified as safety events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Our findings indicated that intravenous lidocaine dose-dependently reduced pain on awakening. The ED\u003csub\u003e50\u003c/sub\u003e of intravenous lidocaine for pain on awakening was 1.75 mg/kg. Significant differences were observed between groups A and D (P ≤ 0.001). No incidents of laryngospasm, bronchospasm, or perioperative stridor were observed. Furthermore, there were significant between-group differences in time to extubation (P ≤ 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e In conclusion, our study demonstrated that lidocaine dose-dependently reduced pain on awakening in children undergoing tonsillectomy with or without adenoidectomy (ED\u003csub\u003e50\u003c/sub\u003e = 1.75 mg/kg), with no severe adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e This study was approved by the Institutional Review Board of Yichang Central People’s Hospital (HEC-KYJJ-2020-038-02), The trial was registered at www.chictr.org.cn (ChiCTR2100053006).\u003c/p\u003e","manuscriptTitle":"Determination of the ED 50 of intravenous lidocaine for pain on awakening after pediatric tonsillectomy: A randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-23 16:44:59","doi":"10.21203/rs.3.rs-5156340/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":"cca56e05-fb19-4f8f-bf87-828f3bbb5202","owner":[],"postedDate":"December 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-16T04:38:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-23 16:44:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5156340","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5156340","identity":"rs-5156340","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}