Optimizing the Subanesthetic Dose of Esketamine Combined with Propofol for Painless Gastroscopy in Adults: A Prospective Observational Study

Optimizing the Subanesthetic Dose of Esketamine Combined with Propofol for Painless Gastroscopy in Adults: A Prospective Observational Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Optimizing the Subanesthetic Dose of Esketamine Combined with Propofol for Painless Gastroscopy in Adults: A Prospective Observational Study Hai-Xia Wang, Huan-Rong Qiu, Fu-Kun Liu, Hong-wei Li, Kai Su This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8171992/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: Propofol sedation is widely used for endoscopic procedures, but its administration alone poses risks of hemodynamic and respiratory depression. Esketamine, as an adjuvant, could reduce propofol requirements and associated adverse events. The median effective dose (ED 50 ) of esketamine combined with propofol in adults undergoing painless gastroscopy remains undetermined. Therefore, we designed a study to determine the ED 50 of esketamine combined with propofol using Dixon and Massey’s up-and-down sequential method to prevent somatic responses to endoscope insertion. Methods: Adult patients scheduled for elective painless gastroscopy who met the inclusion and exclusion criteria were enrolled. Following intravenous administration of esketamine, each participant received an initial propofol dose of 1.5 mg/kg. Esketamine dosing commenced at 0.2 mg/kg and was adjusted using a modified Dixon’s up-and-down method with a dose ratio of 1:1.2 (i.e., 20% increments/decrements) based on the preceding patient’s response to gastroscope insertion. Patient responses were categorized as: Failure: MOAA/S score > 1, swallowing, coughing, or purposeful movement. Success: Absence of the above reactions. If anesthesia induction failed, the esketamine dose was increased for the subsequent patient; if successful, the dose was decreased. The study continued until eight crossover points (failure-to-success transitions) were observed. The ED 50 of esketamine was calculated as the mean of the crossover point doses. And in all patients, blood pressure, pulse oxygen saturation, heart rate, recovery time, and side effects were recorded. Results: A total of 29 adults undergoing elective painless gastroscopy were included. The ED 50 of esketamine co-administered with 1.5 mg/kg propofol, determined via Dixon’s up-and-down method, was 0.172 mg/kg. Probit analysis estimated an ED 50 of 0.159 mg/kg (95% CI: 0.144–0.176) and ED 95 of 0.195 mg/kg (95% CI: 0.178–0.273). Time from induction to scope insertion was 31.6 ± 15.1 s, and total propofol dose was 114.01 ± 22.14 mg. Gastroscopy duration averaged 6.8 ± 2.1 min, with PACU stay time of 16.1 ± 3.7 min. Adverse events included transient sinus tachycardia (n = 1) and mild hypoxemia (SpO2% <90%; n = 1), with no serious adverse events. Conclusion: The ED 50 of esketamine combined with 1.5 mg/kg propofol for painless gastroscopy was 0.172 mg/kg, as determined by Dixon's up-and-down sequential method. Trial registration This study was registered on 19 April 2023 at Chinese Clinical Trial Registry (http//www.chictr.org.cn registration NO. ChiCTR2300070635). Esketamine Gastroscopy Propofol Median effective dose Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Gastroscopy is widely used for diagnosing and treating digestive diseases. To improve patient comfort and procedural efficiency, sedation has become increasingly common. Propofol remains the most frequently administered anesthetic for procedural sedation during painless gastroscopy[ 1 , 2 ]. However, propofol administration alone often requires higher doses, increasing the risk of adverse effects including upper airway obstruction, respiratory depression, hypotension, injection pain, and prolonged recovery[ 3 , 4 ], identifying effective anesthetic adjuvants to enhance efficacy while minimizing these risks is therefore clinically important. Esketamine, the S(+)-enantiomer of ketamine and a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, exhibits rapid onset, potent analgesic properties, hypnotic effects, and minimal respiratory depression[ 5 ]. Recent evidence demonstrates its exceptional utility as an adjunct to propofol for gastroscopy sedation[ 6 , 7 ]. Low-dose esketamine co-administration reduced propofol requirements while decreasing the incidence of desaturation and hypotension by approximately 61% compared to propofol monotherapy[ 8 ]. Despite these benefits, the minimum effective dose of esketamine for achieving deep sedation during propofol-based painless gastroscopy in adults remains undetermined. Therefore, this study employed a modified Dixon's up-and-down method to establish the ED 50 of esketamine combined with 1.5 mg/kg intravenous propofol. Secondary outcomes included the incidence of hypoxemia and hypotension. Methods This study was approved by the Institutional Ethics Committee of Beijing Friendship Hospital, China (Approval No: 2023-P2-081-01) and registered at the Chinese Clinical Trial Registry (Registration ID: ChiCTR2300070635; http://www.chictr.org.cn ). After obtaining written informed consent from all participants, twenty-nine adult patients (18–65 years) scheduled for elective painless gastroscopy were enrolled. All patients were American Society of Anesthesiologists (ASA) physical status I-II with body mass index (BMI) 18–30 kg/m². Patients were excluded for any of the following: (1) Pharmacological Contraindications: Allergy to propofol, esketamine, or opioids. Chronic use (> 3 months) of benzodiazepines, opioids, or CNS depressants. (2) Organ Dysfunction: Cardiovascular: Uncontrolled hypertension (SBP > 180 mmHg), NYHA class III-IV heart failure. Respiratory: FEV₁ <50% predicted, active asthma/COPD exacerbation. Hepatic/Renal: Child-Pugh B/C cirrhosis, eGFR < 60 mL/min/1.73m². Neurological: Epilepsy, stroke history, increased intracranial pressure. (3) Comorbidities: Glaucoma or symptomatic laryngeal pathology; Psychiatric disorders (schizophrenia, major depression) or cognitive impairment (MMSE < 24). Substance abuse history (past 2 years). (4) Airway Risks: Mallampati class IV; Acute upper respiratory infection; Predicted difficult airway. Anesthesia protocol and gastroscopic procedure After fasting for at least 8 hours, the patients were brought into the digestive endoscope preparation room, where intravenous access was established for the infusion of Ringer Lactate solution and administration of medications. Continuous standard anesthesia monitoring of vital signs—including pulse oxygen saturation (SpO 2 ), non-invasive blood pressure, heart rate (HR), and electrocardiogram—was applied throughout the gastroscopy and recovery periods once the patients arrived in the digestive endoscopy room. All patients were positioned in the left lateral decubitus position with a 30° head elevation and neck extension. Oxygen was administered at a rate of 6 L/min via a mask during the gastroscopy. All clinical procedures were conducted by experienced anesthesiologists and endoscopists. Emergency airway management equipment and rescue medications were prepared in advance. For the induction of anesthesia, the first patient received 0.2 mg/kg esketamine, followed by an intravenous injection of 1.5 mg/kg propofol. Once the patient was adequately sedated, the endoscopist commenced the gastroscopy. The sedation level was assessed using the Modified Observer’s Assessment of Alertness/Sedation scale (MOAA/S) [ 9 ] (1. Does not respond to painful trapezius squeeze or shaking; 2. Responds only to painful trapezius squeeze or shaking; 3. Responds only after name is called loudly or repeatedly; 4. Lethargic response to name spoken in normal tone; 5. Responds readily to name spoken in normal tone). According to the MOAA/S criteria, the gastroscope was not inserted until the patient’s eyelash reflex disappeared, the MOAA/S score was ≤ 1, and there was no significant body movement. If the sedation level was inadequate, an additional dose of 0.5 mg/kg propofol was administered intravenously during the induction and maintenance of anesthesia until the gastroscopy was completed. If the SpO 2 fell below 90%, the anesthesiologist immediately performed chin lift, jaw-thrust maneuvers, and rapid oxygenation. Should hypoxemia persist and SpO 2 drop below 80% despite these interventions, the gastroscopic procedure was halted, and the gastroscope was removed immediately. Mask-assisted ventilation with pure oxygen was then performed, and positive pressure ventilation was employed if necessary. In cases of hypotension (systolic blood pressure < 30% of the baseline level), 6 mg of ephedrine was administered intravenously. If bradycardia (HR < 45/min) occurred, 0.5 mg of atropine was given. Other adverse events were documented and managed according to clinical standards for endoscopic examination. Post-procedure, patients were transferred to the post-anesthesia care unit (PACU) upon regaining consciousness. When the patient was fully alert and vital signs were stable, indicated by a modified Aldrete score ≥ 9, they were allowed to leave the hospital accompanied by a family member. This study employed a sequential modified Dixon’s up-and-down method to estimate the median threshold for all-or-nothing responses, a value that is investigated but cannot be directly measured[ 10 ]. The modified Dixon’s up-and-down method was applied to determine the minimum effective dose of esketamine required for gastroscope insertion in adult patients, a technique previously used in similar studies to explore anesthetic methods for gastroscope insertion based on patient responses[ 11 ]. The patient's response was assessed by a second anesthesiologist who was blinded to the dose during gastroscope insertion. Responses were classified as either "failure" or "success." A "failure" was defined as gastroscope insertion resulting in an MOAA/S score > 1, swallowing, coughing, or purposeful body movement that interfered with the procedure. Conversely, the absence of these issues was labeled as "success." Esketamine was initiated at a dose of 0.2 mg/kg, with incremental adjustments based on a step size of 1:1.2 according to the previous patient's response to gastroscope insertion. If the response was "success," the esketamine dose for the next patient was decreased by a step size of 1:1.2. If the response was "failure," the dose was increased by the same step size. Additionally, if any body movement occurred before or after gastroscope insertion, an immediate injection of 0.5 mg/kg propofol was administered. The study continued until eight crossover points from a "failure" response to a "success" response were obtained. Observational indicators The primary outcome was the minimum effective dose of esketamine (ED 50 ) combined with 1.5 mg/kg propofol needed to inhibit the response to gastroscope insertion in adult patients. Secondary outcomes included the following: heart rate (HR) and mean arterial blood pressure (MAP) measured at various time points—before anesthesia (T0), before gastroscope insertion after anesthesia induction (T1), 3 minutes after gastroscope insertion (T2), immediately upon recovery after removal of the gastroscope (T3), and before leaving the PACU (T4); lowest SpO2; total dose of propofol; gastroscopy duration; Time to awakening; PACU stay time; and adverse reactions such as hypoxemia, respiratory depression, arrhythmia, nausea and vomiting, delayed recovery, dizziness, nightmares, delirium, or hallucinations. Time to awakening was defined as the period between the removal of the gastroscope and the point when the MOAA/S score reached 4. PACU stay time was calculated from the time of patient arrival at the PACU until the discharge criteria were met (a modified Aldrete score ≥ 9). Recovery time exceeding 30 minutes was considered delayed awakening. An SpO 2 < 90% indicated the presence of hypoxemia and respiratory depression. Statistical analysis The primary outcome, ED 50 of esketamine, was calculated as the average of the eight crossover midpoints from 'failure' to 'success' responses obtained in all patients using the Dixon’s up-and-down method. The standard deviation (SD) of the ED 50 represented the SD of these crossover midpoints. Additionally, we calculated the ED 50 and its 95% confidence interval (CI) using probit regression curves based on the data collected in this up-and-down sequential study. Heart rate (HR) and blood pressure parameters were analyzed using repeated measures analysis of variance (ANOVA). Patient characteristics were represented as mean (SD), median (IQR [range]), or number (proportion). These data were analyzed using SPSS version 26.0 (SPSS Inc., Chicago, IL, USA). A p-value of < 0.05 was considered statistically significant. Results Table 1 Baseline characteristics of the study participants (n = 29) Parameters Total (n = 29) Age; years 47 ± 10.6 Gender; female 17(58.6) Height, cm 163.0 ± 6.5 Weight, kg 62.0 ± 8.9 BMI, kg/m 2 23.2 ± 2.4 Hypertension 2(6.9) Diabetes mellitus 2(6.9) Data are presented as mean ± standard deviation or numbers (proportion). BMI: body mass index Table 2 Procedural characteristics and outcomes during anesthesia and gastroscopy (n = 29) Parameters Total (n = 29) Anesthesia induction time, s 46.9 ± 12.4 Time from induction to scope insertion, s 31.5 ± 11.6 Total propofol dose, mg 131.6 ± 32.9 Gastroscopy duration, min 7.1 (5.9–10.2 [3.0-12.5]) Time to awakening, min 2.1 ± 1.5 PACU stay time, min 16.1 ± 3.7 Lowest SpO₂, % 98 (97–99 [89–100]) Data are presented as mean ± standard deviation or median (interquartile range [full range]). PACU, post-anesthesia care unit. A total of 29 adult patients (12 males, 17 females) were enrolled, and all completed the study (Fig. 1 ). Baseline demographic and clinical characteristics are summarized in Table 1 . The dose-response sequence obtained using the modified Dixon’s up-and-down method is illustrated in Fig. 2 . The median effective dose (ED 50 ) of esketamine in combination with 1.5 mg/kg propofol for successful gastroscope insertion, as derived from the Dixon method, was 0.172 mg/kg. Probit regression analysis further estimated an ED 50 of 0.159 mg/kg (95% CI: 0.144–0.176) and an ED 95 of 0.195 mg/kg (95% CI: 0.178–0.273), with the dose-probability relationship depicted in Fig. 3 . Hemodynamic and procedural outcomes are presented in Table 2 . Changes in MAP and HR at different time points during the study were shown in Fig. 4 a and b. Although statistically significant variations in HR were observed, these fluctuations were not considered clinically relevant. One patient experienced transient hypoxemia, with SpO 2 declining to 89% during the procedure; this was promptly resolved with chin lift, jaw-thrust maneuver, and supplemental oxygen. No episodes of hypotension, bradycardia, delayed recovery, or other adverse events—such as arrhythmia, nausea, vomiting, nightmares, or hallucinations—were recorded. Discussion This study demonstrated that a sub-anesthetic dose of esketamine combined with propofol provides effective and satisfactory conditions for gastroscope insertion in adults, with a low incidence of adverse events. Using the modified Dixon’s up-and-down method, we determined that the median effective dose (ED 50 ) of esketamine for successful gastroscope insertion in 50% of adults, when co-administered with a fixed dose of 1.5 mg/kg propofol, was 0.172 mg/kg. Probit regression analysis yielded a corroborative ED 50 of 0.159 mg/kg (95% CI: 0.144–0.176) and an ED 95 of 0.195 mg/kg (95% CI: 0.178–0.273). To our knowledge, this is the first study to determine the ED 50 of esketamine for gastroscope insertion when combined with propofol in adults. Propofol remains the most widely used intravenous anesthetic for painless gastroscopy, owing to its rapid onset and short recovery profile [ 12 ]. However, when used alone, it lacks analgesic efficacy and often necessitates higher doses, which can induce adverse effects including respiratory depression, oxygen desaturation, hypotension, and bradycardia [ 12 ]. Consequently, adjuvant agents are commonly co-administered with propofol to enhance analgesia and reduce its dosage [ 13 , 14 ]. While the combination of propofol and opioids is frequently employed, it can exacerbate respiratory and circulatory depression[ 15 ]. In contrast, esketamine, an NMDA receptor antagonist with analgesic and sympathomimetic properties, not only provides analgesia but also helps mitigate the cardiorespiratory depression associated with propofol[ 8 ]. This pharmacodynamic profile makes the propofol-esketamine combination a promising regimen for maintaining hemodynamic and respiratory stability during procedural sedation. Nonetheless, high doses of esketamine carry a risk of neuropsychiatric side effects, underscoring the importance of identifying its minimum effective dose. Our findings are consistent with previous reports supporting the safety and efficacy of low-dose esketamine. For instance, Su et al. reported the successful use of sub-anesthetic esketamine in pediatric gastroscopy [ 16 ], while others have confirmed its safety profile in adults undergoing painless gastroenteroscopy [ 17 , 18 ]. Notably, Feng et al. observed an increased incidence of visual disturbances and delayed recovery with 0.5 mg/kg esketamine [ 19 ]. In our study, however, no such adverse effects were observed within the esketamine dose range of 0.116–0.2 mg/kg, suggesting that lower doses may preserve efficacy while minimizing side effects. Several comparative studies support this advantage. Multiple clinical trials have directly compared sedation protocols and found that the combination of esketamine and propofol offers a more stable hemodynamic profile and reduces propofol consumption compared to propofol alone or propofol-opioid combinations, with a comparable or improved safety margin [ 20 – 22 ]. The typical dose ranges identified in these studies (propofol 1–3 mg/kg; esketamine 0.15–0.5 mg/kg) encompass the lower doses we employed. Our results refine this range by identifying the minimum effective dose, thereby helping to minimize the risk of dose-dependent side effects while maintaining efficacy. The favorable safety profile observed in our study—with only one transient hypoxemia event that was promptly managed—may be attributed to two key factors: the use of a moderate propofol induction dose (1.5 mg/kg) based on pre-experimental titration, and the sympathetic-activating effect of low-dose esketamine, which helps maintain hemodynamic and respiratory stability [ 8 ]. Several limitations of this study should be acknowledged. First, as a single-center sequential study with a small sample size, the generalizability of our findings may be limited. Second, the ED 95 estimated by probit regression should be interpreted with caution, as the sequential design does not fully account for potential side effects at higher doses; validation in larger randomized trials is warranted. Third, due to the use of low, sub-anesthetic esketamine doses and careful propofol titration, this study was not powered to detect rare or dose-dependent adverse events. Finally, our inclusion criteria were restricted to ASA I–II patients aged 18–65 years with a BMI of 18–30 kg/m²; thus, the results may not be generalizable to obese, elderly, or higher-risk populations. Conclusion In adult patients undergoing painless gastroscopy, the median effective dose of esketamine combined with 1.5 mg/kg propofol is 0.172 mg/kg, as determined by the Dixon’s up-and-down method. This low-dose combination provides effective sedation with a favorable safety profile and minimal adverse effects. Abbreviations ASA American Society of Anesthesiologists BMI Body Mass Index CI Confidence Interval ED 50 Median Effective Dose ED 95 95% Effective Dose HR Heart Rate MAP Mean Arterial Pressure MOAA/S Modified Observer's Assessment of Alertness/Sedation NMDA N-methyl-D-aspartate PACU Post-anesthesia Care Unit SPO 2 Oxygen saturation Declarations Ethics approval and consent to participate This study was approved by the Institutional Ethics Committee of Beijing Friendship Hospital, China (Approval No: 2023-P2-081-01) and was prospectively registered at the Chinese Clinical Trial Registry (No. ChiCTR2300070635). Written informed consent was obtained from all individual participants included in the study. Consent for publication Written informed consent for publication of their clinical data was obtained from all participants in this study. Data availability The data of this study are available from the corresponding author by reasonable request. Competing interest The authors declare that they have no competing interests. Funding This study was funded by Beijing Health Science and Technology Achievement and Appropriate Technology Promotion Project (NO. BHTPP2022081). Authors’ contributions HXW contributed to the study design, data collection, data analysis, and was a major contributor in writing the manuscript. HRQ performed the data analysis and interpretation. FKL and HWL contributed to data curation and investigation. KS conceptualized the study, supervised the project, and critically revised the manuscript. All authors read and approved the final manuscript. Acknowledgements The authors sincerely thank the staff of the Digestive Endoscopy Center at Beijing Friendship Hospital for their strong support of this study. References Li DN, Zhao GQ, Su ZB. Propofol Target-controlled Infusion in Anesthesia Induction during Painless Gastroscopy. J Coll Physicians Surg Pak. 2019;29(7):604–7. 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Front Pharmacol. 2022;13:1034236. Chu T, Zhou S, Wan Y, Liu Q, Xin Y, Tian Z, Yan T, Xu A. Comparison of remimazolam and propofol combined with low dose esketamine for pediatric same-day painless bidirectional endoscopy: a randomized, controlled clinical trial. Front Pharmacol. 2024;15:1298409. Wang LL, Guan ZY, Wang CM, Zhang YW, Zhang J, Zhao P. A comparative study on the efficacy and safety of propofol combined with different doses of alfentanil in gastroscopy: a randomized controlled trial. J Anesth. 2023;37(2):201–9. Huang X, Ai P, Wei C, Sun Y, Wu A. Comparison of the Effects of Esketamine/Propofol and Sufentanil/Propofol on the Incidence of Intraoperative Hypoxemia during Bronchoscopy: Protocol for a Randomized, Prospective, Parallel-Group Trial. J Clin Med 2022, 11(15). Additional Declarations No competing interests reported. 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Su","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYBACCQYGxgcfGBh4+OBCBwhrYTacAdTCRooWNmkeIIN4LZL9Z4yNbXPsZNgYmB9+utnGIMd3I4HxcwEeLdISOYaPc7clAx3GZiyd28ZgLHkjgVl6Bh4tchI8xsa525iBWnjYmIFaEjfcSGBj5sGnhf+MmbTltnq4lnqCWqQZcsykGbcdhmtJMCCkRXJGWrFh77bjQPVAv+SckzCceeZhszQ+LRLnD2988HNbtT0/e/PDzzllNvJ8x5MPfsanBQGYIUYAMWMDURpGwSgYBaNgFOAGAGK+O5GR/dO/AAAAAElFTkSuQmCC","orcid":"","institution":"Beijing Friendship Hospital, Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Kai","middleName":"","lastName":"Su","suffix":""}],"badges":[],"createdAt":"2025-11-21 10:05:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8171992/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8171992/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98048917,"identity":"d965c8a2-1cf9-4416-892b-9dc6146c3c45","added_by":"auto","created_at":"2025-12-12 08:36:19","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":353157,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript8.docx","url":"https://assets-eu.researchsquare.com/files/rs-8171992/v1/ae2ca33b71b31d3fad21bdc8.docx"},{"id":98427364,"identity":"d7fde065-cd4e-4dcd-b8ce-55f1e784321a","added_by":"auto","created_at":"2025-12-17 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08:36:19","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":70527,"visible":true,"origin":"","legend":"","description":"","filename":"8a9f1fe3bddb45c390bd7e085dea54261structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8171992/v1/8ea338c1e4f865b0361502d8.xml"},{"id":98428409,"identity":"c9a534fc-f7c2-4efa-b3f2-a4ada1394c64","added_by":"auto","created_at":"2025-12-17 16:41:59","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80056,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8171992/v1/4dfb3207772b8191cc58335a.html"},{"id":98048925,"identity":"7f874b66-36d6-4f80-be4e-c3c8f9163fcd","added_by":"auto","created_at":"2025-12-12 08:36:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":387683,"visible":true,"origin":"","legend":"\u003cp\u003eFlow of participants using the modified Dixon’s up-and-down method.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8171992/v1/aafdea36207e0b93a7327f6d.png"},{"id":98048914,"identity":"b9bb60b5-a7f0-4762-bf27-7114cb7f4382","added_by":"auto","created_at":"2025-12-12 08:36:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":133922,"visible":true,"origin":"","legend":"\u003cp\u003eSequential allocation and responses of 29 patients.\u0026nbsp;The arrows indicate the midpoint doses between consecutive 'failure' (\u003cstrong\u003e○\u003c/strong\u003e) and 'success' (●) responses, the mean of which defines the ED\u003csub\u003e50\u0026nbsp;\u003c/sub\u003eof esketamine.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8171992/v1/6f1b077ba668b06e7fa61cb7.png"},{"id":98048924,"identity":"c323c8e3-5aa6-4f85-bac0-48c08bbcad02","added_by":"auto","created_at":"2025-12-12 08:36:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":47554,"visible":true,"origin":"","legend":"\u003cp\u003eDose-response curve of esketamine for successful gastroscope insertion, derived from probit regression analysis. The probability of success is plotted against the esketamine dose. The median effective dose (ED\u003csub\u003e50\u003c/sub\u003e) and 95% effective dose (ED\u003csub\u003e95\u003c/sub\u003e) are 0.159 mg/kg (95% CI: 0.144–0.176) and 0.195 mg/kg (95% CI: 0.178–0.273), respectively.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8171992/v1/8168a4dd004b1bba51cd029d.png"},{"id":98048913,"identity":"ba236dfe-e305-48f8-869b-4b22d16d317f","added_by":"auto","created_at":"2025-12-12 08:36:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":96766,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in (a) mean arterial pressure (MAP) and (b) heart rate (HR) at different time points during the study. T0, before anesthesia; T1, before gastroscope insertion after anesthesia induction; T2, 3 min after gastroscope insertion; T3, immediately after removal of the gastroscope; T4, before leaving the post-anesthesia care unit (PACU). Data are presented as mean ± standard deviation (SD). *P \u0026lt; 0.05 compared with T0 by repeated-measures analysis of variance (ANOVA).\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8171992/v1/9dc61645b7f9dd1107bec45c.png"},{"id":101753285,"identity":"50a798b8-0d77-482b-be3c-95233d5d519b","added_by":"auto","created_at":"2026-02-03 10:39:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1162116,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8171992/v1/4216294e-d37e-4f4e-bad2-14998ad89125.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Optimizing the Subanesthetic Dose of Esketamine Combined with Propofol for Painless Gastroscopy in Adults: A Prospective Observational Study","fulltext":[{"header":"Background","content":"\u003cp\u003eGastroscopy is widely used for diagnosing and treating digestive diseases. To improve patient comfort and procedural efficiency, sedation has become increasingly common. Propofol remains the most frequently administered anesthetic for procedural sedation during painless gastroscopy[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, propofol administration alone often requires higher doses, increasing the risk of adverse effects including upper airway obstruction, respiratory depression, hypotension, injection pain, and prolonged recovery[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], identifying effective anesthetic adjuvants to enhance efficacy while minimizing these risks is therefore clinically important.\u003c/p\u003e\u003cp\u003eEsketamine, the S(+)-enantiomer of ketamine and a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, exhibits rapid onset, potent analgesic properties, hypnotic effects, and minimal respiratory depression[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Recent evidence demonstrates its exceptional utility as an adjunct to propofol for gastroscopy sedation[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Low-dose esketamine co-administration reduced propofol requirements while decreasing the incidence of desaturation and hypotension by approximately 61% compared to propofol monotherapy[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite these benefits, the minimum effective dose of esketamine for achieving deep sedation during propofol-based painless gastroscopy in adults remains undetermined. Therefore, this study employed a modified Dixon's up-and-down method to establish the ED\u003csub\u003e50\u003c/sub\u003e of esketamine combined with 1.5 mg/kg intravenous propofol. Secondary outcomes included the incidence of hypoxemia and hypotension.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis study was approved by the Institutional Ethics Committee of Beijing Friendship Hospital, China (Approval No: 2023-P2-081-01) and registered at the Chinese Clinical Trial Registry (Registration ID: ChiCTR2300070635; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.chictr.org.cn\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). After obtaining written informed consent from all participants, twenty-nine adult patients (18\u0026ndash;65 years) scheduled for elective painless gastroscopy were enrolled. All patients were American Society of Anesthesiologists (ASA) physical status I-II with body mass index (BMI) 18\u0026ndash;30 kg/m\u0026sup2;.\u003c/p\u003e\u003cp\u003ePatients were excluded for any of the following: (1) Pharmacological Contraindications: Allergy to propofol, esketamine, or opioids. Chronic use (\u0026gt;\u0026thinsp;3 months) of benzodiazepines, opioids, or CNS depressants. (2) Organ Dysfunction: Cardiovascular: Uncontrolled hypertension (SBP\u0026thinsp;\u0026gt;\u0026thinsp;180 mmHg), NYHA class III-IV heart failure. Respiratory: FEV₁ \u0026lt;50% predicted, active asthma/COPD exacerbation. Hepatic/Renal: Child-Pugh B/C cirrhosis, eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min/1.73m\u0026sup2;. Neurological: Epilepsy, stroke history, increased intracranial pressure. (3) Comorbidities: Glaucoma or symptomatic laryngeal pathology; Psychiatric disorders (schizophrenia, major depression) or cognitive impairment (MMSE\u0026thinsp;\u0026lt;\u0026thinsp;24). Substance abuse history (past 2 years). (4) Airway Risks: Mallampati class IV; Acute upper respiratory infection; Predicted difficult airway.\u003c/p\u003e\u003cp\u003eAnesthesia protocol and gastroscopic procedure\u003c/p\u003e\u003cp\u003eAfter fasting for at least 8 hours, the patients were brought into the digestive endoscope preparation room, where intravenous access was established for the infusion of Ringer Lactate solution and administration of medications. Continuous standard anesthesia monitoring of vital signs\u0026mdash;including pulse oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e), non-invasive blood pressure, heart rate (HR), and electrocardiogram\u0026mdash;was applied throughout the gastroscopy and recovery periods once the patients arrived in the digestive endoscopy room.\u003c/p\u003e\u003cp\u003eAll patients were positioned in the left lateral decubitus position with a 30\u0026deg; head elevation and neck extension. Oxygen was administered at a rate of 6 L/min via a mask during the gastroscopy. All clinical procedures were conducted by experienced anesthesiologists and endoscopists. Emergency airway management equipment and rescue medications were prepared in advance.\u003c/p\u003e\u003cp\u003eFor the induction of anesthesia, the first patient received 0.2 mg/kg esketamine, followed by an intravenous injection of 1.5 mg/kg propofol. Once the patient was adequately sedated, the endoscopist commenced the gastroscopy. The sedation level was assessed using the Modified Observer\u0026rsquo;s Assessment of Alertness/Sedation scale (MOAA/S) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] (1. Does not respond to painful trapezius squeeze or shaking; 2. Responds only to painful trapezius squeeze or shaking; 3. Responds only after name is called loudly or repeatedly; 4. Lethargic response to name spoken in normal tone; 5. Responds readily to name spoken in normal tone). According to the MOAA/S criteria, the gastroscope was not inserted until the patient\u0026rsquo;s eyelash reflex disappeared, the MOAA/S score was \u0026le;\u0026thinsp;1, and there was no significant body movement. If the sedation level was inadequate, an additional dose of 0.5 mg/kg propofol was administered intravenously during the induction and maintenance of anesthesia until the gastroscopy was completed.\u003c/p\u003e\u003cp\u003eIf the SpO\u003csub\u003e2\u003c/sub\u003e fell below 90%, the anesthesiologist immediately performed chin lift, jaw-thrust maneuvers, and rapid oxygenation. Should hypoxemia persist and SpO\u003csub\u003e2\u003c/sub\u003e drop below 80% despite these interventions, the gastroscopic procedure was halted, and the gastroscope was removed immediately. Mask-assisted ventilation with pure oxygen was then performed, and positive pressure ventilation was employed if necessary. In cases of hypotension (systolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;30% of the baseline level), 6 mg of ephedrine was administered intravenously. If bradycardia (HR\u0026thinsp;\u0026lt;\u0026thinsp;45/min) occurred, 0.5 mg of atropine was given. Other adverse events were documented and managed according to clinical standards for endoscopic examination.\u003c/p\u003e\u003cp\u003ePost-procedure, patients were transferred to the post-anesthesia care unit (PACU) upon regaining consciousness. When the patient was fully alert and vital signs were stable, indicated by a modified Aldrete score\u0026thinsp;\u0026ge;\u0026thinsp;9, they were allowed to leave the hospital accompanied by a family member.\u003c/p\u003e\u003cp\u003eThis study employed a sequential modified Dixon\u0026rsquo;s up-and-down method to estimate the median threshold for all-or-nothing responses, a value that is investigated but cannot be directly measured[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The modified Dixon\u0026rsquo;s up-and-down method was applied to determine the minimum effective dose of esketamine required for gastroscope insertion in adult patients, a technique previously used in similar studies to explore anesthetic methods for gastroscope insertion based on patient responses[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe patient's response was assessed by a second anesthesiologist who was blinded to the dose during gastroscope insertion. Responses were classified as either \"failure\" or \"success.\" A \"failure\" was defined as gastroscope insertion resulting in an MOAA/S score\u0026thinsp;\u0026gt;\u0026thinsp;1, swallowing, coughing, or purposeful body movement that interfered with the procedure. Conversely, the absence of these issues was labeled as \"success.\" Esketamine was initiated at a dose of 0.2 mg/kg, with incremental adjustments based on a step size of 1:1.2 according to the previous patient's response to gastroscope insertion. If the response was \"success,\" the esketamine dose for the next patient was decreased by a step size of 1:1.2. If the response was \"failure,\" the dose was increased by the same step size.\u003c/p\u003e\u003cp\u003eAdditionally, if any body movement occurred before or after gastroscope insertion, an immediate injection of 0.5 mg/kg propofol was administered. The study continued until eight crossover points from a \"failure\" response to a \"success\" response were obtained.\u003c/p\u003e\u003cp\u003eObservational indicators\u003c/p\u003e\u003cp\u003eThe primary outcome was the minimum effective dose of esketamine (ED\u003csub\u003e50\u003c/sub\u003e) combined with 1.5 mg/kg propofol needed to inhibit the response to gastroscope insertion in adult patients. Secondary outcomes included the following: heart rate (HR) and mean arterial blood pressure (MAP) measured at various time points\u0026mdash;before anesthesia (T0), before gastroscope insertion after anesthesia induction (T1), 3 minutes after gastroscope insertion (T2), immediately upon recovery after removal of the gastroscope (T3), and before leaving the PACU (T4); lowest SpO2; total dose of propofol; gastroscopy duration; Time to awakening; PACU stay time; and adverse reactions such as hypoxemia, respiratory depression, arrhythmia, nausea and vomiting, delayed recovery, dizziness, nightmares, delirium, or hallucinations.\u003c/p\u003e\u003cp\u003eTime to awakening was defined as the period between the removal of the gastroscope and the point when the MOAA/S score reached 4. PACU stay time was calculated from the time of patient arrival at the PACU until the discharge criteria were met (a modified Aldrete score\u0026thinsp;\u0026ge;\u0026thinsp;9). Recovery time exceeding 30 minutes was considered delayed awakening. An SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;90% indicated the presence of hypoxemia and respiratory depression.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe primary outcome, ED\u003csub\u003e50\u003c/sub\u003e of esketamine, was calculated as the average of the eight crossover midpoints from 'failure' to 'success' responses obtained in all patients using the Dixon\u0026rsquo;s up-and-down method. The standard deviation (SD) of the ED\u003csub\u003e50\u003c/sub\u003e represented the SD of these crossover midpoints. Additionally, we calculated the ED\u003csub\u003e50\u003c/sub\u003e and its 95% confidence interval (CI) using probit regression curves based on the data collected in this up-and-down sequential study.\u003c/p\u003e\u003cp\u003eHeart rate (HR) and blood pressure parameters were analyzed using repeated measures analysis of variance (ANOVA). Patient characteristics were represented as mean (SD), median (IQR [range]), or number (proportion). These data were analyzed using SPSS version 26.0 (SPSS Inc., Chicago, IL, USA). A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\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 characteristics of the study participants (n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;29)\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\u003e47\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender; female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17(58.6)\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\u003e163.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\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\u003e62.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(6.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes mellitus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(6.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or numbers (proportion). BMI: body mass index\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\u003eProcedural characteristics and outcomes during anesthesia and gastroscopy (n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnesthesia induction time, s\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime from induction to scope insertion, s\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal propofol dose, mg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e131.6\u0026thinsp;\u0026plusmn;\u0026thinsp;32.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastroscopy duration, min\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.1 (5.9\u0026ndash;10.2 [3.0-12.5])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime to awakening, min\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePACU stay time, min\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLowest SpO₂, %\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98 (97\u0026ndash;99 [89\u0026ndash;100])\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range [full range]). PACU, post-anesthesia care unit.\u003c/p\u003e\u003cp\u003eA total of 29 adult patients (12 males, 17 females) were enrolled, and all completed the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Baseline demographic and clinical characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eThe dose-response sequence obtained using the modified Dixon\u0026rsquo;s up-and-down method is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The median effective dose (ED\u003csub\u003e50\u003c/sub\u003e) of esketamine in combination with 1.5 mg/kg propofol for successful gastroscope insertion, as derived from the Dixon method, was 0.172 mg/kg. Probit regression analysis further estimated an ED\u003csub\u003e50\u003c/sub\u003e of 0.159 mg/kg (95% CI: 0.144\u0026ndash;0.176) and an ED\u003csub\u003e95\u003c/sub\u003e of 0.195 mg/kg (95% CI: 0.178\u0026ndash;0.273), with the dose-probability relationship depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eHemodynamic and procedural outcomes are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Changes in MAP and HR at different time points during the study were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea and b. Although statistically significant variations in HR were observed, these fluctuations were not considered clinically relevant. One patient experienced transient hypoxemia, with SpO\u003csub\u003e2\u003c/sub\u003e declining to 89% during the procedure; this was promptly resolved with chin lift, jaw-thrust maneuver, and supplemental oxygen. No episodes of hypotension, bradycardia, delayed recovery, or other adverse events\u0026mdash;such as arrhythmia, nausea, vomiting, nightmares, or hallucinations\u0026mdash;were recorded.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrated that a sub-anesthetic dose of esketamine combined with propofol provides effective and satisfactory conditions for gastroscope insertion in adults, with a low incidence of adverse events. Using the modified Dixon\u0026rsquo;s up-and-down method, we determined that the median effective dose (ED\u003csub\u003e50\u003c/sub\u003e) of esketamine for successful gastroscope insertion in 50% of adults, when co-administered with a fixed dose of 1.5 mg/kg propofol, was 0.172 mg/kg. Probit regression analysis yielded a corroborative ED\u003csub\u003e50\u003c/sub\u003e of 0.159 mg/kg (95% CI: 0.144\u0026ndash;0.176) and an ED\u003csub\u003e95\u003c/sub\u003e of 0.195 mg/kg (95% CI: 0.178\u0026ndash;0.273).\u003c/p\u003e\u003cp\u003eTo our knowledge, this is the first study to determine the ED\u003csub\u003e50\u003c/sub\u003e of esketamine for gastroscope insertion when combined with propofol in adults. Propofol remains the most widely used intravenous anesthetic for painless gastroscopy, owing to its rapid onset and short recovery profile [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, when used alone, it lacks analgesic efficacy and often necessitates higher doses, which can induce adverse effects including respiratory depression, oxygen desaturation, hypotension, and bradycardia [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Consequently, adjuvant agents are commonly co-administered with propofol to enhance analgesia and reduce its dosage [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWhile the combination of propofol and opioids is frequently employed, it can exacerbate respiratory and circulatory depression[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In contrast, esketamine, an NMDA receptor antagonist with analgesic and sympathomimetic properties, not only provides analgesia but also helps mitigate the cardiorespiratory depression associated with propofol[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This pharmacodynamic profile makes the propofol-esketamine combination a promising regimen for maintaining hemodynamic and respiratory stability during procedural sedation. Nonetheless, high doses of esketamine carry a risk of neuropsychiatric side effects, underscoring the importance of identifying its minimum effective dose.\u003c/p\u003e\u003cp\u003eOur findings are consistent with previous reports supporting the safety and efficacy of low-dose esketamine. For instance, Su et al. reported the successful use of sub-anesthetic esketamine in pediatric gastroscopy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], while others have confirmed its safety profile in adults undergoing painless gastroenteroscopy [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Notably, Feng et al. observed an increased incidence of visual disturbances and delayed recovery with 0.5 mg/kg esketamine [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In our study, however, no such adverse effects were observed within the esketamine dose range of 0.116\u0026ndash;0.2 mg/kg, suggesting that lower doses may preserve efficacy while minimizing side effects.\u003c/p\u003e\u003cp\u003eSeveral comparative studies support this advantage. Multiple clinical trials have directly compared sedation protocols and found that the combination of esketamine and propofol offers a more stable hemodynamic profile and reduces propofol consumption compared to propofol alone or propofol-opioid combinations, with a comparable or improved safety margin [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The typical dose ranges identified in these studies (propofol 1\u0026ndash;3 mg/kg; esketamine 0.15\u0026ndash;0.5 mg/kg) encompass the lower doses we employed. Our results refine this range by identifying the minimum effective dose, thereby helping to minimize the risk of dose-dependent side effects while maintaining efficacy.\u003c/p\u003e\u003cp\u003eThe favorable safety profile observed in our study\u0026mdash;with only one transient hypoxemia event that was promptly managed\u0026mdash;may be attributed to two key factors: the use of a moderate propofol induction dose (1.5 mg/kg) based on pre-experimental titration, and the sympathetic-activating effect of low-dose esketamine, which helps maintain hemodynamic and respiratory stability [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral limitations of this study should be acknowledged. First, as a single-center sequential study with a small sample size, the generalizability of our findings may be limited. Second, the ED\u003csub\u003e95\u003c/sub\u003e estimated by probit regression should be interpreted with caution, as the sequential design does not fully account for potential side effects at higher doses; validation in larger randomized trials is warranted. Third, due to the use of low, sub-anesthetic esketamine doses and careful propofol titration, this study was not powered to detect rare or dose-dependent adverse events. Finally, our inclusion criteria were restricted to ASA I\u0026ndash;II patients aged 18\u0026ndash;65 years with a BMI of 18\u0026ndash;30 kg/m\u0026sup2;; thus, the results may not be generalizable to obese, elderly, or higher-risk populations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn adult patients undergoing painless gastroscopy, the median effective dose of esketamine combined with 1.5 mg/kg propofol is 0.172 mg/kg, as determined by the Dixon\u0026rsquo;s up-and-down method. This low-dose combination provides effective sedation with a favorable safety profile and minimal adverse effects.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\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\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBody Mass Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eConfidence Interval\u003c/p\u003e\u003c/div\u003e\u003c/div\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\"\u003eED\u003csub\u003e95\u003c/sub\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e95% Effective Dose\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\"\u003eMAP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMean Arterial Pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMOAA/S\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eModified Observer's Assessment of Alertness/Sedation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNMDA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eN-methyl-D-aspartate\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\"\u003eSPO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOxygen saturation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Ethics Committee of Beijing Friendship Hospital, China (Approval No: 2023-P2-081-01) and was prospectively registered at the Chinese Clinical Trial Registry (No. ChiCTR2300070635). Written informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of their clinical data was obtained from all participants in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data of this study are available from the corresponding author by reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Beijing Health Science and Technology Achievement and Appropriate Technology Promotion Project (NO. BHTPP2022081).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHXW contributed to the study design, data collection, data analysis, and was a major contributor in writing the manuscript. HRQ performed the data analysis and interpretation. FKL and HWL contributed to data curation and investigation. KS conceptualized the study, supervised the project, and critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors sincerely thank the staff of the Digestive Endoscopy Center at Beijing Friendship Hospital for their strong support of this study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi DN, Zhao GQ, Su ZB. Propofol Target-controlled Infusion in Anesthesia Induction during Painless Gastroscopy. J Coll Physicians Surg Pak. 2019;29(7):604\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRiphaus A, Geist C, Schrader K, Martchenko K, Wehrmann T. Intermittent manually controlled versus continuous infusion of propofol for deep sedation during interventional endoscopy: a prospective randomized trial. Scand J Gastroenterol. 2012;47(8\u0026ndash;9):1078\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim MG, Park SW, Kim JH, Lee J, Kae SH, Jang HJ, Koh DH, Choi MH. Etomidate versus propofol sedation for complex upper endoscopic procedures: a prospective double-blinded randomized controlled trial. Gastrointest Endosc. 2017;86(3):452\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSneyd JR. Making sense of propofol sedation for endoscopy. Br J Anaesth. 2017;118(1):6\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEberl S, Koers L, van Hooft J, de Jong E, Hermanides J, Hollmann MW, Preckel B. The effectiveness of a low-dose esketamine versus an alfentanil adjunct to propofol sedation during endoscopic retrograde cholangiopancreatography: A randomised controlled multicentre trial. Eur J Anaesthesiol. 2020;37(5):394\u0026ndash;401.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhan Y, Liang S, Yang Z, Luo Q, Li S, Li J, Liang Z, Li Y. Efficacy and safety of subanesthetic doses of esketamine combined with propofol in painless gastrointestinal endoscopy: a prospective, double-blind, randomized controlled trial. BMC Gastroenterol. 2022;22(1):391.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSong N, Peng K. Esketamine as an adjuvant to propofol sedation for gastrointestinal endoscopy. Anesthesiology Perioperative Sci. 2024;2(3):29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSong N, Yang Y, Zheng Z, Shi WC, Tan AP, Shan XS, Liu H, Meng L, Peng K, Ji FH. Effect of Esketamine Added to Propofol Sedation on Desaturation and Hypotension in Bidirectional Endoscopy: A Randomized Clinical Trial. JAMA Netw Open. 2023;6(12):e2347886.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990;10(4):244\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDixon WJ. Staircase bioassay: the up-and-down method. Neurosci Biobehav Rev. 1991;15(1):47\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTang L, Ye C, Wang N, Chen C, Chen S, Gao S, Liu X. The median effective doses of propofol combined with two different doses of nalbuphine for adult patients during painless gastroscopy. Front Pharmacol. 2022;13:1014486.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEberl S, Koers L, van Hooft JE, de Jong E, Schneider T, Hollmann MW, Preckel B. Sedation with propofol during ERCP: is the combination with esketamine more effective and safer than with alfentanil? Study protocol for a randomized controlled trial. Trials. 2017;18(1):472.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang C, Gao Y, Li J, Zhang L, Li Q, Li Y, Lu Y, Sun J, Zhang Y, Cheng Y, et al. Safety and effectiveness of the combination of remimazolam tosilate and propofol in gastroscopy: a multicenter, randomized controlled, single-blind clinical trial. Front Pharmacol. 2023;14:1124667.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZheng Y, Xu Y, Huang B, Mai Y, Zhang Y, Zhang Z. Effective dose of propofol combined with a low-dose esketamine for gastroscopy in elderly patients: A dose finding study using dixon's up-and-down method. Front Pharmacol. 2022;13:956392.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJansen SC, Dahan A. Opioid-induced respiratory depression. BJA Educ. 2024;24(3):100\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSu M, Zhu Y, Liu S, Song L, Qu J, Zhang Y, Zhang Q. Median effective dose (ED(50)) of esketamine combined with propofol for children to inhibit response of gastroscope insertion. BMC Anesthesiol. 2023;23(1):240.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDeng J, Yu YF, Tang ZG, Lei HJ, Tan CC. Efficacy and safety of low-dose esketamine for painless gastrointestinal endoscopy in adults: a systematic evaluation and meta-analysis. Front Pharmacol. 2024;15:1364546.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang J, Huang J, Yang S, Cui C, Ye L, Wang SY, Yang GP, Pei Q. Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. Drug Des Devel Ther. 2019;13:4135\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeng M, Shi G, Cui W, Zhang N, Xie Q, Zhang W. The median effective concentration of propofol in combination with different doses of esketamine during gastrointestinal endoscopy in adults. Front Pharmacol. 2022;13:1034236.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChu T, Zhou S, Wan Y, Liu Q, Xin Y, Tian Z, Yan T, Xu A. Comparison of remimazolam and propofol combined with low dose esketamine for pediatric same-day painless bidirectional endoscopy: a randomized, controlled clinical trial. Front Pharmacol. 2024;15:1298409.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang LL, Guan ZY, Wang CM, Zhang YW, Zhang J, Zhao P. A comparative study on the efficacy and safety of propofol combined with different doses of alfentanil in gastroscopy: a randomized controlled trial. J Anesth. 2023;37(2):201\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang X, Ai P, Wei C, Sun Y, Wu A. Comparison of the Effects of Esketamine/Propofol and Sufentanil/Propofol on the Incidence of Intraoperative Hypoxemia during Bronchoscopy: Protocol for a Randomized, Prospective, Parallel-Group Trial. J Clin Med 2022, 11(15).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Esketamine, Gastroscopy, Propofol, Median effective dose","lastPublishedDoi":"10.21203/rs.3.rs-8171992/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8171992/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003ePropofol sedation is widely used for endoscopic procedures, but its administration alone poses risks of hemodynamic and respiratory depression. Esketamine, as an adjuvant, could reduce propofol requirements and associated adverse events. The median effective dose (ED\u003csub\u003e50\u003c/sub\u003e) of esketamine combined with propofol in adults undergoing painless gastroscopy remains undetermined. Therefore, we designed a study to determine the ED\u003csub\u003e50\u003c/sub\u003e of esketamine combined with propofol using Dixon and Massey\u0026rsquo;s up-and-down sequential method to prevent somatic responses to endoscope insertion.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eAdult patients scheduled for elective painless gastroscopy who met the inclusion and exclusion criteria were enrolled. Following intravenous administration of esketamine, each participant received an initial propofol dose of 1.5 mg/kg. Esketamine dosing commenced at 0.2 mg/kg and was adjusted using a modified Dixon\u0026rsquo;s up-and-down method with a dose ratio of 1:1.2 (i.e., 20% increments/decrements) based on the preceding patient\u0026rsquo;s response to gastroscope insertion. Patient responses were categorized as: Failure: MOAA/S score\u0026thinsp;\u0026gt;\u0026thinsp;1, swallowing, coughing, or purposeful movement. Success: Absence of the above reactions. If anesthesia induction failed, the esketamine dose was increased for the subsequent patient; if successful, the dose was decreased. The study continued until eight crossover points (failure-to-success transitions) were observed. The ED\u003csub\u003e50\u003c/sub\u003e of esketamine was calculated as the mean of the crossover point doses. And in all patients, blood pressure, pulse oxygen saturation, heart rate, recovery time, and side effects were recorded.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eA total of 29 adults undergoing elective painless gastroscopy were included. The ED\u003csub\u003e50\u003c/sub\u003e of esketamine co-administered with 1.5 mg/kg propofol, determined via Dixon\u0026rsquo;s up-and-down method, was 0.172 mg/kg. Probit analysis estimated an ED\u003csub\u003e50\u003c/sub\u003e of 0.159 mg/kg (95% CI: 0.144\u0026ndash;0.176) and ED\u003csub\u003e95\u003c/sub\u003e of 0.195 mg/kg (95% CI: 0.178\u0026ndash;0.273). Time from induction to scope insertion was 31.6\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1 s, and total propofol dose was 114.01\u0026thinsp;\u0026plusmn;\u0026thinsp;22.14 mg. Gastroscopy duration averaged 6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 min, with PACU stay time of 16.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7 min. Adverse events included transient sinus tachycardia (n\u0026thinsp;=\u0026thinsp;1) and mild hypoxemia (SpO2% \u0026lt;90%; n\u0026thinsp;=\u0026thinsp;1), with no serious adverse events.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e\u003cp\u003eThe ED\u003csub\u003e50\u003c/sub\u003e of esketamine combined with 1.5 mg/kg propofol for painless gastroscopy was 0.172 mg/kg, as determined by Dixon's up-and-down sequential method.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e\u003cp\u003eThis study was registered on 19 April 2023 at Chinese Clinical Trial Registry (http//www.chictr.org.cn registration NO. ChiCTR2300070635).\u003c/p\u003e","manuscriptTitle":"Optimizing the Subanesthetic Dose of Esketamine Combined with Propofol for Painless Gastroscopy in Adults: A Prospective Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-12 08:36:13","doi":"10.21203/rs.3.rs-8171992/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":"0e82783e-e582-4530-a911-dc4a9a634e1f","owner":[],"postedDate":"December 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T07:56:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-12 08:36:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8171992","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8171992","identity":"rs-8171992","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}