{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:24:35Z","timestamp":1784953475780,"version":"3.55.0"},"reference-count":50,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T00:00:00Z","timestamp":1749945600000},"content-version":"unspecified","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Zhongyuan Science and Technology Innovation Leadership Program of Henan Province","award":["ZYYCYU202012030"],"award-info":[{"award-number":["ZYYCYU202012030"]}]},{"DOI":"10.13039\/501100017700","name":"Henan Provincial Science and Technology Research Project","doi-asserted-by":"publisher","award":["242102310135"],"award-info":[{"award-number":["242102310135"]}],"id":[{"id":"10.13039\/501100017700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,5,30]]},"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Postoperative delirium (POD) is a common and serious complication in older adult patients undergoing cardiovascular surgery. Esketamine is known for its anti-inflammatory and neuroprotective properties. While it has shown preventive effects on POD in those not undergoing cardiovascular surgery, its efficacy in older adult patients undergoing cardiovascular surgery remains uncertain. Therefore, we herein aimed to evaluate the preventive effect of intraoperative subanaesthetic esketamine on POD in this specific population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This single-centre, randomised, double-blind, placebo-controlled trial will enrol 778 patients aged 60\u201380 years undergoing open-heart cardiovascular surgery in China, from September 2023 to December 2025. The participants will be randomly assigned in a 1:1 ratio to the following groups: the esketamine group and the control group. In the esketamine group, esketamine (2\u2009mg\/mL) will be administered intravenously at a dosage of 0.3\u2009mg\/kg over 10\u2009min following tracheal intubation, followed by a continuous infusion at 0.15\u2009mg\/kg\/h until the end of the surgery. Patients in the control group will receive a placebo following the same dosage and regimen. The incidence of POD will be the primary outcome and will be assessed twice daily from the first to the seventh postoperative day. The postoperative sleep quality, duration of postoperative mechanical ventilation, and length of hospital and intensive care unit stay will be the secondary outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>Ethical approval was obtained from the Institutional Review Board of Fuwai Central China Cardiovascular Hospital (No. 2023068). Public disclosure is guaranteed post-trial, and the results will be published in a peer-reviewed scientific journal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>ChiCTR2300074395.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-089719","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T14:20:26Z","timestamp":1750083626000},"page":"e089719","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy of subanaesthetic esketamine on the prevention of postoperative delirium in older adult patients after cardiovascular surgery: protocol for a single-centre, randomised, double-blind, placebo-controlled trial (SEPDOC trial) in China"],"prefix":"10.1136","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6854-7748","authenticated-orcid":false,"given":"Ju-Min","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"},{"name":"Department of Anesthesiology and Perioperative Medicine, Central China Branch of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Province Clinical Research Center for Cardiovascular Disease, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0753-8810","authenticated-orcid":false,"given":"Qing-Ren","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Wuxi Xishan People\u2019s Hospital, Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5780-3870","authenticated-orcid":false,"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Central China Branch of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Province Clinical Research Center for Cardiovascular Disease, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6785-9627","authenticated-orcid":false,"given":"Jian-Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2027-0617","authenticated-orcid":false,"given":"Hong-Qi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Central China Branch of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Province Clinical Research Center for Cardiovascular Disease, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Yu","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Central China Branch of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Province Clinical Research Center for Cardiovascular Disease, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Ran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Central China Branch of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Province Clinical Research Center for Cardiovascular Disease, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Xin","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Central China Branch of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Province Clinical Research Center for Cardiovascular Disease, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Central China Branch of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Province Clinical Research Center for Cardiovascular Disease, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Di","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Central China Branch of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Province Clinical Research Center for Cardiovascular Disease, Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"2025121403201015000_15.6.e089719.1","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-014-0141-2","article-title":"The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is safer","volume":"12","year":"2014","journal-title":"BMC Med"},{"key":"2025121403201015000_15.6.e089719.2","doi-asserted-by":"crossref","first-page":"340","DOI":"10.5001\/omj.2014.91","article-title":"Factors associated with post-surgical delirium in patients undergoing open heart surgery","volume":"29","author":"Jannati","year":"2014","journal-title":"Oman Med J"},{"key":"2025121403201015000_15.6.e089719.3","doi-asserted-by":"publisher","DOI":"10.1093\/ejcts\/ezr031"},{"key":"2025121403201015000_15.6.e089719.4","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.hrtlng.2018.04.005","article-title":"Delirium after cardiac surgery. Incidence, phenotypes, predisposing and precipitating risk factors, and effects","volume":"47","author":"Sanson","year":"2018","journal-title":"Heart & Lung"},{"key":"2025121403201015000_15.6.e089719.5","doi-asserted-by":"publisher","DOI":"10.1093\/icvts\/ivt323"},{"key":"2025121403201015000_15.6.e089719.6","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.21.2703"},{"key":"2025121403201015000_15.6.e089719.7","doi-asserted-by":"crossref","DOI":"10.1186\/s13019-021-01496-w","article-title":"Risk factors of postoperative delirium after cardiac surgery: a meta-analysis","volume":"16","author":"Chen","year":"2021","journal-title":"J Cardiothorac Surg"},{"key":"2025121403201015000_15.6.e089719.8","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3182783b72"},{"key":"2025121403201015000_15.6.e089719.9","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.12885"},{"key":"2025121403201015000_15.6.e089719.10","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2010.1013"},{"key":"2025121403201015000_15.6.e089719.11","doi-asserted-by":"publisher","DOI":"10.1001\/jama.291.14.1753"},{"key":"2025121403201015000_15.6.e089719.12","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200904-0537OC"},{"key":"2025121403201015000_15.6.e089719.13","doi-asserted-by":"crossref","first-page":"251","DOI":"10.4103\/0019-5049.135026","article-title":"Post-operative delirium in elderly patients","volume":"58","author":"Vijayakumar","year":"2014","journal-title":"Indian J Anaesth"},{"key":"2025121403201015000_15.6.e089719.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jagp.2013.09.005"},{"key":"2025121403201015000_15.6.e089719.15","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1093\/icvts\/ivaa277","article-title":"Depression as a predictor of postoperative delirium after cardiac surgery: a systematic review and meta-analysis","volume":"32","author":"Falk","year":"2021","journal-title":"Interact Cardiovasc Thorac Surg"},{"key":"2025121403201015000_15.6.e089719.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2020.06.063"},{"key":"2025121403201015000_15.6.e089719.17","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.chest.2023.11.041","article-title":"Prophylactic Minocycline for Delirium in Critically Ill Patients: A Randomized Controlled Trial","volume":"165","author":"Dal-Pizzol","year":"2024","journal-title":"Chest"},{"key":"2025121403201015000_15.6.e089719.18","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1097\/ALN.0000000000004439","article-title":"Prevention of Postoperative Cognitive Dysfunction by Minocycline in Elderly Patients after Total Knee Arthroplasty: A Randomized, Double-blind, Placebo-controlled Clinical Trial","volume":"138","author":"Takazawa","year":"2023","journal-title":"Anesthesiology"},{"key":"2025121403201015000_15.6.e089719.19","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0b013e3182662e30"},{"key":"2025121403201015000_15.6.e089719.20","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1213\/ANE.0000000000001856","article-title":"In Vogue: Ketamine for Neuroprotection in Acute Neurologic Injury","volume":"124","author":"Bell","year":"2017","journal-title":"Anesth Analg"},{"key":"2025121403201015000_15.6.e089719.21","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291716000064"},{"key":"2025121403201015000_15.6.e089719.22","article-title":"Effects of sevoflurane versus other general anaesthesia on emergence agitation in children","volume":"2014","author":"Costi","year":"2014","journal-title":"Cochrane Database Syst Rev"},{"key":"2025121403201015000_15.6.e089719.23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/00008506-200004000-00003","article-title":"S(+)-ketamine up-regulates neuronal regeneration associated proteins following glutamate injury in cultured rat hippocampal neurons","volume":"12","author":"Himmelseher","year":"2000","journal-title":"J Neurosurg Anesthesiol"},{"key":"2025121403201015000_15.6.e089719.24","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1111\/aas.13168","article-title":"Intraoperative ketamine administration to prevent delirium or postoperative cognitive dysfunction: A systematic review and meta-analysis","volume":"62","author":"Hovaguimian","year":"2018","journal-title":"Acta Anaesthesiol Scand"},{"key":"2025121403201015000_15.6.e089719.25","doi-asserted-by":"publisher","DOI":"10.1053\/j.jvca.2008.12.021"},{"key":"2025121403201015000_15.6.e089719.26","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41380-021-01121-1","article-title":"Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor","volume":"27","author":"Wei","year":"2022","journal-title":"Mol Psychiatry"},{"key":"2025121403201015000_15.6.e089719.27","first-page":"431","article-title":"Stereoselective pharmacokinetics of ketamine: R(-)-ketamine inhibits the elimination of S(+)-ketamine","volume":"70","author":"Ihmsen","year":"2001","journal-title":"Clin Pharmacol Ther"},{"key":"2025121403201015000_15.6.e089719.28","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.2147\/DDDT.S406568","article-title":"The Effect of Low-Dose Esketamine on Postoperative Neurocognitive Dysfunction in Elderly Patients Undergoing General Anesthesia for Gastrointestinal Tumors: A Randomized Controlled Trial","volume":"17","author":"Ma","year":"2023","journal-title":"Drug Des Devel Ther"},{"key":"2025121403201015000_15.6.e089719.29","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.e7586","article-title":"SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials","volume":"346","author":"Chan","year":"2013","journal-title":"BMJ"},{"key":"2025121403201015000_15.6.e089719.30","doi-asserted-by":"publisher","DOI":"10.7326\/M14-0865"},{"key":"2025121403201015000_15.6.e089719.31","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181cabb42"},{"key":"2025121403201015000_15.6.e089719.32","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-007-0920-8"},{"key":"2025121403201015000_15.6.e089719.33","doi-asserted-by":"crossref","DOI":"10.3389\/fmed.2021.640785","article-title":"Association Between Preadmission Metformin Use and Outcomes in Intensive Care Unit Patients With Sepsis and Type 2 Diabetes: A Cohort Study","volume":"8","author":"Yang","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"2025121403201015000_15.6.e089719.34","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8191.2012.01472.x"},{"key":"2025121403201015000_15.6.e089719.35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.bja.2022.01.005","article-title":"Postoperative delirium and changes in the blood\u2013brain barrier, neuroinflammation, and cerebrospinal fluid lactate: a prospective cohort study","volume":"129","author":"Taylor","year":"2022","journal-title":"Br J Anaesth"},{"key":"2025121403201015000_15.6.e089719.36","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60688-1"},{"key":"2025121403201015000_15.6.e089719.37","doi-asserted-by":"crossref","first-page":"e150","DOI":"10.1213\/ANE.0000000000004179","article-title":"Flow Cytometry Characterization of Cerebrospinal Fluid Monocytes in Patients With Postoperative Cognitive Dysfunction: A Pilot Study","volume":"129","author":"Berger","year":"2019","journal-title":"Anesth Analg"},{"key":"2025121403201015000_15.6.e089719.38","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/63.2.184"},{"key":"2025121403201015000_15.6.e089719.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2016.10.043"},{"key":"2025121403201015000_15.6.e089719.40","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-91314-z","article-title":"Comparative effectiveness of pharmacological interventions to prevent postoperative delirium: a network meta-analysis","volume":"11","author":"Park","year":"2021","journal-title":"Sci Rep"},{"key":"2025121403201015000_15.6.e089719.41","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30631-0"},{"key":"2025121403201015000_15.6.e089719.42","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/anae.15983","article-title":"A randomised controlled trial of dexmedetomidine for delirium in adults undergoing heart valve surgery","volume":"78","author":"Wang","year":"2023","journal-title":"Anaesthesia"},{"key":"2025121403201015000_15.6.e089719.43","doi-asserted-by":"crossref","DOI":"10.1515\/biol-2022-0816","article-title":"The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor-CaMKII pathway","volume":"19","author":"Wang","year":"2024","journal-title":"Open Life Sci"},{"key":"2025121403201015000_15.6.e089719.44","doi-asserted-by":"crossref","DOI":"10.1186\/s12871-023-02357-w","article-title":"The ED50 and ED95 of esketamine for preventing early postoperative pain in patients undergoing laparoscopic cholecystectomy: a prospective, double-blinded trial","volume":"23","author":"Xu","year":"2023","journal-title":"BMC Anesthesiol"},{"key":"2025121403201015000_15.6.e089719.45","doi-asserted-by":"crossref","first-page":"257","DOI":"10.36076\/ppj.2023.26.257","article-title":"Sub-Anesthesia Dose of S-Ketamine Reduces Postoperative Pain and Anxiety in Patients Receiving Breast and Thyroid Surgery: A Randomized, Controlled Trial","volume":"26","author":"Zhou","year":"2023","journal-title":"Pain Physician"},{"key":"2025121403201015000_15.6.e089719.46","doi-asserted-by":"crossref","first-page":"463","DOI":"10.2147\/DDDT.S448336","article-title":"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","volume":"18","author":"Zeng","year":"2024","journal-title":"Drug Des Devel Ther"},{"key":"2025121403201015000_15.6.e089719.47","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2022.44514","article-title":"Effect of Intraoperative Esketamine Infusion on Postoperative Sleep Disturbance After Gynecological Laparoscopy: A Randomized Clinical Trial","volume":"5","author":"Qiu","year":"2022","journal-title":"JAMA Netw Open"},{"key":"2025121403201015000_15.6.e089719.48","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.bja.2023.05.001","article-title":"Mini-dose esketamine-dexmedetomidine combination to supplement analgesia for patients after scoliosis correction surgery: a double-blind randomised trial","volume":"131","author":"Zhang","year":"2023","journal-title":"Br J Anaesth"},{"key":"2025121403201015000_15.6.e089719.49","doi-asserted-by":"crossref","DOI":"10.1186\/s12871-023-02376-7","article-title":"Esketamine use is associated with shortened postoperative hospital stay in patients after knee arthroscopic surgery: a propensity score\u2013matched cohort study","volume":"24","author":"Liu","year":"2024","journal-title":"BMC Anesthesiol"},{"key":"2025121403201015000_15.6.e089719.50","doi-asserted-by":"crossref","DOI":"10.1186\/s13018-023-03728-2","article-title":"Effect of subanesthetic dose of esketamine on postoperative rehabilitation in elderly patients undergoing hip arthroplasty","volume":"18","author":"Min","year":"2023","journal-title":"J Orthop Surg Res"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2024-089719","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T11:20:21Z","timestamp":1765711221000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2024-089719"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,16]]},"published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1136\/bmjopen-2024-089719"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2024-089719","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6]]}}}