Effect of Subanesthetic Dose of Esketamine Infusion on Postoperative Sleep Disturbance in Elderly Undergoing Laparoscopic Gastrointestinal Surgery：protocol for a randomized controlled trial（RCT）

Effect of Subanesthetic Dose of Esketamine Infusion on Postoperative Sleep Disturbance in Elderly Undergoing Laparoscopic Gastrointestinal Surgery：protocol for a randomized controlled trial（RCT） | 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 Study protocol Effect of Subanesthetic Dose of Esketamine Infusion on Postoperative Sleep Disturbance in Elderly Undergoing Laparoscopic Gastrointestinal Surgery：protocol for a randomized controlled trial（RCT） Rongrong Li, Hao Yin, Xingying He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6064246/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 Objective Postoperative sleep disturbance (PSD) is a common problem in elderly patients, affecting postoperative recovery and potentially increasing the risk of complications. Esketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has the potential to improve postoperative sleep. The aim of this randomized controlled trial is to evaluate the impact of intraoperative infusion of sub-anesthetic doses of esketamine on PSD in elderly patients undergoing laparoscopic gastrointestinal tumor resection. Methods This study is a randomized, single-center, double-blind, placebo-controlled trial. We plan to recruit 90 elderly patients (aged 65-80 years) who are scheduled for elective laparoscopic gastrointestinal tumor resection. The patients will be randomly assigned to two groups in a 1:1 ratio using a random number table. Patients in the esketamine group (group K) will receive a continuous intraoperative infusion of esketamine (0.1mg/kg·h), while patients in the control group (group C) will receive an equal volume of normal saline. The primary outcome is the incidence of PSD assessed by the Numerical Rating Scale (NRS) and the Athens Insomnia Scale (AIS). The secondary outcomes are the emotional status evaluated by the Hospital Anxiety and Depression Scale (HADS), postoperative pain intensity evaluated by the Visual Analogue Scale (VAS), the incidence of postoperative adverse reactions, and the plasma concentration of relevant inflammatory markers. Ethics and Dissemination The study has been approved by the Ethics Committee of the Second Affiliated Hospital of the Naval Medical University (Approvall Number: 2024SL073, 15 December 2024). Patients need to provide written consent before taking part in the study. The findings will be published with open access. This study was conducted in accordance with the Declaration of Helsinki. Trial registration： The study protocol has been registered in the Chinese Clinical Trial Registry (ChiCTR2400087222) on July 23, 2024. Sleep disturbance Esketamine Elderly Gastrointestinal surgery Figures Figure 1 INTRODUCTION Current studies have indicated that the incidence of postoperative sleep disturbance (PSD) is approximately 15–72% [ 1 ] . PSD is mainly due to postoperative sleep pattern disturbance, often manifesting as sleep deprivation, circadian rhythm disturbance, or structural abnormalities [ 2 ] . The occurrence of PSD can affect the patient's postoperative recovery, exacerbate postoperative pain, and may lead to postoperative delirium in severe cases [ 3 – 5 ] . The sleep architecture changes with the aging process, making the elderly typically a high-risk group for PSD [ 6 ] . Once PSD occurs, it can be relieved by taking medicine or some other methods. Ketamine, as an NMDA receptor antagonist, binds to the NMDA receptor, reducing the frequency and duration of Ca 2+ channel opening, effectively inhibiting dopaminergic signal transmission [ 7 ] . In 2019, the FDA approved the use of ketamine for the treatment of patients with depression who have not responded to multiple antidepressant medications [ 8 ] . Esketamine, as the enantiomer of ketamine, not only has superior analgesic effects compared to ketamine but also shows great potential in the treatment of treatment-resistant depression [ 9 , 10 ] . In recent years, the application of esketamine has been continuously expanding, especially in clinical procedures such as gastrointestinal endoscopy, endoscopic retrograde cholangiopancreatography, and abortion surgery, [ 11 , 12 ] where its use has attracted widespread attention from anesthesiologists. As an adjunct to general anesthesia, intravenous administration of esketamine not only reduces patients' dependence on opioid drugs but also effectively promotes postoperative recovery and reduces the incidence of adverse reactions [ 10 ] . The latest research has also found that sub-anesthetic doses of esketamine has a significant effect on maintaining hemodynamic stability during anesthesia induction, alleviating postoperative pain in elderly patients, and reducing the occurrence of early postoperative cognitive dysfunction [ 13 ] . However, there is currently a lack of sufficient data on the impact of sub-anesthetic doses of esketamine on PSD in elderly patients. Thus, we designed this randomized, double-blind, placebo-controlled clinical trial, aiming to explore the impact of continuous infusion of sub-anesthetic doses of esketamine on PSD in elderly patients undergoing laparoscopic gastrointestinal tumor resection, trying to provide new insights into the application of esketamine in this specific field. METHODS Trial design This is a single-center, double-blind, placebo-controlled, randomized trial. Study settings and ethical considerations The study has been approved by the Academic Committee (2024-077-01) and Ethics Committee (2024SL073) of the Second Affiliated Hospital of the Naval Medical University, and will be conducted in the Department of Anesthesiology at the Second Affiliated Hospital of the Naval Medical University. The study protocol has been registered in the Chinese Clinical Trial Registry (ChiCTR2400087222). Participants We plan to recruit 90 patients (aged between 65 and 80 years), who are scheduled for elective laparoscopic gastrointestinal tumor resection surgery, with no gender restrictions. The screening and assessment will be performed one day before the scheduled surgery. Those who meet the inclusion criteria and have signed the informed consent form will proceed to the next step of the study. Additional inclusion criteria include: 1.ASA classification I-III, 2.BMI: 18-30 kg/m². However, patients with any of the following conditions will be excluded: 1.Long-term use of analgesics or psychotropic medications, or contraindications to opioids or esketamine, 2.Severe renal or hepatic dysfunction, 3.History of delayed awakening after general anesthesia, 4.Preoperative Pittsburgh Sleep Quality Index (PSQI) score above 7, 5.History of schizophrenia or neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease), 6.Preoperative delirium or communication disturbance. If a patient has been included in the study but experiences any of the following, they will be withdrawn from the study protocol: 1.Inability to extubate postoperatively, requiring further treatment in the ICU, 2.Occurrence of severe subcutaneous emphysema, 3.Intraoperative bleeding of more than 1000ml or severe hemodynamic fluctuations and other serious adverse events, 4.Reoperation or discharge within 48 hours after surgery, 5.Violation of the study protocol after being included in the study. Randomization and Blinding This study is a randomized controlled trial. Prior to the operation, an independent statistician generated a computerized random sequence, and the allocation results were printed and placed in sealed envelopes. Patients were randomly divided into two groups in a 1:1 ratio. The esketamine group (Group K) received a continuous intraoperative infusion of esketamine at a dosage of 0.1mg/kg·h, while the control group (Group N) received an equal volume of normal saline. Neither the patients nor the principal investigators were aware of the specific group assignments, and the allocation results would be revealed after the final statistical analysis. Anesthesia and intervention programs General anesthesia was induced in both groups using i.v. dexamethasone 0.1mg/kg, sufentanil 0.3μg/kg and ciprofol 0.3mg/kg. Tracheal intubation was facilitated by i.v. cisatracurium 0.15mg/kg. Anesthesia was maintained using 1%-1.5% sevoflurane (a MAC value of 0.7) in 60% oxygen (2L/min) inhalation, and continuous infusion of remifentanil at 0.1-0.2μg/(kg·min) to keep heart rate and arterial blood pressure fluctuations within ±20% of baseline levels. Intermittent boluses of cisatracurium 0.15mg/kg were administered to maintain appropriate muscle relaxation according to the surgical situation. Group K received 0.1mg/(kg·h) esketamine in the course of surgery, while Group N receives an equal volume of normal saline. At the end of surgery, 12.5mg dolasetron was administered intravenously to prevent postoperative nausea and vomiting. The analgesic pump formula consisted of sufentanil 2μg/kg + dolasetron 12.5mg diluted in normal saline, with a total volume of 100mL for both groups. The analgesic pump was set with parameters for a 48-hour continuous infusion, i.e.,a background infusion rate of 2mL/h, a single press dose of 2mL, a PCA dose of 1.5mL, and a lockout time of 15 minutes. If the pain score is greater than 4, intravenous flurbiprofen axetil 50mg were administered intravenously as rescue analgesia. Outcome Primary outcome The primary outcome is the incidence of PSD until postoperative 7th days. To comprehensively assess sleep quality and accurately detect PSD, we have chosen three well-validated scales: the Pittsburgh Sleep Quality Index (PSQI) [14] , the Athens Insomnia Scale (AIS) [15] , and the Numeric Rating Scale (NRS) [16] . 1.PSQI: The PSQI is a widely used scale for evaluating overall sleep quality over the past month. It consists of seven components that cover various aspects of sleep, such as sleep latency, sleep duration, sleep efficiency, and daytime dysfunction. Using the PSQI, we can comprehensively assess patients' preoperative sleep quality (PSQ) one day before surgery, primarily for preoperative screening. Patients with a PSQI score greater than 7 will be excluded from the study to ensure a more homogeneous baseline for the primary outcome assessment. 2.AIS: The AIS is specifically designed to assess insomnia symptoms and their impact on daily functioning. It consists of eight items: night awakenings, sleep onset, final awakening, total sleep time, sleep quality, mood, functional capacity, and daytime sleepiness, with a scoring range of 0 to 24 points. A total score of ≥6 points clearly indicates the occurrence of postoperative insomnia. 3.NRS: The NRS is a single-dimensional tool for assessing patients' immediate subjective perception of sleep quality. Its scoring range is from 0 to 10, with 10 representing the inability to sleep all night. The NRS is suitable for short-term dynamic tracking of changes in patients' sleep experiences after surgery, especially the impact of short-term interfering factors such as pain and anxiety on sleep. By using multiple tools, such as comparing the “total sleep time” item in the AIS with the “sleep duration” component in the PSQI, we expect to reduce potential biases from a single scale and to enhance the credibility of the results. Additionally, the high-frequency data from the NRS can identify the fluctuation patterns of PSD (a peak on the second day after surgery). Meanwhile, the structured items of the AIS and PSQI can be used to further analyze related risk factors (e.g., the correlation between the number of night awakenings and pain scores). This multi-layered analysis approach allows for a more comprehensive understanding of the characteristics of PSD and their potential influencing factors. Secondary outcomes Emotional State The Hospital Anxiety and Depression Scale (HADS) [17] will be used to assess the patients' anxiety and depression on the first day before surgery and on the first and third days postoperatively. The HADS consists of 14 questions, with 7 items for anxiety and 7 for depression, each item scored from 0 to 3 points. The scores are summed to yield separate scores for anxiety (HADS-A) and depression (HADS-D), with a total score of 8 or higher indicating a diagnosis of depression or anxiety. Pain Assessment The Visual Analogue Scale (VAS) [18] will be used to evaluate the pain scores at rest and during activity 24 and 48 hours postoperatively. The VAS is a widely used pain assessment tool, which is a straight line that is 10 centimeters long, with "0" marked at one end and "10" at the other. "0" signifies "no pain," and "10" signifies "the most intense pain." Patients are guided to mark on the scale based on their own perception of the current pain intensity, with marks closer to "10" indicating a stronger sensation of pain. Plasma inflammatory markers Before the surgery and one day postoperatively, the plasma concentrations of S100β, IL-6, IL-10, and melatonin will be detected. Other Indicators The intraoperative consumption of sufentanil and remifentanil, the number of effective pressing times of the analgesic pump within 24 and 48 hours postoperatively, the amount of medication used in the analgesic pump, the situation of rescue analgesia, and postoperative complications, including nausea and vomiting, dizziness, somnolence, diplopia, hallucinations, daydreams and nightmares were recorded. Sample Size and trial status Previous studies have shown that the incidence rate of PSD exceeds 60% [1] . Qiu [8] and others conducted a clinical trial that demonstrated the use of esketamine during surgery could reduce the incidence of PSD by nearly more than half. Then a preliminary trial was conducted from April to May 2024. Twelve elective patients undergoing laparoscopic gastrointestinal tumor resection were recruited, of which 6 cases received continuous infusion of sub-anesthetic dose of esketamine and 6 cases received an equal volume of normal saline. On the postoperative first day follow-up, 2 patients in the group K suffered from PSD (incidence rate of 33.3%), and 4 patients in the group C suffered from PSD (incidence rate of 66.7%). To achieve a statistical power of 80% and a significance level of 0.05，64 patients were required in this trial with 32 in each group (PASS 11.0.7; NCSS, LCC, Kaysville, UT, USA). To account for possible dropouts, we set the sample size to 78 patients (39 in each group). It is currently in the patient recruitment phase, with the expectation of completing the trial by the end of 2025. Statistical Analysis : In this study, we utilized SPSS 25.0 software for all statistical analyses. The normality of variables was assessed using the Kolmogorov-Smirnov test. For continuous data, if the data were normally distributed, they were presented as mean (standard deviation) and compared using the independent samples t-test. If the data did not conform to a normal distribution, they were presented as median (interquartile range) and analyzed using the Mann-Whitney U test. Categorical data were presented as numbers (percentages) and compared using the chi-square test or Fisher's exact test, depending on the situation. For the primary outcome analysis, the differences between the two groups were compared using the independent samples t-test or Mann-Whitney U test. The assessment of postoperative sleep quality (NRS and AIS scores) was analyzed using repeated measures analysis of variance (ANOVA) or mixed-effects models to examine changes in scores at different postoperative time points. For the secondary outcome analysis, changes of emotional state (HADS scores) and postoperative pain intensity (VAS scores) were analyzed using repeated measures ANOVA or mixed-effects models. The plasma concentrations of inflammatory markers (S100β, IL-6 and IL-10) were compared between the two groups using the independent samples t-test or Mann-Whitney U test. The incidence of postoperative complications was compared between the two groups using the chi-square test or Fisher's exact test. Finally, for risk factor analysis, potential risk factors were assessed using a logistic regression model, with a significance level set at P<0.05. DISCUSSION Significance of the study PSD is a common postoperative complication that might affect the postoperative recovery and prolong hospital stays [19, 20] . Therefore, it is necessary to introduce effective perioperative management measures to prevent PSD. Previous clinical studies have shown that intravenous injection of esketamine can improve the PSQ of patients undergoing gynecological laparoscopy and scoliosis correction surgery [8] . However, there are currently few clinical studies about the impact of sub-anesthetic esketamine on PSD for the elderly. In this trial, we will adopt the PSQI, AIS, and NRS to assess sleep quality. Preoperatively, the PSQI will be used to screen for existing sleep issues. Postoperatively, the NRS and AIS will be combined to evaluate sleep quality from the first to the seventh day. Given that patients' physical strength and attention may be limited postoperatively, the simplicity of the NRS (a single-item rating) makes it ideal for quick daily completion. The phased use of the AIS and PSQI ensures data depth while minimizing patient burden. If the incidence of PSD significantly increases, the NRS might identify the timing for intervention, while the AIS could guide targeted interventions. The primary outcome is the incidence of PSD as defined by the AIS. By integrating the dynamic monitoring of the NRS and the multidimensional analysis of the PSQI, this study might relatively balance scientific rigor, sensitivity, and practicality, providing a comprehensive understanding of the epidemiological characteristics and potential mechanisms of PSD. At the same time, the HADS are used to evaluate the emotional state of the patients, trying to explore whether PSD is accompanied with anxiety or depression [17] . In addition, plasma concentration of S100β and melatonin are detected. S100β is a protein mainly found in glial cells (such as astrocytes), which can serve as a biomarker for neurological damage and neurodegenerative diseases [21, 22] . Although it is not a hormone that directly participates in sleep regulation, its role in neurological damage and inflammation might indirectly affect sleep [22] . Melatonin is a hormone secreted by the pineal gland, mainly responsible for regulating the sleep-wake cycle and circadian rhythm [23] . In summary, we aim to not only assess postoperative sleep quality but also evaluate emotional status, postoperative pain, and inflammatory responses comprehensively. This multidimensional assessment might shed new light on the role of esketamine for the elderly recovery. Potential Limitations Although the sample size calculation is based on data from the preliminary study, the actual sample size may not be sufficient to adequately assess the statistical significance of secondary outcome measures. In addition, this study is limited to elderly patients undergoing laparoscopic gastrointestinal tumor resection, which might restrict the generalizability of the results. Future studies should consider increasing the sample size and including a broader range of hoptitals to validate the effects of esketamine. Future Research Directions Future research will be designed for the exploration of esketamine in different types of surgeries and various ages. Additionally, long-term follow-up studies should be conducted to assess the possible long-term impact of esketamine on PSD. These will help to provide more comprehensive guidance for clinical practice. Declarations Conflict of Interest All authors declare no conflicts of interest. Funding This study is funded by the Shanghai Municipal Healthcare Commission Clinical Research Grant (202440226). Authors' Contributions Rong-rong Li and Hao Yin: Study design, data collection and manuscript writing. Xing-ying He: Study design, statistical analysis and manuscript revision. References Gögenur I, Wildschiøtz G, Rosenberg J. Circadian distribution of sleep phases after major abdominal surgery[J]. Br J Anaesth, 2008,100(1):45-49. Su X, Wang D X. Improve postoperative sleep: what can we do?[J]. Curr Opin Anaesthesiol, 2018,31(1):83-88. Fernandes N M, Nield L E, Popel N, et al. Symptoms of disturbed sleep predict major adverse cardiac events after percutaneous coronary intervention[J]. Can J Cardiol, 2014,30(1):118-124. Leung J M, Sands L P, Newman S, et al. Preoperative Sleep Disruption and Postoperative Delirium[J]. J Clin Sleep Med, 2015,11(8):907-913. Todd O M, Gelrich L, MacLullich A M, et al. Sleep Disruption at Home As an Independent Risk Factor for Postoperative Delirium[J]. J Am Geriatr Soc, 2017,65(5):949-957. Todd O M, Gelrich L, MacLullich A M, et al. Sleep Disruption at Home As an Independent Risk Factor for Postoperative Delirium[J]. J Am Geriatr Soc, 2017,65(5):949-957. Rueda C L, Garcia K A, Yalcin N, et al. Ketamine and Its Emergence in the Field of Neurology[J]. Cureus, 2022,14(7):e27389. Qiu D, Wang X M, Yang J J, et al. Effect of Intraoperative Esketamine Infusion on Postoperative Sleep Disturbance After Gynecological Laparoscopy: A Randomized Clinical Trial[J]. JAMA Netw Open, 2022,5(12):e2244514. Kohtala S, Alitalo O, Rosenholm M, et al. Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine[J]. Pharmacol Ther, 2021,221:107741. Wang X, Lin C, Lan L, et al. Perioperative intravenous S-ketamine for acute postoperative pain in adults: A systematic review and meta-analysis[J]. J Clin Anesth, 2021,68:110071. Wang J, Huang J, Yang S, et al. Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study[J]. Drug Des Devel Ther, 2019,13:4135-4144. Yang H, Zhao Q, Chen H Y, et al. The median effective concentration of propofol with different doses of esketamine during gastrointestinal endoscopy in elderly patients: A randomized controlled trial[J]. Br J Clin Pharmacol, 2022,88(3):1279-1287. Li J, Wang Z, Wang A, et al. Clinical effects of low-dose esketamine for anaesthesia induction in the elderly: A randomized controlled trial[J]. J Clin Pharm Ther, 2022,47(6):759-766. Mollayeva T, Thurairajah P, Burton K, et al. The Pittsburgh sleep quality index as a screening tool for sleep dysfunction in clinical and non-clinical samples: A systematic review and meta-analysis[J]. Sleep Med Rev, 2016,25:52-73. Song B, Li Y, Teng X, et al. Comparison of Morning and Evening Operation Under General Anesthesia on Intraoperative Anesthetic Requirement, Postoperative Sleep Quality, and Pain: A Randomized Controlled Trial[J]. Nat Sci Sleep, 2020,12:467-475. Cai J, Chen Y, Hao X, et al. Effect of Intraoperative Dexmedetomidine Dose on Postoperative First Night Sleep Quality in Elderly Surgery Patients: A Retrospective Study With Propensity Score-Matched Analysis[J]. Front Med (Lausanne), 2020,7:528. Yang R, Xu X X, Liu H, et al. The Impact of Morning Surgery or Afternoon Surgery on Postoperative Sleep Quality and Melatonin Levels of Elderly Patients: A Prospective, Randomized Study[J]. Nat Sci Sleep, 2022,14:1677-1686. Hwang W Y, Kim K, Cho H Y, et al. The voiding VAS score is a simple and useful method for predicting POUR after laparoscopy for benign gynaecologic diseases: a pilot study[J]. J Obstet Gynaecol, 2022,42(6):2469-2473. Wang X, Hua D, Tang X, et al. The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders[J]. Nat Sci Sleep, 2021,13:1395-1410. O'Gara B P, Gao L, Marcantonio E R, et al. Sleep, Pain, and Cognition: Modifiable Targets for Optimal Perioperative Brain Health[J]. Anesthesiology, 2021,135(6):1132-1152. Linstedt U, Meyer O, Kropp P, et al. Serum concentration of S-100 protein in assessment of cognitive dysfunction after general anesthesia in different types of surgery[J]. Acta Anaesthesiol Scand, 2002,46(4):384-389. Michetti F, Corvino V, Geloso M C, et al. The S100B protein in biological fluids: more than a lifelong biomarker of brain distress[J]. J Neurochem, 2012,120(5):644-659. Vasey C, McBride J, Penta K. Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin[J]. Nutrients, 2021,13(10). 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-6064246","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":421782222,"identity":"f2d3554e-c3ac-47a0-9891-2f40472a9225","order_by":0,"name":"Rongrong Li","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rongrong","middleName":"","lastName":"Li","suffix":""},{"id":421782223,"identity":"43fadd64-9231-41ff-88fb-c2caffa22606","order_by":1,"name":"Hao Yin","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Yin","suffix":""},{"id":421782224,"identity":"dd79640b-813c-4914-a6cf-15a7584bd81a","order_by":2,"name":"Xingying He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYBACAwbGB1AmYwMDQ4ENDz9/AyEtzAZIWgzSZCRnHCBaC5h72MagIQG/FnP2ZsbHFRV1idulDzd/+GBwnseA4QDjh485uLVY9hxmNjxz5nDizr7ENskZBrd5zJkbmCVnbsPjsBv5xyQb2w4kbjjD2MbMA9Ri2XCAjZkXn5b7j9kkG//VgbQ0f/5jcI7H4EACAS03mIFaGphBWhqkGQwOENZi2ZPMbNhw7LAxyGGSPQbJPJIzDjbj9Ys5+2HGhw01dbIbzrA//vCjws6en7/54IePeLRgA6A4HQWjYBSMglFAEQAAQ3dTfC2xEJUAAAAASUVORK5CYII=","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Xingying","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2025-02-19 12:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6064246/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6064246/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77681582,"identity":"3e3db6ad-af60-4b34-9107-0cf2835e34ad","added_by":"auto","created_at":"2025-03-04 08:39:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":112942,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of patient sections.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6064246/v1/ec11cb584d4f133bf912d44c.png"},{"id":83537342,"identity":"f523c949-10b6-4894-b211-0f4090fc0e05","added_by":"auto","created_at":"2025-05-28 06:54:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":622571,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6064246/v1/c958cf33-4d37-4229-af0a-0468e3a87fb0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Subanesthetic Dose of Esketamine Infusion on Postoperative Sleep Disturbance in Elderly Undergoing Laparoscopic Gastrointestinal Surgery：protocol for a randomized controlled trial（RCT）","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCurrent studies have indicated that the incidence of postoperative sleep disturbance (PSD) is approximately 15\u0026ndash;72% \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. PSD is mainly due to postoperative sleep pattern disturbance, often manifesting as sleep deprivation, circadian rhythm disturbance, or structural abnormalities\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The occurrence of PSD can affect the patient's postoperative recovery, exacerbate postoperative pain, and may lead to postoperative delirium in severe cases \u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. The sleep architecture changes with the aging process, making the elderly typically a high-risk group for PSD\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Once PSD occurs, it can be relieved by taking medicine or some other methods.\u003c/p\u003e \u003cp\u003eKetamine, as an NMDA receptor antagonist, binds to the NMDA receptor, reducing the frequency and duration of Ca\u003csup\u003e2+\u003c/sup\u003e channel opening, effectively inhibiting dopaminergic signal transmission\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. In 2019, the FDA approved the use of ketamine for the treatment of patients with depression who have not responded to multiple antidepressant medications\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Esketamine, as the enantiomer of ketamine, not only has superior analgesic effects compared to ketamine but also shows great potential in the treatment of treatment-resistant depression\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn recent years, the application of esketamine has been continuously expanding, especially in clinical procedures such as gastrointestinal endoscopy, endoscopic retrograde cholangiopancreatography, and abortion surgery,\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e where its use has attracted widespread attention from anesthesiologists. As an adjunct to general anesthesia, intravenous administration of esketamine not only reduces patients' dependence on opioid drugs but also effectively promotes postoperative recovery and reduces the incidence of adverse reactions\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe latest research has also found that sub-anesthetic doses of esketamine has a significant effect on maintaining hemodynamic stability during anesthesia induction, alleviating postoperative pain in elderly patients, and reducing the occurrence of early postoperative cognitive dysfunction\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. However, there is currently a lack of sufficient data on the impact of sub-anesthetic doses of esketamine on PSD in elderly patients.\u003c/p\u003e \u003cp\u003eThus, we designed this randomized, double-blind, placebo-controlled clinical trial, aiming to explore the impact of continuous infusion of sub-anesthetic doses of esketamine on PSD in elderly patients undergoing laparoscopic gastrointestinal tumor resection, trying to provide new insights into the application of esketamine in this specific field.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eTrial design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a single-center, double-blind, placebo-controlled, randomized trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy settings and ethical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study has been approved by the Academic\u0026nbsp;Committee (2024-077-01) and Ethics Committee (2024SL073) of the Second Affiliated Hospital of the Naval Medical University, and will be conducted in the Department of Anesthesiology at the Second Affiliated Hospital of the Naval Medical University. The study protocol has been registered in the Chinese Clinical Trial Registry (ChiCTR2400087222).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe plan to recruit 90 patients (aged between 65 and 80 years), who are scheduled for elective laparoscopic gastrointestinal tumor resection surgery, with no gender restrictions. The screening and assessment will be performed one day before the scheduled surgery. Those who meet the inclusion criteria and have signed the informed consent form will proceed to the next step of the study. Additional inclusion criteria include: 1.ASA classification I-III, 2.BMI: 18-30 kg/m\u0026sup2;. However, patients with any of the following conditions will be excluded: 1.Long-term use of analgesics or psychotropic medications, or contraindications to opioids or esketamine, 2.Severe renal or hepatic dysfunction, 3.History of delayed awakening after general anesthesia, 4.Preoperative Pittsburgh Sleep Quality Index (PSQI) score above 7, 5.History of schizophrenia or neurodegenerative diseases (such as Alzheimer\u0026apos;s disease and Parkinson\u0026apos;s disease), 6.Preoperative delirium or communication disturbance. If a patient has been included in the study but experiences any of the following, they will be withdrawn from the study protocol: 1.Inability to extubate postoperatively, requiring further treatment in the ICU, 2.Occurrence of severe subcutaneous emphysema, 3.Intraoperative bleeding of more than 1000ml or severe hemodynamic fluctuations and other serious adverse events, 4.Reoperation or discharge within 48 hours after surgery, 5.Violation of the study protocol after being included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization and Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a randomized controlled trial. Prior to the operation, an independent statistician generated a computerized random sequence, and the allocation results were printed and placed in sealed envelopes. Patients were randomly divided into two groups in a 1:1 ratio. The esketamine group (Group K) received a continuous intraoperative infusion of esketamine at a dosage of 0.1mg/kg\u0026middot;h, while the control group (Group N) received an equal volume of normal saline. Neither the patients nor the principal investigators were aware of the specific group assignments, and the allocation results would be revealed after the final statistical analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnesthesia and intervention programs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGeneral anesthesia was induced in both groups using i.v. dexamethasone 0.1mg/kg, sufentanil 0.3\u0026mu;g/kg and ciprofol 0.3mg/kg. Tracheal intubation was facilitated by i.v. cisatracurium 0.15mg/kg. Anesthesia was maintained using 1%-1.5% sevoflurane (a MAC value of 0.7) in 60% oxygen (2L/min) inhalation, and continuous infusion of remifentanil at 0.1-0.2\u0026mu;g/(kg\u0026middot;min) to keep heart rate and arterial blood pressure fluctuations within \u0026plusmn;20% of baseline levels. Intermittent boluses of cisatracurium 0.15mg/kg were administered to maintain appropriate muscle relaxation according to the surgical situation. Group K received 0.1mg/(kg\u0026middot;h) esketamine in the course of surgery, while Group N receives an equal volume of normal saline. At the end of surgery, 12.5mg dolasetron was administered intravenously to prevent postoperative nausea and vomiting.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe analgesic pump formula consisted of sufentanil 2\u0026mu;g/kg + dolasetron 12.5mg diluted in normal saline, with a total volume of 100mL for both groups. The analgesic pump was set with parameters for a 48-hour continuous infusion, i.e.,a background infusion rate of 2mL/h, a single press dose of 2mL, a PCA dose of 1.5mL, and a lockout time of 15 minutes. If the pain score is greater than 4, intravenous flurbiprofen axetil\u0026nbsp;50mg were administered intravenously as rescue analgesia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome is the incidence of PSD until postoperative 7th days. To comprehensively assess sleep quality and accurately detect PSD, we have chosen three well-validated scales: the Pittsburgh Sleep Quality Index (PSQI)\u003csup\u003e[14]\u003c/sup\u003e, the Athens Insomnia Scale (AIS)\u003csup\u003e[15]\u003c/sup\u003e, and the Numeric Rating Scale (NRS)\u003csup\u003e[16]\u003c/sup\u003e. 1.PSQI: The PSQI is a widely used scale for evaluating overall sleep quality over the past month. It consists of seven components that cover various aspects of sleep, such as sleep latency, sleep duration, sleep efficiency, and daytime dysfunction. Using the PSQI, we can comprehensively assess patients\u0026apos; preoperative sleep quality (PSQ) one day before surgery, primarily for preoperative screening. Patients with a PSQI score greater than 7 will be excluded from the study to ensure a more homogeneous baseline for the primary outcome assessment. 2.AIS: The AIS is specifically designed to assess insomnia symptoms and their impact on daily functioning. It consists of eight items: night awakenings, sleep onset, final awakening, total sleep time, sleep quality, mood, functional capacity, and daytime sleepiness, with a scoring range of 0 to 24 points. A total score of\u0026nbsp;\u0026ge;6 points clearly indicates the occurrence of postoperative insomnia. 3.NRS: The NRS is a single-dimensional tool for assessing patients\u0026apos; immediate subjective perception of sleep quality. Its scoring range is from 0 to 10, with 10 representing the inability to sleep all night. The NRS is suitable for short-term dynamic tracking of changes in patients\u0026apos; sleep experiences after surgery, especially the impact of short-term interfering factors such as pain and anxiety on sleep.\u003c/p\u003e\n\u003cp\u003eBy using multiple tools, such as comparing the \u0026ldquo;total sleep time\u0026rdquo; item in the AIS with the \u0026ldquo;sleep duration\u0026rdquo; component in the PSQI, we expect to reduce potential biases from a single scale and to enhance the credibility of the results. Additionally, the high-frequency data from the NRS can identify the fluctuation patterns of PSD (a peak on the second day after surgery). Meanwhile, the structured items of the AIS and PSQI can be used to further analyze related risk factors (e.g., the correlation between the number of night awakenings and pain scores). This multi-layered analysis approach allows for a more comprehensive understanding of the characteristics of PSD and their potential influencing factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEmotional State\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Hospital Anxiety and Depression Scale (HADS)\u003csup\u003e[17]\u003c/sup\u003e will be used to assess the patients\u0026apos; anxiety and depression on the first day before surgery and on the first and third days postoperatively. The HADS consists of 14 questions, with 7 items for anxiety and 7 for depression, each item scored from 0 to 3 points. The scores are summed to yield separate scores for anxiety (HADS-A) and depression (HADS-D), with a total score of 8 or higher indicating a diagnosis of depression or anxiety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePain Assessment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Visual Analogue Scale (VAS)\u003csup\u003e[18]\u003c/sup\u003e will be used to evaluate the pain scores at rest and during activity 24 and 48 hours postoperatively. The VAS is a widely used pain assessment tool, which is a straight line that is 10 centimeters long, with \u0026quot;0\u0026quot; marked at one end and \u0026quot;10\u0026quot; at the other. \u0026quot;0\u0026quot; signifies \u0026quot;no pain,\u0026quot; and \u0026quot;10\u0026quot; signifies \u0026quot;the most intense pain.\u0026quot; Patients are guided to mark on the scale based on their own perception of the current pain intensity, with marks closer to \u0026quot;10\u0026quot; indicating a stronger sensation of pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePlasma inflammatory markers\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore the surgery and one day postoperatively, the plasma concentrations of S100\u0026beta;, IL-6, IL-10, and melatonin will be detected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOther Indicators\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe intraoperative consumption of sufentanil and remifentanil, the number of effective pressing times of the analgesic pump within 24 and 48 hours postoperatively, the amount of medication used in the analgesic pump, the situation of rescue analgesia, and postoperative complications, including nausea and vomiting, dizziness, somnolence, diplopia, hallucinations, daydreams and nightmares were recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size and\u003c/strong\u003e \u003cstrong\u003etrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrevious studies have shown that the incidence rate of PSD exceeds 60%\u003csup\u003e[1]\u003c/sup\u003e. Qiu\u003csup\u003e[8]\u003c/sup\u003e and others conducted a clinical trial that demonstrated the use of esketamine during surgery could reduce the incidence of PSD by nearly more than half.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThen a preliminary trial was conducted from April to May 2024. Twelve elective patients undergoing laparoscopic gastrointestinal tumor resection were recruited, of which 6 cases received continuous infusion of sub-anesthetic dose of esketamine and 6 cases received an equal volume of normal saline. On the postoperative first day follow-up, 2 patients in the group K suffered from PSD (incidence rate of 33.3%), and 4 patients in the group C suffered from PSD (incidence rate of 66.7%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo achieve a statistical power of 80% and a significance level of 0.05，64 patients were required in this trial with 32 in each group (PASS 11.0.7; NCSS, LCC, Kaysville, UT, USA). To account for possible dropouts, we set the sample size to 78 patients (39 in each group).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIt is currently in the patient recruitment phase, with the expectation of completing the trial by the end of 2025.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, we utilized SPSS 25.0 software for all statistical analyses. The normality of variables was assessed using the Kolmogorov-Smirnov test. For continuous data, if the data were normally distributed, they were presented as mean (standard deviation) and compared using the independent samples t-test. If the data did not conform to a normal distribution, they were presented as median (interquartile range) and analyzed using the Mann-Whitney U test. Categorical data were presented as numbers (percentages) and compared using the chi-square test or Fisher\u0026apos;s exact test, depending on the situation.\u003c/p\u003e\n\u003cp\u003eFor the primary outcome analysis, the differences between the two groups were compared using the independent samples t-test or Mann-Whitney U test. The assessment of postoperative sleep quality (NRS and AIS scores) was analyzed using repeated measures analysis of variance (ANOVA) or mixed-effects models to examine changes in scores at different postoperative time points.\u003c/p\u003e\n\u003cp\u003eFor the secondary outcome analysis, changes of emotional state (HADS scores) and postoperative pain intensity (VAS scores) were analyzed using repeated measures ANOVA or mixed-effects models. The plasma concentrations of inflammatory markers (S100\u0026beta;, IL-6 and IL-10) were compared between the two groups using the independent samples t-test or Mann-Whitney U test. The incidence of postoperative complications was compared between the two groups using the \u003cem\u003echi-square\u003c/em\u003e test or Fisher\u0026apos;s exact test.\u003c/p\u003e\n\u003cp\u003eFinally, for risk factor analysis, potential risk factors were assessed using a logistic regression model, with a significance level set at P\u0026lt;0.05.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003e\u003cstrong\u003eSignificance of the study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePSD is a common postoperative complication that might affect the postoperative recovery and prolong hospital stays\u003csup\u003e[19, 20]\u003c/sup\u003e. Therefore, it is necessary to introduce effective perioperative management measures to prevent PSD. Previous clinical studies have shown that intravenous injection of esketamine can improve the PSQ of patients undergoing gynecological laparoscopy and scoliosis correction surgery\u003csup\u003e[8]\u003c/sup\u003e. However, there are currently few clinical studies about the impact of sub-anesthetic esketamine on PSD for the elderly.\u003c/p\u003e\n\u003cp\u003eIn this trial, we will adopt the PSQI, AIS, and NRS to assess sleep quality. Preoperatively, the PSQI will be used to screen for existing sleep issues. Postoperatively, the NRS and AIS will be combined to evaluate sleep quality from the first to the seventh day. Given that patients\u0026apos; physical strength and attention may be limited postoperatively, the simplicity of the NRS (a single-item rating) makes it ideal for quick daily completion. The phased use of the AIS and PSQI ensures data depth while minimizing patient burden. If the incidence of PSD significantly increases, the NRS might identify the timing for intervention, while the AIS could guide targeted interventions. The primary outcome is the incidence of PSD as defined by the AIS. By integrating the dynamic monitoring of the NRS and the multidimensional analysis of the PSQI, this study might relatively balance scientific rigor, sensitivity, and practicality, providing a comprehensive understanding of the epidemiological characteristics and potential mechanisms of PSD. At the same time, the HADS are used to evaluate the emotional state of the patients, trying to explore whether PSD is accompanied with anxiety or depression\u003csup\u003e[17]\u003c/sup\u003e. In addition, plasma concentration of S100\u0026beta; and melatonin are detected. S100\u0026beta; is a protein mainly found in glial cells (such as astrocytes), which can serve as a biomarker for neurological damage and neurodegenerative diseases\u003csup\u003e[21, 22]\u003c/sup\u003e. Although it is not a hormone that directly participates in sleep regulation, its role in neurological damage and inflammation might indirectly affect sleep\u003csup\u003e[22]\u003c/sup\u003e. Melatonin is a hormone secreted by the pineal gland, mainly responsible for regulating the sleep-wake cycle and circadian rhythm\u003csup\u003e[23]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn summary, we aim to not only assess postoperative sleep quality but also evaluate emotional status, postoperative pain, and inflammatory responses comprehensively. This multidimensional assessment might shed new light on the role of esketamine for the elderly recovery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePotential Limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough the sample size calculation is based on data from the preliminary study, the actual sample size may not be sufficient to adequately assess the statistical significance of secondary outcome measures. In addition, this study is limited to elderly patients undergoing laparoscopic gastrointestinal tumor resection, which might restrict the generalizability of the results. Future studies should consider increasing the sample size and including a broader range of hoptitals to validate the effects of esketamine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFuture Research Directions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFuture research will be designed for the exploration of esketamine in different types of surgeries and various ages. Additionally, long-term follow-up studies should be conducted to assess the possible long-term impact of esketamine on PSD. These will help to provide more comprehensive guidance for clinical practice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by the Shanghai Municipal Healthcare Commission Clinical Research Grant (202440226).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRong-rong Li and Hao Yin: Study design, data collection and manuscript writing.\u003c/p\u003e\n\u003cp\u003eXing-ying He: Study design, statistical analysis and manuscript revision.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eG\u0026ouml;genur I, Wildschi\u0026oslash;tz G, Rosenberg J. Circadian distribution of sleep phases after major abdominal surgery[J]. Br J Anaesth, 2008,100(1):45-49.\u003c/li\u003e\n\u003cli\u003eSu X, Wang D X. Improve postoperative sleep: what can we do?[J]. Curr Opin Anaesthesiol, 2018,31(1):83-88.\u003c/li\u003e\n\u003cli\u003eFernandes N M, Nield L E, Popel N, et al. Symptoms of disturbed sleep predict major adverse cardiac events after percutaneous coronary intervention[J]. Can J Cardiol, 2014,30(1):118-124.\u003c/li\u003e\n\u003cli\u003eLeung J M, Sands L P, Newman S, et al. Preoperative Sleep Disruption and Postoperative Delirium[J]. J Clin Sleep Med, 2015,11(8):907-913.\u003c/li\u003e\n\u003cli\u003eTodd O M, Gelrich L, MacLullich A M, et al. Sleep Disruption at Home As an Independent Risk Factor for Postoperative Delirium[J]. J Am Geriatr Soc, 2017,65(5):949-957.\u003c/li\u003e\n\u003cli\u003eTodd O M, Gelrich L, MacLullich A M, et al. Sleep Disruption at Home As an Independent Risk Factor for Postoperative Delirium[J]. J Am Geriatr Soc, 2017,65(5):949-957.\u003c/li\u003e\n\u003cli\u003eRueda C L, Garcia K A, Yalcin N, et al. Ketamine and Its Emergence in the Field of Neurology[J]. Cureus, 2022,14(7):e27389.\u003c/li\u003e\n\u003cli\u003eQiu D, Wang X M, Yang J J, et al. Effect of Intraoperative Esketamine Infusion on Postoperative Sleep Disturbance After Gynecological Laparoscopy: A Randomized Clinical Trial[J]. JAMA Netw Open, 2022,5(12):e2244514.\u003c/li\u003e\n\u003cli\u003eKohtala S, Alitalo O, Rosenholm M, et al. Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine[J]. Pharmacol Ther, 2021,221:107741.\u003c/li\u003e\n\u003cli\u003eWang X, Lin C, Lan L, et al. Perioperative intravenous S-ketamine for acute postoperative pain in adults: A systematic review and meta-analysis[J]. J Clin Anesth, 2021,68:110071.\u003c/li\u003e\n\u003cli\u003eWang J, Huang J, Yang S, et al. Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study[J]. Drug Des Devel Ther, 2019,13:4135-4144.\u003c/li\u003e\n\u003cli\u003eYang H, Zhao Q, Chen H Y, et al. The median effective concentration of propofol with different doses of esketamine during gastrointestinal endoscopy in elderly patients: A randomized controlled trial[J]. Br J Clin Pharmacol, 2022,88(3):1279-1287.\u003c/li\u003e\n\u003cli\u003eLi J, Wang Z, Wang A, et al. Clinical effects of low-dose esketamine for anaesthesia induction in the elderly: A randomized controlled trial[J]. J Clin Pharm Ther, 2022,47(6):759-766.\u003c/li\u003e\n\u003cli\u003eMollayeva T, Thurairajah P, Burton K, et al. The Pittsburgh sleep quality index as a screening tool for sleep dysfunction in clinical and non-clinical samples: A systematic review and meta-analysis[J]. Sleep Med Rev, 2016,25:52-73.\u003c/li\u003e\n\u003cli\u003eSong B, Li Y, Teng X, et al. Comparison of Morning and Evening Operation Under General Anesthesia on Intraoperative Anesthetic Requirement, Postoperative Sleep Quality, and Pain: A Randomized Controlled Trial[J]. Nat Sci Sleep, 2020,12:467-475.\u003c/li\u003e\n\u003cli\u003eCai J, Chen Y, Hao X, et al. Effect of Intraoperative Dexmedetomidine Dose on Postoperative First Night Sleep Quality in Elderly Surgery Patients: A Retrospective Study With Propensity Score-Matched Analysis[J]. Front Med (Lausanne), 2020,7:528.\u003c/li\u003e\n\u003cli\u003eYang R, Xu X X, Liu H, et al. The Impact of Morning Surgery or Afternoon Surgery on Postoperative Sleep Quality and Melatonin Levels of Elderly Patients: A Prospective, Randomized Study[J]. Nat Sci Sleep, 2022,14:1677-1686.\u003c/li\u003e\n\u003cli\u003eHwang W Y, Kim K, Cho H Y, et al. The voiding VAS score is a simple and useful method for predicting POUR after laparoscopy for benign gynaecologic diseases: a pilot study[J]. J Obstet Gynaecol, 2022,42(6):2469-2473.\u003c/li\u003e\n\u003cli\u003eWang X, Hua D, Tang X, et al. The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders[J]. Nat Sci Sleep, 2021,13:1395-1410.\u003c/li\u003e\n\u003cli\u003eO\u0026apos;Gara B P, Gao L, Marcantonio E R, et al. Sleep, Pain, and Cognition: Modifiable Targets for Optimal Perioperative Brain Health[J]. Anesthesiology, 2021,135(6):1132-1152.\u003c/li\u003e\n\u003cli\u003eLinstedt U, Meyer O, Kropp P, et al. Serum concentration of S-100 protein in assessment of cognitive dysfunction after general anesthesia in different types of surgery[J]. Acta Anaesthesiol Scand, 2002,46(4):384-389.\u003c/li\u003e\n\u003cli\u003eMichetti F, Corvino V, Geloso M C, et al. The S100B protein in biological fluids: more than a lifelong biomarker of brain distress[J]. J Neurochem, 2012,120(5):644-659.\u003c/li\u003e\n\u003cli\u003eVasey C, McBride J, Penta K. Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin[J]. Nutrients, 2021,13(10). \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":"Sleep disturbance, Esketamine, Elderly, Gastrointestinal surgery","lastPublishedDoi":"10.21203/rs.3.rs-6064246/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6064246/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePostoperative sleep disturbance (PSD) is a common problem in elderly patients, affecting postoperative recovery and potentially increasing the risk of complications. Esketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has the potential to improve postoperative sleep. The aim of this randomized controlled trial is to evaluate the impact of intraoperative infusion of sub-anesthetic doses of esketamine on PSD in elderly patients undergoing laparoscopic gastrointestinal tumor resection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a randomized, single-center, double-blind, placebo-controlled trial. We plan to recruit 90 elderly patients (aged 65-80 years) who are scheduled for elective laparoscopic gastrointestinal tumor resection. The patients will be randomly assigned to two groups in a 1:1 ratio using a random number table. Patients in the esketamine group (group K) will receive a continuous intraoperative infusion of esketamine (0.1mg/kg·h), while patients in the control group (group C) will receive an equal volume of normal saline. The primary outcome is the incidence of PSD assessed by the Numerical Rating Scale (NRS) and the Athens Insomnia Scale (AIS). The secondary outcomes are the emotional status evaluated by the Hospital Anxiety and Depression Scale (HADS), postoperative pain intensity evaluated by the Visual Analogue Scale (VAS), the incidence of postoperative adverse reactions, and the plasma concentration of relevant inflammatory markers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and Dissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study has been approved by the Ethics Committee of the Second Affiliated Hospital of the Naval Medical University (Approvall Number: 2024SL073, 15 December 2024). Patients need to provide written consent before taking part in the study. The findings will be published with open access. This study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration：\u003c/strong\u003eThe study protocol has been registered in the Chinese Clinical Trial Registry (ChiCTR2400087222) on July 23, 2024.\u003c/p\u003e","manuscriptTitle":"Effect of Subanesthetic Dose of Esketamine Infusion on Postoperative Sleep Disturbance in Elderly Undergoing Laparoscopic Gastrointestinal Surgery：protocol for a randomized controlled trial（RCT）","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-04 08:39:53","doi":"10.21203/rs.3.rs-6064246/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":"ac5fd65f-98df-4422-8f43-abb3d5631ec4","owner":[],"postedDate":"March 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-28T06:54:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-04 08:39:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6064246","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6064246","identity":"rs-6064246","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}