Ultrasound-Guided Thoracic Paravertebral Block with Levobupivacaine-Esketamine Combination for Thoracoscopic Lung Cancer Surgery

Ultrasound-Guided Thoracic Paravertebral Block with Levobupivacaine-Esketamine Combination for Thoracoscopic Lung Cancer Surgery | 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 Ultrasound-Guided Thoracic Paravertebral Block with Levobupivacaine-Esketamine Combination for Thoracoscopic Lung Cancer Surgery Yibing Jing, Xiaoqin Jiang, Bo Hu, Yong Wang, Bingxin Song, Chao Han This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6444599/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 : This retrospective cohort study evaluated the efficacy of esketamine combined with levobupivacaine in ultrasound-guided thoracic paravertebral block (TPVB) for improving opioid-sparing analgesia and enhancing recovery after thoracoscopic lung cancer surgery. Methods : Patients undergoing thoracoscopic radical resection of non-small cell lung cancer (NSCLC) between 2020–2024 were stratified into two groups: the intervention group received TPVB with 0.375% levobupivacaine plus esketamine (0.5 mg/kg), while the control group received levobupivacaine alone. Primary outcomes included cumulative sufentanil consumption and resting/movement-associated pain scores (VAS, 0–10) within 48 hours postoperatively. Secondary outcomes encompassed time to first ambulation, chest tube duration, hospital stay, and safety profiles. Results : Among 216 patients (108 per group), the intervention group demonstrated a 32% reduction in 48-hour sufentanil consumption (53.5 ± 10.2 μg vs. 78.6 ± 12.4 μg, P < 0.001) and significantly lower VAS scores at rest (1.6 ± 0.5 vs. 2.7 ± 0.6, P < 0.001) and during movement (2.4 ± 0.6 vs. 4.0 ± 0.9, P < 0.001) at 48 hours. Recovery metrics improved markedly, with shorter time to first ambulation (12.6 ± 2.8 h vs. 18.4 ± 3.2 h, P < 0.001), reduced chest tube retention (2.9 ± 0.7 vs. 4.1 ± 1.0 days, P < 0.001), and decreased hospital stay (5.1 ± 1.0 vs. 6.5 ± 1.2 days, P = 0.002). Transient hallucinations occurred more frequently in the intervention group (8.3% vs. 0%, P = 0.006), with no severe adverse events. Conclusion : Esketamine-levobupivacaine TPVB significantly reduces postoperative opioid requirements, enhances analgesia, and accelerates functional recovery in thoracoscopic lung cancer surgery. This multimodal approach aligns with ERAS protocols while advocating for opioid stewardship, though dose optimization may further improve safety. ChiCTR2400093803 Esketamine Levobupivacaine Pain Management Lung Cancer Functional Recovery Figures Figure 1 1. Introduction Non-small cell lung cancer (NSCLC) is a prevalent and aggressive form of lung cancer, with surgical resection being a critical treatment option for many patients. The advent of thoracoscopic radical resection for NSCLC has significantly transformed surgical outcomes by reducing invasiveness and accelerating recovery [1]. However, despite these advancements, the management of postoperative pain remains a critical challenge. Inadequate postoperative analgesia can impede the recovery process, as it often hinders early mobilization and discharge [2]. Pain not only hinders recovery but also significantly impacts the survival of patients with active cancers. Studies have shown that pain intensity is significantly correlated with 5-year survival in patients with advanced NSCLC [3]. Meanwhile, excessive opioid use, especially in the postoperative period, can lead to several adverse outcomes. For example, opioid overuse is linked to a higher risk of chronic dependency, complicating recovery and prolonging hospital stays. Moreover, certain comorbidities, such as diabetes, heart failure, and lung disease, can further increase the risk and negative consequences of opioid overuse [4]. While ultrasound-guided thoracic paravertebral block (TPVB) effectively reduces acute pain intensity, the limited duration of single-agent local anesthetics (e.g., levobupivacaine) often necessitates supplemental opioids, contradicting Enhanced Recovery After Surgery (ERAS) principles [5]. Esketamine, a potent NMDA receptor antagonist, has garnered attention as an adjuvant to regional anesthesia due to its unique dual action: suppression of central sensitization and prevention of opioid-induced hyperalgesia [6]. Recent clinical trials have demonstrated that the addition of low-dose esketamine (0.25–0.5 mg/kg) to local anesthetics in peripheral nerve blocks significantly prolongs the duration of sensory blockade. This effect may thereby reduce postoperative opioid requirements, potentially improving postoperative recovery outcomes [7][8]. Notably, in thoracic surgery, preliminary evidence suggests that esketamine-enhanced TPVB may decrease rescue analgesia demands and facilitate earlier chest tube removal [9]. However, existing studies predominantly focus on short-term pain scores, leaving critical gaps in understanding its opioid-sparing efficacy and impact on functional recovery in oncologic populations. This retrospective cohort study investigates the hypothesis that combining esketamine with levobupivacaine in ultrasound-guided TPVB will (1) reduce cumulative opioid consumption within 48 hours postoperatively, (2) improve pain control during mobilization, and (3) accelerate key ERAS milestones (e.g., ambulation and hospital discharge) compared to conventional levobupivacaine TPVB. By addressing these objectives, we aim to establish a pharmacological framework for optimizing perioperative analgesia while aligning with opioid stewardship initiatives in thoracic oncology. 2. Methods 2.1 Study Design and Participants This retrospective cohort study was conducted at our hospital between January 2020 and December 2024, following approval from the Institutional Review Board (IRB No.2024-LW-017). Patients who underwent elective thoracoscopic radical resection of non-small cell lung cancer (NSCLC) under general anesthesia combined with ultrasound-guided thoracic paravertebral block (TPVB) were screened. Inclusion criteria were: (1) age 18–75 years; (2) ASA physical status I–III; (3) unilateral surgery; (4) complete perioperative records. Exclusion criteria included: (1) contraindications to TPVB (e.g., coagulopathy, infection at the puncture site); (2) chronic opioid use; (3) severe hepatic or renal dysfunction; (4) psychiatric disorders affecting pain perception. This study was approved by the Institutional Review Board of The Affiliated Yixing Clinical School of Medical school of Yangzhou University (Approval number: KY-202301012) and conducted in accordance with the ethical standards of the Declaration of Helsinki. Individual informed consent was waived due to the retrospective and anonymized nature of the data analysis. Clinical trial registration number: ChiCTR2400093803 2.2 Intervention Protocols Patients were stratified into two cohorts based on the administered thoracic paravertebral block (TPVB) regimen. The control group received ultrasound-guided TPVB with 20 mL of 0.375% levobupivacaine (maximum dose ≤150 mg), injected into the paravertebral space using a linear ultrasound probe (8–12 MHz). In contrast, the intervention group received a combination of 0.375% levobupivacaine (20 mL) and esketamine (0.5 mg/kg, diluted to 1 mg/mL) under identical ultrasound guidance. General anesthesia was standardized for all patients, comprising induction with propofol, rocuronium, and sufentanil, followed by maintenance with sevoflurane and remifentanil. Postoperatively, a patient-controlled analgesia (PCA) pump delivering sufentanil (2 μg/kg total dose, background infusion rate 0.5 mL/h, bolus dose 2 mL, 15-minute lockout interval) was utilized for pain management. 2.3 Data Collection and Outcomes Clinical data were systematically retrieved from institutional electronic medical records and anesthesia databases. The primary outcomes focused on postoperative pain intensity, quantified using resting and movement-associated visual analog scale (VAS) scores (range: 0–10) at 6, 24, and 48 hours post-surgery, alongside cumulative sufentanil consumption via PCA within the first 48 hours. Secondary outcomes included postoperative recovery parameters such as time to first ambulation, duration of chest tube retention, and length of hospital stay. Safety assessments documented the incidence of postoperative nausea and vomiting (PONV), hallucinations, respiratory depression, and hemodynamic instability. Additionally, oncological markers, including serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) levels, were analyzed one week postoperatively to explore potential interactions between the anesthetic regimen and tumor-associated biomarkers. 2.4 Statistical Analysis Continuous variables are presented as mean ± standard deviation or median (interquartile range) and compared using Student’s t-test or Mann-Whitney U test, as appropriate. Categorical variables are expressed as counts (%) and analyzed via χ² or Fisher’s exact tests. Multivariable linear regression adjusted for confounders (age, tumor stage, and baseline inflammation markers) was performed to evaluate the independent effects of esketamine. A two-tailed P < 0.05 was considered statistically significant. Statistical analyses were conducted using SPSS 26.0 (IBM Corp., Armonk, NY). 3. Results 3.1 Baseline Characteristics A total of 216 patients (Control: n = 108; Intervention: n = 108) were included in the final analysis. No significant differences were observed in age, sex, ASA classification, or tumor stage between groups ( Table 1 ). Table 1. Demographic and Clinical Characteristics Variable Control Group (n=108) Intervention Group (n=108) P -value Age (years) 62.3 ± 8.5 61.8 ± 9.1 0.674 Male sex, n (%) 68 (63.0%) 71 (65.7%) 0.682 ASA class II/III, n (%) 84 (77.8%) 79 (73.1%) 0.423 Tumor stage 0.886 I 45 48 II 38 35 III 25 25 BMI (kg/m²) 24.1 ± 3.2 23.8 ± 2.9 0.453 Current smoker, n (%) 35 (32.4%) 38 (35.2%) 0.663 Preoperative FEV1% predicted 78.5 ± 12.3 80.2 ± 11.6 0.312 Preoperative DLCO% predicted 72.4 ± 10.8 74.1 ± 9.7 0.215 Hypertension, n (%) 52 (48.1%) 49 (45.4%) 0.699 Diabetes mellitus, n (%) 22 (20.4%) 25 (23.1%) 0.617 Coronary artery disease, n (%) 15 (13.9%) 12 (11.1%) 0.543 Preoperative VAS score 1.2 ± 0.5 1.1 ± 0.4 0.189 3.2 Primary Outcomes Patients receiving levobupivacaine-esketamine TPVB exhibited significantly lower resting and movement-associated pain scores at all timepoints compared to the control group ( Figure.1 ). Cumulative sufentanil consumption within 48 hours was reduced by 32% in the intervention group (Control: 78.6 ± 12.4 μg vs. Intervention: 53.5 ± 10.2 μg; P < 0.001). 3.3 Secondary Outcomes The intervention group demonstrated accelerated recovery, with shorter time to first ambulation (Control: 18.4 ± 3.2 h vs. Intervention: 12.6 ± 2.8 h; P < 0.001), reduced chest tube duration (Control: 4.1 ± 1.0 days vs. Intervention: 2.9 ± 0.7 days; P < 0.001), and decreased hospital stay (Control: 6.5 ± 1.2 days vs. Intervention: 5.1 ± 1.0 days; P = 0.002, Table.2 ). Table.2 Comparison of secondary outcome between intervention and control group Control Group Intervention Group P Time to first ambulation (h) 18.4 ± 3.2 12.6 ± 2.8 < 0.001 Chest tube duration (Day) 4.1 ± 1.0 2.9 ± 0.7 < 0.001 Hospital stay 6.5 ± 1.2 5.1 ± 1.0 0.002 3.4 Analgesic effects of esketamine in lung cancer surgery To delineate the independent analgesic effects of esketamine, multivariable linear regression models were constructed adjusting for potential confounders, including age, tumor stage (I/II/III), and preoperative baseline inflammation markers (IL-6 and TNF-α levels). The analysis revealed that esketamine administration remained a significant predictor of reduced postoperative sufentanil consumption (β = -24.8, 95% CI: -28.3 to -21.3, P < 0.001) and lower resting VAS scores at 48 hours (β = -1.1, 95% CI: -1.4 to -0.8, P < 0.001) after controlling for covariates. Tumor stage III was independently associated with higher opioid requirements (β = +8.6, 95% CI: 2.1–15.1, P = 0.011), whereas baseline IL-6 levels did not significantly influence outcomes (P = 0.213, Table.3 ). Table 3. Analgesic effects of esketamine in lung cancer surgery Outcome Variable Independent Variable Adjusted β (95% CI) P Cumulative sufentanil consumption (μg) Esketamine use -24.8 (-28.3 to -21.3) <0.001 Tumor stage III +8.6 (2.1 to 15.1) 0.011 Age +0.3 (-0.1 to 0.7) 0.172 Resting VAS at 48 hours Esketamine use -1.1 (-1.4 to -0.8) <0.001 Baseline IL-6 +0.01 (-0.005 to 0.025) 0.213 3.5 Safety Outcomes The incidence of hallucinations was higher in the intervention group (Control: 0% vs. Intervention: 8.3%; P = 0.006), whereas PONV (Control: 22.2% vs. Intervention: 18.5%; P = 0.492) and respiratory depression (Control: 3.7% vs. Intervention: 2.8%; P = 0.999) showed no significant differences. No intergroup differences were observed in postoperative CEA (Control: 5.2 ± 1.8 ng/mL vs. Intervention: 5.0 ± 1.6 ng/mL; P = 0.412) or CYFRA21-1 levels (Control: 3.1 ± 0.9 ng/mL vs. Intervention: 3.0 ± 0.8 ng/mL; P = 0.587). 4. Discussion Our findings demonstrate that the addition of esketamine (0.5 mg/kg) to levobupivacaine in ultrasound-guided TPVB significantly reduces postoperative opioid consumption and accelerates functional recovery in patients undergoing thoracoscopic lung cancer surgery. By integrating opioid stewardship within Enhanced ERAS frameworks, this study provides actionable insights into optimizing perioperative analgesia while minimizing opioid-related complications. The intervention group exhibited a 32% reduction in cumulative sufentanil consumption within 48 hours compared to the conventional TPVB group (P < 0.001), confirming the opioid-sparing potential of esketamine in regional anesthesia [10][11]. This effect can be attributed to esketamine's dual mechanism as an NMDA receptor antagonist, which suppresses central sensitization and prevents opioid-induced hyperalgesia [12]. This mechanism enhances the quality and duration of regional anesthesia, as supported by prior studies showing that low-dose esketamine prolongs sensory blockade when combined with local anesthetics in peripheral nerve blocks [13][14]. The improved pain control observed in the intervention group, particularly during movement, may also be explained by esketamine's ability to modulate spinal and supraspinal pain processing. Unlike traditional local anesthetics, which act primarily peripherally, esketamine exerts central effects that mitigate the transition from acute to chronic pain [15]. This is particularly relevant in thoracic surgery, where postoperative pain often persists beyond the acute phase, contributing to chronic pain syndromes [16][17]. Multivariable analysis confirmed the independent effect of esketamine on opioid reduction (β = -24.8, P < 0.001), even after adjusting for tumor stage and baseline characteristics. The shortened time to first ambulation (12.6 vs. 18.4 hours, P < 0.001) and reduced hospital stay (5.1 vs. 6.5 days, P = 0.002) in the intervention group underscore the synergy between effective regional analgesia and ERAS principles [18]. Early mobilization is critical for reducing postoperative pulmonary complications and venous thromboembolism risk, yet traditional opioid-centric regimens often impede progress [19][20]. Our protocol's success in bridging this gap mirrors findings from recent ERAS trials advocating for multimodal, opioid-sparing strategies [21]. The intervention group exhibited a significant reduction in chest tube duration (2.9 vs. 4.1 days, P < 0.001). This improvement is likely due to enhanced pain control during critical activities such as coughing and deep breathing, which are essential for effective pleural drainage [22]. Traditional opioid-based regimens often suppress respiratory effort and limit patient participation in these activities due to their inherent respiratory depressant effects [23]. By reducing opioid requirements and minimizing respiratory depression, the combination of levobupivacaine and esketamine facilitates earlier pleural drainage removal. The reduction in hospital stay further highlights the economic and patient-centered benefits of esketamine-enhanced TPVB. Shorter hospital stays not only reduce healthcare costs but also improve patient satisfaction by enabling earlier return to daily activities, aligning with recent ERAS trials emphasizing patient-centered outcomes while minimizing opioid-related adverse effects [24]. Our results are consistent with prior studies investigating esketamine as an adjuvant to regional anesthesia. Zeng et al. demonstrated that the use of esketamine-augmented paravertebral blocks in patients undergoing VATS can effectively treat rebound pain and reduce opioid consumption postoperatively [25]. Similarly, Hou et al. demonstrated that sub-anesthetic doses of esketamine decrease postoperative opioid after spine surgery [26]. These findings collectively suggest that esketamine's analgesic effects are reproducible across surgical cohorts and anatomical regions, reinforcing its utility in multimodal analgesia protocols. This study extends previous work by incorporating oncological outcomes, including postoperative tumor biomarker levels (CEA and CYFRA21-1). The absence of significant differences in these markers between groups suggests that esketamine does not adversely affect tumor biology, addressing a critical concern in cancer surgery. This finding is particularly relevant given growing evidence linking opioid use to immune modulation and cancer progression [27]. While the intervention group experienced a higher incidence of transient hallucinations (8.3% vs. 0%, P = 0.006), no severe psychomimetic adverse events were observed. This aligns with dose-dependent neuropsychiatric effects reported in pediatric studies, where esketamine ≤0.5 mg/kg was associated with manageable side effects [28]. Given the favorable risk-benefit ratio observed, our findings support the feasibility of esketamine-enhanced TPVB in adults. However, future studies should explore lower doses (e.g., 0.25 mg/kg) to further mitigate adverse events without compromising efficacy. This study has several limitations. First, its retrospective design precludes definitive causal inferences, despite rigorous adjustment for confounders. Second, the single-center cohort and lack of long-term follow-up limit generalizability; prospective trials are needed to evaluate chronic pain incidence and oncologic outcomes. Third, while tumor stage III was associated with increased opioid requirements (β = +8.6, P = 0.011), subgroup analyses by cancer subtype were not performed—a critical consideration given the heterogeneity of non-small cell lung cancer (NSCLC). Finally, standardized ERAS protocols (e.g., uniform chest tube management criteria) could enhance the interpretability of recovery metrics in future research. 5. Conclusion In conclusion, esketamine-levobupivacaine TPVB offers a pragmatic strategy to reduce opioid reliance and expedite recovery in thoracoscopic lung cancer surgery. By addressing both nociceptive signaling and opioid-induced hyperalgesia, this approach aligns with contemporary ERAS mandates while providing a template for safer perioperative care. Further investigation into dose optimization and long-term functional outcomes will solidify its role in thoracic oncology enhanced recovery programs. Abbreviations TPVB - Thoracic Paravertebral Block NSCLC - Non-Small Cell Lung Cancer VAS - Visual Analog Scale PCA - Patient-Controlled Analgesia ERAS - Enhanced Recovery After Surgery ASA - American Society of Anesthesiologists BMI - Body Mass Index FEV1 - Forced Expiratory Volume in 1 Second DLCO - Diffusing Capacity of the Lung for Carbon Monoxide PONV - Postoperative Nausea and Vomiting CEA - Carcinoembryonic Antigen CYFRA21-1 - Cytokeratin 19 Fragment IL-6 - Interleukin-6 TNF-α - Tumor Necrosis Factor-alpha Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of The Affiliated Yixing Clinical School of Medical school of Yangzhou University (Approval number: KY-202301012) and conducted in accordance with the ethical standards of the Declaration of Helsinki. Individual informed consent was waived due to the retrospective and anonymized nature of the data analysis. Clinical trial registration number: ChiCTR2400093803 Consent for publication Not applicable Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing Interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding No funding Authors' contributions All authors made substantial contributions to this research: conceptionand design of the study; Gathering of data, analysis and interpreta-tion of the data. Writing the paper, critical revision of the manuscript. Approval of the final version for publication: all authors Acknowledgements Not applicable Clinical trial number Not applicable References Li, Y, Mei, J, Yang, Z, et al. 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Biomedicines. 2023; 12 Biomedicines. doi: 10.3390/biomedicines12102283 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-6444599","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":463730744,"identity":"bd555604-eae7-48f3-ae51-8edbbe9b2407","order_by":0,"name":"Yibing Jing","email":"","orcid":"","institution":"The Affiliated Yixing Clinical School of Medical school of Yangzhou University","correspondingAuthor":false,"prefix":"","firstName":"Yibing","middleName":"","lastName":"Jing","suffix":""},{"id":463730745,"identity":"abc622b8-d375-48d7-b59e-7f95c87f39e3","order_by":1,"name":"Xiaoqin Jiang","email":"","orcid":"","institution":"The Affiliated Yixing Hospital of Traditional Chinese Medicine of Clinical Medical College of Yangzhou University School","correspondingAuthor":false,"prefix":"","firstName":"Xiaoqin","middleName":"","lastName":"Jiang","suffix":""},{"id":463730746,"identity":"5cc5df48-3781-45f1-b920-cfa0d9ceeaea","order_by":2,"name":"Bo Hu","email":"","orcid":"","institution":"The Affiliated Yixing Hospital of Traditional Chinese Medicine of Clinical Medical College of Yangzhou University School","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Hu","suffix":""},{"id":463730747,"identity":"34ab0aa5-d7ba-486a-9db5-07aa439d7316","order_by":3,"name":"Yong Wang","email":"","orcid":"","institution":"The Affiliated Yixing Hospital of Traditional Chinese Medicine of Clinical Medical College of Yangzhou University School","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Wang","suffix":""},{"id":463730748,"identity":"10457227-51f2-4c51-ba42-bdbff8270992","order_by":4,"name":"Bingxin Song","email":"","orcid":"","institution":"The Affiliated Yixing Hospital of Traditional Chinese Medicine of Clinical Medical College of Yangzhou University School","correspondingAuthor":false,"prefix":"","firstName":"Bingxin","middleName":"","lastName":"Song","suffix":""},{"id":463730749,"identity":"71b304b9-391a-4141-ba56-f914da185b76","order_by":5,"name":"Chao Han","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYJCCDxUVbDz8QAYzcerZGBhnnDnDJyfZQJKWs21yxgYHiNUiP7/5YcPBNrPEzTdyzB4XMNjJ6TYQ0GJwjM2w4cC5tMRtN9LSjWcwJBubHSCkhY3B/PGHsmNALcnHpHkYDiRuI6RFvo39Y8MBtv+Jm2ckthGnheEYD9BhbWzGBhLE2mJwLKew4cAZNjmJM8/SjXkMiPCLfPPxjQ0HQFHZDgwxngo7OYJaEEAggQ1oKdHKQYD/ABtJ6kfBKBgFo2DkAABHD0UsW6AODQAAAABJRU5ErkJggg==","orcid":"","institution":"The Affiliated Yixing Hospital of Traditional Chinese Medicine of Clinical Medical College of Yangzhou University School","correspondingAuthor":true,"prefix":"","firstName":"Chao","middleName":"","lastName":"Han","suffix":""}],"badges":[],"createdAt":"2025-04-14 09:38:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6444599/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6444599/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83836603,"identity":"0b1fc244-61f9-47c2-ae2b-a22c646245fb","added_by":"auto","created_at":"2025-06-03 13:18:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79302,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of postoperative pain scores between intervention and control group\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6444599/v1/0218db32aff198a7458d938b.png"},{"id":108605701,"identity":"be81f13a-3882-4449-b74d-614173849e9f","added_by":"auto","created_at":"2026-05-06 12:13:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":331348,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6444599/v1/bedd35ba-7880-4816-89c1-1fbd04126757.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ultrasound-Guided Thoracic Paravertebral Block with Levobupivacaine-Esketamine Combination for Thoracoscopic Lung Cancer Surgery","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eNon-small cell lung cancer (NSCLC) is a prevalent and aggressive form of lung cancer, with surgical resection being a critical treatment option for many patients. The advent of thoracoscopic radical resection for NSCLC has significantly transformed surgical outcomes by reducing invasiveness and accelerating recovery [1]. However, despite these advancements, the management of postoperative pain remains a critical challenge. Inadequate postoperative analgesia can impede the recovery process, as it often hinders early mobilization and discharge [2]. Pain not only hinders recovery but also significantly impacts the survival of patients with active cancers. Studies have shown that pain intensity is significantly correlated with 5-year survival in patients with advanced NSCLC [3]. Meanwhile, excessive opioid use, especially in the postoperative period, can lead to several adverse outcomes. For example, opioid overuse is linked to a higher risk of chronic dependency, complicating recovery and prolonging hospital stays. Moreover, certain comorbidities, such as diabetes, heart failure, and lung disease, can further increase the risk and negative consequences of opioid overuse [4]. While ultrasound-guided thoracic paravertebral block (TPVB) effectively reduces acute pain intensity, the limited duration of single-agent local anesthetics (e.g., levobupivacaine) often necessitates supplemental opioids, contradicting Enhanced Recovery After Surgery (ERAS) principles\u0026nbsp;[5].\u003c/p\u003e\n\u003cp\u003eEsketamine, a potent NMDA receptor antagonist, has garnered attention as an adjuvant to regional anesthesia due to its unique dual action: suppression of central sensitization and prevention of opioid-induced hyperalgesia [6]. Recent clinical trials have demonstrated that the addition of low-dose esketamine (0.25\u0026ndash;0.5 mg/kg) to local anesthetics in peripheral nerve blocks significantly prolongs the duration of sensory blockade. This effect may thereby reduce postoperative opioid requirements, potentially improving postoperative recovery outcomes\u0026nbsp;[7][8]. Notably, in thoracic surgery, preliminary evidence suggests that esketamine-enhanced TPVB may decrease rescue analgesia demands and facilitate earlier chest tube removal [9]. However, existing studies predominantly focus on short-term pain scores, leaving critical gaps in understanding its opioid-sparing efficacy and impact on functional recovery in oncologic populations.\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study investigates the hypothesis that combining esketamine with levobupivacaine in ultrasound-guided TPVB will (1) reduce cumulative opioid consumption within 48 hours postoperatively, (2) improve pain control during mobilization, and (3) accelerate key ERAS milestones (e.g., ambulation and hospital discharge) compared to conventional levobupivacaine TPVB. By addressing these objectives, we aim to establish a pharmacological framework for optimizing perioperative analgesia while aligning with opioid stewardship initiatives in thoracic oncology.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1\u003c/strong\u003e \u003cstrong\u003e\u003cem\u003eStudy Design and Participants\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study was conducted at our hospital between January 2020 and December 2024, following approval from the Institutional Review Board (IRB No.2024-LW-017). Patients who underwent elective thoracoscopic radical resection of non-small cell lung cancer (NSCLC) under general anesthesia combined with ultrasound-guided thoracic paravertebral block (TPVB) were screened. Inclusion criteria were: (1) age 18\u0026ndash;75 years; (2) ASA physical status I\u0026ndash;III; (3) unilateral surgery; (4) complete perioperative records. Exclusion criteria included: (1) contraindications to TPVB (e.g., coagulopathy, infection at the puncture site); (2) chronic opioid use; (3) severe hepatic or renal dysfunction; (4) psychiatric disorders affecting pain perception.\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of The Affiliated Yixing Clinical School of Medical school of Yangzhou University (Approval number: KY-202301012) and conducted in accordance with the ethical standards of the Declaration of Helsinki. Individual informed consent was waived due to the retrospective and anonymized nature of the data analysis. Clinical trial registration number: ChiCTR2400093803\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.2\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eIntervention Protocols\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were stratified into two cohorts based on the administered thoracic paravertebral block (TPVB) regimen. The control group received ultrasound-guided TPVB with 20 mL of 0.375% levobupivacaine (maximum dose \u0026le;150 mg), injected into the paravertebral space using a linear ultrasound probe (8\u0026ndash;12 MHz). In contrast, the intervention group received a combination of 0.375% levobupivacaine (20 mL) and esketamine (0.5 mg/kg, diluted to 1 mg/mL) under identical ultrasound guidance. General anesthesia was standardized for all patients, comprising induction with propofol, rocuronium, and sufentanil, followed by maintenance with sevoflurane and remifentanil. Postoperatively, a patient-controlled analgesia (PCA) pump delivering sufentanil (2 \u0026mu;g/kg total dose, background infusion rate 0.5 mL/h, bolus dose 2 mL, 15-minute lockout interval) was utilized for pain management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.3\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eData Collection and Outcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical data were systematically retrieved from institutional electronic medical records and anesthesia databases. The primary outcomes focused on postoperative pain intensity, quantified using resting and movement-associated visual analog scale (VAS) scores (range: 0\u0026ndash;10) at 6, 24, and 48 hours post-surgery, alongside cumulative sufentanil consumption via PCA within the first 48 hours. Secondary outcomes included postoperative recovery parameters such as time to first ambulation, duration of chest tube retention, and length of hospital stay. Safety assessments documented the incidence of postoperative nausea and vomiting (PONV), hallucinations, respiratory depression, and hemodynamic instability. Additionally, oncological markers, including serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) levels, were analyzed one week postoperatively to explore potential interactions between the anesthetic regimen and tumor-associated biomarkers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.4\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables are presented as mean \u0026plusmn; standard deviation or median (interquartile range) and compared using Student\u0026rsquo;s t-test or Mann-Whitney U test, as appropriate. Categorical variables are expressed as counts (%) and analyzed via \u0026chi;\u0026sup2; or Fisher\u0026rsquo;s exact tests. Multivariable linear regression adjusted for confounders (age, tumor stage, and baseline inflammation markers) was performed to evaluate the independent effects of esketamine. A two-tailed \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 was considered statistically significant. Statistical analyses were conducted using SPSS 26.0 (IBM Corp., Armonk, NY).\u003c/p\u003e"},{"header":"3. Results","content":"\u003ch4\u003e\u003cstrong\u003e3.1 Baseline Characteristics\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003eA total of 216 patients (Control: \u003cem\u003en\u003c/em\u003e = 108; Intervention: \u003cem\u003en\u003c/em\u003e = 108) were included in the final analysis. No significant differences were observed in age, sex, ASA classification, or tumor stage between groups (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Demographic and Clinical Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl Group (n=108)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention Group (n=108)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e62.3 \u0026plusmn; 8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e61.8 \u0026plusmn; 9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.674\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMale sex, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e68 (63.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e71 (65.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.682\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eASA class II/III, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e84 (77.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e79 (73.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.423\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTumor stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.886\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBMI (kg/m\u0026sup2;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.1 \u0026plusmn; 3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.8 \u0026plusmn; 2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.453\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCurrent smoker,\u0026nbsp;n\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35 (32.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38 (35.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.663\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePreoperative FEV1% predicted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78.5 \u0026plusmn; 12.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e80.2 \u0026plusmn; 11.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.312\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePreoperative DLCO% predicted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e72.4 \u0026plusmn; 10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e74.1 \u0026plusmn; 9.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.215\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHypertension,\u0026nbsp;n\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e52 (48.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e49 (45.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.699\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDiabetes mellitus,\u0026nbsp;n\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22 (20.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25 (23.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.617\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCoronary artery disease,\u0026nbsp;n\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (13.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (11.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.543\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePreoperative VAS score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.2 \u0026plusmn; 0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.1 \u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.189\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch4\u003e\u003cstrong\u003e3.2 Primary Outcomes\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003ePatients receiving levobupivacaine-esketamine TPVB exhibited significantly lower resting and movement-associated pain scores at all timepoints compared to the control group (\u003cstrong\u003eFigure.1\u003c/strong\u003e). Cumulative sufentanil consumption within 48 hours was reduced by 32% in the intervention group (Control: 78.6 \u0026plusmn; 12.4 \u0026mu;g vs. Intervention: 53.5 \u0026plusmn; 10.2 \u0026mu;g; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Secondary Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe intervention group demonstrated accelerated recovery, with shorter time to first ambulation (Control: 18.4 \u0026plusmn; 3.2 h vs. Intervention: 12.6 \u0026plusmn; 2.8 h; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), reduced chest tube duration (Control: 4.1 \u0026plusmn; 1.0 days vs. Intervention: 2.9 \u0026plusmn; 0.7 days; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), and decreased hospital stay (Control: 6.5 \u0026plusmn; 1.2 days vs. Intervention: 5.1 \u0026plusmn; 1.0 days; \u003cem\u003eP\u003c/em\u003e = 0.002, \u003cstrong\u003eTable.2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable.2\u003c/strong\u003e Comparison of secondary outcome between intervention and control group\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"557\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTime to first ambulation (h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18.4 \u0026plusmn; 3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.6 \u0026plusmn; 2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChest tube duration (Day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.1 \u0026plusmn; 1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.9 \u0026plusmn; 0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHospital stay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.5 \u0026plusmn; 1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.1 \u0026plusmn; 1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Analgesic effects of esketamine in lung cancer surgery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo delineate the independent analgesic effects of esketamine, multivariable linear regression models were constructed adjusting for potential confounders, including age, tumor stage (I/II/III), and preoperative baseline inflammation markers (IL-6 and TNF-\u0026alpha; levels). The analysis revealed that esketamine administration remained a significant predictor of reduced postoperative sufentanil consumption (\u0026beta; = -24.8, 95% CI: -28.3 to -21.3, P \u0026lt; 0.001) and lower resting VAS scores at 48 hours (\u0026beta; = -1.1, 95% CI: -1.4 to -0.8, P \u0026lt; 0.001) after controlling for covariates. Tumor stage III was independently associated with higher opioid requirements (\u0026beta; = +8.6, 95% CI: 2.1\u0026ndash;15.1, P = 0.011), whereas baseline IL-6 levels did not significantly influence outcomes (P = 0.213, \u003cstrong\u003eTable.3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Analgesic effects of esketamine in lung cancer surgery\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"101%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eOutcome Variable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003eIndependent Variable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eAdjusted \u0026beta; (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eCumulative sufentanil consumption (\u0026mu;g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003eEsketamine use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e-24.8 (-28.3 to -21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003eTumor stage III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e+8.6 (2.1 to 15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e+0.3 (-0.1 to 0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.172\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eResting VAS at 48 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003eEsketamine use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e-1.1 (-1.4 to -0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003eBaseline IL-6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e+0.01 (-0.005 to 0.025)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.213\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Safety Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incidence of hallucinations was higher in the intervention group (Control: 0% vs. Intervention: 8.3%; \u003cem\u003eP\u003c/em\u003e = 0.006), whereas PONV (Control: 22.2% vs. Intervention: 18.5%; \u003cem\u003eP\u003c/em\u003e = 0.492) and respiratory depression (Control: 3.7% vs. Intervention: 2.8%; \u003cem\u003eP\u003c/em\u003e = 0.999) showed no significant differences.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo intergroup differences were observed in postoperative CEA (Control: 5.2 \u0026plusmn; 1.8 ng/mL vs. Intervention: 5.0 \u0026plusmn; 1.6 ng/mL; \u003cem\u003eP\u003c/em\u003e = 0.412) or CYFRA21-1 levels (Control: 3.1 \u0026plusmn; 0.9 ng/mL vs. Intervention: 3.0 \u0026plusmn; 0.8 ng/mL; \u003cem\u003eP\u003c/em\u003e = 0.587).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOur findings demonstrate that the addition of esketamine (0.5 mg/kg) to levobupivacaine in ultrasound-guided TPVB significantly reduces postoperative opioid consumption and accelerates functional recovery in patients undergoing thoracoscopic lung cancer surgery. By integrating opioid stewardship within Enhanced ERAS frameworks, this study provides actionable insights into optimizing perioperative analgesia while minimizing opioid-related complications.\u003c/p\u003e\n\u003cp\u003eThe intervention group exhibited a 32% reduction in cumulative sufentanil consumption within 48 hours compared to the conventional TPVB group (P \u0026lt; 0.001), confirming the opioid-sparing potential of esketamine in regional anesthesia [10][11]. This effect can be attributed to esketamine\u0026apos;s dual mechanism as an NMDA receptor antagonist, which suppresses central sensitization and prevents opioid-induced hyperalgesia [12]. This mechanism enhances the quality and duration of regional anesthesia, as supported by prior studies showing that low-dose esketamine prolongs sensory blockade when combined with local anesthetics in peripheral nerve blocks [13][14].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe improved pain control observed in the intervention group, particularly during movement, may also be explained by esketamine\u0026apos;s ability to modulate spinal and supraspinal pain processing. Unlike traditional local anesthetics, which act primarily peripherally, esketamine exerts central effects that mitigate the transition from acute to chronic pain [15]. This is particularly relevant in thoracic surgery, where postoperative pain often persists beyond the acute phase, contributing to chronic pain syndromes [16][17].\u003c/p\u003e\n\u003cp\u003eMultivariable analysis confirmed the independent effect of esketamine on opioid reduction (\u0026beta; = -24.8, P \u0026lt; 0.001), even after adjusting for tumor stage and baseline characteristics. The shortened time to first ambulation (12.6 vs. 18.4 hours, P \u0026lt; 0.001) and reduced hospital stay (5.1 vs. 6.5 days, P = 0.002) in the intervention group underscore the synergy between effective regional analgesia and ERAS principles [18]. Early mobilization is critical for reducing postoperative pulmonary complications and venous thromboembolism risk, yet traditional opioid-centric regimens often impede progress [19][20]. Our protocol\u0026apos;s success in bridging this gap mirrors findings from recent ERAS trials advocating for multimodal, opioid-sparing strategies [21].\u0026nbsp;The intervention group exhibited a significant reduction in chest tube duration (2.9 vs. 4.1 days, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001). This improvement is likely due to enhanced pain control during critical activities such as coughing and deep breathing, which are essential for effective pleural drainage [22]. Traditional opioid-based regimens often suppress respiratory effort and limit patient participation in these activities due to their inherent respiratory depressant effects\u0026nbsp;[23]. By reducing opioid requirements and minimizing respiratory depression, the combination of levobupivacaine and esketamine facilitates earlier pleural drainage removal. The reduction in hospital stay further highlights the economic and patient-centered benefits of esketamine-enhanced TPVB. Shorter hospital stays not only reduce healthcare costs but also improve patient satisfaction by enabling earlier return to daily activities, aligning with recent ERAS trials emphasizing patient-centered outcomes while minimizing opioid-related adverse effects\u0026nbsp;[24].\u003c/p\u003e\n\u003cp\u003eOur results are consistent with prior studies investigating esketamine as an adjuvant to regional anesthesia. Zeng et al. demonstrated that the use of esketamine-augmented paravertebral blocks in patients undergoing VATS can effectively treat rebound pain and reduce opioid consumption postoperatively [25]. Similarly, Hou et al. demonstrated that sub-anesthetic doses of esketamine decrease postoperative opioid after spine surgery [26]. These findings collectively suggest that esketamine\u0026apos;s analgesic effects are reproducible across surgical cohorts and anatomical regions, reinforcing its utility in multimodal analgesia protocols.\u003c/p\u003e\n\u003cp\u003eThis study extends previous work by incorporating oncological outcomes, including postoperative tumor biomarker levels (CEA and CYFRA21-1). The absence of significant differences in these markers between groups suggests that esketamine does not adversely affect tumor biology, addressing a critical concern in cancer surgery. This finding is particularly relevant given growing evidence linking opioid use to immune modulation and cancer progression [27].\u003c/p\u003e\n\u003cp\u003eWhile the intervention group experienced a higher incidence of transient hallucinations (8.3% vs. 0%, P = 0.006), no severe psychomimetic adverse events were observed. This aligns with dose-dependent neuropsychiatric effects reported in pediatric studies, where esketamine \u0026le;0.5 mg/kg was associated with manageable side effects\u0026nbsp;[28]. Given the favorable risk-benefit ratio observed, our findings support the feasibility of esketamine-enhanced TPVB in adults. However, future studies should explore lower doses (e.g., 0.25 mg/kg) to further mitigate adverse events without compromising efficacy.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, its retrospective design precludes definitive causal inferences, despite rigorous adjustment for confounders. Second, the single-center cohort and lack of long-term follow-up limit generalizability; prospective trials are needed to evaluate chronic pain incidence and oncologic outcomes. Third, while tumor stage III was associated with increased opioid requirements (\u0026beta; = +8.6, P = 0.011), subgroup analyses by cancer subtype were not performed\u0026mdash;a critical consideration given the heterogeneity of non-small cell lung cancer (NSCLC). Finally, standardized ERAS protocols (e.g., uniform chest tube management criteria) could enhance the interpretability of recovery metrics in future research.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn conclusion, esketamine-levobupivacaine TPVB offers a pragmatic strategy to reduce opioid reliance and expedite recovery in thoracoscopic lung cancer surgery. By addressing both nociceptive signaling and opioid-induced hyperalgesia, this approach aligns with contemporary ERAS mandates while providing a template for safer perioperative care. Further investigation into dose optimization and long-term functional outcomes will solidify its role in thoracic oncology enhanced recovery programs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTPVB - Thoracic Paravertebral Block\u003c/p\u003e\n\u003cp\u003eNSCLC - Non-Small Cell Lung Cancer\u003c/p\u003e\n\u003cp\u003eVAS - Visual Analog Scale\u003c/p\u003e\n\u003cp\u003ePCA - Patient-Controlled Analgesia\u003c/p\u003e\n\u003cp\u003eERAS - Enhanced Recovery After Surgery\u003c/p\u003e\n\u003cp\u003eASA - American Society of Anesthesiologists\u003c/p\u003e\n\u003cp\u003eBMI - Body Mass Index\u003c/p\u003e\n\u003cp\u003eFEV1 - Forced Expiratory Volume in 1 Second\u003c/p\u003e\n\u003cp\u003eDLCO - Diffusing Capacity of the Lung for Carbon Monoxide\u003c/p\u003e\n\u003cp\u003ePONV - Postoperative Nausea and Vomiting\u003c/p\u003e\n\u003cp\u003eCEA - Carcinoembryonic Antigen\u003c/p\u003e\n\u003cp\u003eCYFRA21-1 - Cytokeratin 19 Fragment\u003c/p\u003e\n\u003cp\u003eIL-6 - Interleukin-6\u003c/p\u003e\n\u003cp\u003eTNF-\u0026alpha; - Tumor Necrosis Factor-alpha\u003c/p\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 Review Board of The Affiliated Yixing Clinical School of Medical school of Yangzhou University (Approval number: KY-202301012) and conducted in accordance with the ethical standards of the Declaration of Helsinki. Individual informed consent was waived due to the retrospective and anonymized nature of the data analysis. Clinical trial registration number: ChiCTR2400093803\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors made substantial contributions to this research: conceptionand design of the study; Gathering of data, analysis and interpreta-tion of the data. Writing the paper, critical revision of the manuscript. Approval of the final version for publication: all authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLi, Y, Mei, J, Yang, Z, et al. Ten-year survival outcomes of video-assisted thoracic surgery vs. open major lung resection for stage I-III non-small cell lung cancer: a large cohort study in China. TRANSL LUNG CANCER R. 2023; 13 TRANSL LUNG CANCER R. doi: 10.21037/tlcr-24-150\u003c/li\u003e\n \u003cli\u003eGan, TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017; 10 2287-2298. doi: 10.2147/JPR.S144066\u003c/li\u003e\n \u003cli\u003eTan, VS, Tjong, MC, Chan, WC, et al. Pain and Interventions in Stage IV Non-Small Cell Lung Cancer: A Province-Wide Analysis. CURR ONCOL. 2023; 30 (3): 3461-3472. doi: 10.3390/curroncol30030262\u003c/li\u003e\n \u003cli\u003eZhao, S, Chen, F, Feng, A, et al. Risk Factors and Prevention Strategies for Postoperative Opioid Abuse. PAIN RES MANAG. 2019; 2019 7490801. doi: 10.1155/2019/7490801\u003c/li\u003e\n \u003cli\u003eKomasawa, N. Revitalizing Postoperative Pain Management in Enhanced Recovery After Surgery via Inter-departmental Collaboration Toward Precision Medicine: A Narrative Review. Cureus. 2023; 16 Cureus. doi: 10.7759/cureus.59031\u003c/li\u003e\n \u003cli\u003eXiang, J, Cao, C, Chen, J, et al. Efficacy and safety of ketamine as an adjuvant to regional anesthesia: A systematic review and meta-analysis of randomized controlled trials. J CLIN ANESTH. 2023; 94 111415. doi: 10.1016/j.jclinane.2024.111415\u003c/li\u003e\n \u003cli\u003eHu, Y, Zhang, QY, Qin, GC, et al. Balanced opioid-free anesthesia with lidocaine and esketamine versus balanced anesthesia with sufentanil for gynecological endoscopic surgery: a randomized controlled trial. Sci Rep. 2023; 14 (1): 11759. doi: 10.1038/s41598-024-62824-3\u003c/li\u003e\n \u003cli\u003eZheng, H, Zhang, P, Shi, S, et al. Sub-anesthetic dose of esketamine decreases postoperative opioid self-administration after spine surgery: a retrospective cohort analysis. Sci Rep. 2023; 14 Sci Rep. doi: 10.1038/s41598-024-54617-5\u003c/li\u003e\n \u003cli\u003eYuan, J, Chen, S, Xie, Y, et al. Intraoperative Intravenous Infusion of Esmketamine Has Opioid-Sparing Effect and Improves the Quality of Recovery in Patients Undergoing Thoracic Surgery: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. PAIN PHYSICIAN. 2022; 25 (9): E1389-E1397. PMID: 36608010\u003c/li\u003e\n \u003cli\u003eHuan, C, Zhang, T, Jiang, Y, et al. Intraoperative Administration of Esketamine is Associated with Reduced Opioid Consumption After Laparoscopic Gynecological Surgery: A Randomized Controlled Trial. Drug Des Devel Ther. 2023; 19 229-238. doi: 10.2147/DDDT.S502938\u003c/li\u003e\n \u003cli\u003eLiu, J, Yin, J, Yin, J, et al. Effect of esketamine-based opioid-sparing anesthesia strategy on postoperative pain and recovery quality in patients undergoing total laparoscopic hysterectomy: A randomized controlled trail. Heliyon. 2023; 10 Heliyon. doi: 10.1016/j.heliyon.2024.e24941\u003c/li\u003e\n \u003cli\u003eWang, J, Feng, Y, Qi, Z, et al. The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor-CaMKII pathway. Open Life Sci. 2023; 19 (1): 20220816. doi: 10.1515/biol-2022-0816\u003c/li\u003e\n \u003cli\u003eYu, L, Zhou, Q, Li, W, et al. Effects of Esketamine Combined with Ultrasound-Guided Pectoral Nerve Block Type II on the Quality of Early Postoperative Recovery in Patients Undergoing a Modified Radical Mastectomy for Breast Cancer: A Randomized Controlled Trial. J Pain Res. 2022; 15 J Pain Res. doi: 10.2147/JPR.S380354\u003c/li\u003e\n \u003cli\u003eZhu, S, Wang, D, Gao, H, et al. Clinical value of esketamine combined with ropivacaine in rebound pain after brachial plexus block in patients with upper limb fractures. Front Surg. 2023; 11 Front Surg. doi: 10.3389/fsurg.2024.1470205\u003c/li\u003e\n \u003cli\u003eSubramanian, S, Haroutounian, S, Palanca, BJA, et al. Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence. J NEUROL SCI. 2022; 434 J NEUROL SCI. doi: 10.1016/j.jns.2022.120152\u003c/li\u003e\n \u003cli\u003eKhan, JS, Dana, E, Xiao, MZX, et al. Prevalence and Risk Factors for Chronic Postsurgical Pain After Thoracic Surgery: A Prospective Cohort Study. J CARDIOTHOR VASC AN. 2023; 38 J CARDIOTHOR VASC AN. doi: 10.1053/j.jvca.2023.09.042\u003c/li\u003e\n \u003cli\u003eWang, H, Li, S, Liang, N, et al. Postoperative pain experiences in Chinese adult patients after thoracotomy and video-assisted thoracic surgery. J CLIN NURS. 2017; 26 J CLIN NURS. doi: 10.1111/jocn.13789\u003c/li\u003e\n \u003cli\u003eDunkman, WJ, Manning, MW. Enhanced Recovery After Surgery and Multimodal Strategies for Analgesia. SURG CLIN N AM. 2018; 98 SURG CLIN N AM. doi: 10.1016/j.suc.2018.07.005\u003c/li\u003e\n \u003cli\u003eTazreean, R, Nelson, G, Twomey, R. Early mobilization in enhanced recovery after surgery\u0026nbsp;pathways: current evidence and recent advancements. J COMP EFFECT RES. 2022; 11 J COMP EFFECT RES. doi: 10.2217/cer-2021-0258\u003c/li\u003e\n \u003cli\u003eAlaparthi, GK, Gatty, A, Samuel, SR, et al. Effectiveness, Safety, and Barriers to Early Mobilization in the Intensive Care Unit. CRIT CARE RES PRACT. 2020; 2020 7840743. doi: 10.1155/2020/7840743\u003c/li\u003e\n \u003cli\u003eChitnis, SS, Tang, R, Mariano, ER. The role of regional analgesia in personalized postoperative pain management. KOREAN J ANESTHESIOL. 2020; 73 KOREAN J ANESTHESIOL. doi: 10.4097/kja.20323\u003c/li\u003e\n \u003cli\u003eZunzunwala, S, Jaiswal, PR. Effectiveness of Physiotherapy Interventions in Pleural Effusion Patients: A Comprehensive Review. Cureus. 2023; 16 Cureus. doi: 10.7759/cureus.61195\u003c/li\u003e\n \u003cli\u003eFan, YZ, Duan, YL, Chen, CT, et al. Advances in attenuating opioid-induced respiratory depression: A narrative review. MEDICINE. 2023; 103 (29): e38837. doi: 10.1097/MD.0000000000038837\u003c/li\u003e\n \u003cli\u003eFoster, L, Foppiani, J, Patel, A, et al. The use of enhanced recovery after surgery (ERAS) protocols in plastic surgery: A systematic review and meta-analysis of the literature. J PLAST RECONSTR AES. 2023; 103 J PLAST RECONSTR AES. doi: 10.1016/j.bjps.2025.01.072\u003c/li\u003e\n \u003cli\u003eZeng X, Zhang X, Jiang W, Zhou X. Efficacy of Intravenous Administration of Esketamine in Preventing and Treating Rebound Pain After Thoracic Paravertebral Nerve Block: A Prospective Randomized, Double-Blind, Placebo-Controlled Trial. Drug Des Devel Ther. 2024 Feb 17;18:463-473. doi: 10.2147/DDDT.S448336. PMID: 38384750; PMCID: PMC10880457.\u003c/li\u003e\n \u003cli\u003eHou NN, Zhang MY, Zhang YW, Wu HJ, Luo H, Yang H. Safety and efficacy of low-dose esketamine weakly opioidized anesthesia in elderly patients with lumbar spinal stenosis undergoing surgery: a prospective, double-blind randomized controlled trial. BMC Anesthesiol. 2025 Feb 5;25(1):57. doi: 10.1186/s12871-025-02908-3. PMID: 39910473; PMCID: PMC11796069.\u003c/li\u003e\n \u003cli\u003eCheraghi, Z, Azmi-Naei, B, Azmi-Naei, N, et al. The significant impact of opium use on various types of cancer: an updated - systematic review and meta-analysis. BMC Cancer. 2023; 25 BMC Cancer. doi: 10.1186/s12885-025-13768-y\u003c/li\u003e\n \u003cli\u003eKawczak, P, Feszak, I, Bączek, T. Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. Biomedicines. 2023; 12 Biomedicines. doi: 10.3390/biomedicines12102283\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":"Esketamine, Levobupivacaine, Pain Management, Lung Cancer, Functional Recovery","lastPublishedDoi":"10.21203/rs.3.rs-6444599/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6444599/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/em\u003e: This retrospective cohort study evaluated the efficacy of esketamine combined with levobupivacaine in ultrasound-guided thoracic paravertebral block (TPVB) for improving opioid-sparing analgesia and enhancing recovery after thoracoscopic lung cancer surgery.\u003cbr\u003e\n \u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e: Patients undergoing thoracoscopic radical resection of non-small cell lung cancer (NSCLC) between 2020–2024 were stratified into two groups: the intervention group received TPVB with 0.375% levobupivacaine plus esketamine (0.5 mg/kg), while the control group received levobupivacaine alone. Primary outcomes included cumulative sufentanil consumption and resting/movement-associated pain scores (VAS, 0–10) within 48 hours postoperatively. Secondary outcomes encompassed time to first ambulation, chest tube duration, hospital stay, and safety profiles.\u003cbr\u003e\n \u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e: Among 216 patients (108 per group), the intervention group demonstrated a 32% reduction in 48-hour sufentanil consumption (53.5 ± 10.2 μg vs. 78.6 ± 12.4 μg, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001) and significantly lower VAS scores at rest (1.6 ± 0.5 vs. 2.7 ± 0.6, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001) and during movement (2.4 ± 0.6 vs. 4.0 ± 0.9, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001) at 48 hours. Recovery metrics improved markedly, with shorter time to first ambulation (12.6 ± 2.8 h vs. 18.4 ± 3.2 h, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), reduced chest tube retention (2.9 ± 0.7 vs. 4.1 ± 1.0 days, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), and decreased hospital stay (5.1 ± 1.0 vs. 6.5 ± 1.2 days, \u003cem\u003eP\u003c/em\u003e = 0.002). Transient hallucinations occurred more frequently in the intervention group (8.3% vs. 0%, \u003cem\u003eP\u003c/em\u003e = 0.006), with no severe adverse events.\u003cbr\u003e\n \u003cem\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/em\u003e: Esketamine-levobupivacaine TPVB significantly reduces postoperative opioid requirements, enhances analgesia, and accelerates functional recovery in thoracoscopic lung cancer surgery. This multimodal approach aligns with ERAS protocols while advocating for opioid stewardship, though dose optimization may further improve safety. 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