{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T06:28:14Z","timestamp":1775111294587,"version":"3.50.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Postoperative neurocognitive dysfunction (PND) is a common and serious complication following surgery. Neostigmine, an acetylcholinesterase inhibitor commonly administered during anesthesia to reverse residual neuromuscular blockade, has been suggested in recent studies to potentially reduce the incidence of PND. However, findings have been inconsistent across studies. Therefore, this study conducts a systematic review and meta-analysis to evaluate the effect of neostigmine on PND.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a comprehensive literature search across multiple databases, including PubMed, EmBase, Web of Science, Cochrane Library, Scopus, SinoMed, and CNKI, to identify all relevant studies for inclusion. We included randomized controlled trials and cohort studies in our analysis. The risk of bias was assessed using the Risk of Bias 2 tool for randomized trials and the ROBINS-I tool for cohort studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 11 studies were included in this analysis, consisting of 8 randomized controlled trials and 3 cohort studies. The incidence of PND was significantly lower in the neostigmine group compared to the control group (log(OR): \u22120.54, 95% CI [\u22121.04, \u22120. 05]; OR: 0.58, 95% CI: [0.35, 0.95], <jats:italic>p<\/jats:italic>\u202f=\u202f0.03, I<jats:sup>2<\/jats:sup>\u202f=\u202f81.95%). Sensitivity analysis led to the exclusion of one cohort study. Consequently, the final meta-analysis comprised 10 studies, encompassing a total of 50,881 participants. The results indicate that the incidence of PND was significantly lower in the neostigmine group compared to the control group (log(OR):\u22120. 27, 95% CI [\u22120.47, \u22120. 08]; OR: 0.76, 95% CI: [0.62, 0.91], <jats:italic>p<\/jats:italic>\u202f=\u202f0.01, I<jats:sup>2<\/jats:sup>\u202f=\u202f2.50%). However, Meta-analysis of RCTs and cohort studies showed no significant difference. Subgroup analysis indicated that neostigmine reduced the incidence of delayed neurocognitive recovery (dNCR), but its impact on POD was unclear, with no significant association to nausea and vomiting. These findings suggest that neostigmine may reduce the risk of PND, but caution is needed in interpretation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Neostigmine may have a potential positive effect in reducing the incidence of PND. However, no statistical difference was observed when meta-analyses were performed separately for randomized controlled trials (RCTs) and cohort studies. Given the limited number of studies available and the limitations of the current research, further investigation is needed to clarify the impact of neostigmine on PND.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic review registration<\/jats:title><jats:p><jats:uri>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD42024537647<\/jats:uri>, Identifier CRD42024537647.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2025.1464272","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T06:47:52Z","timestamp":1741330072000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Effects of neostigmine on postoperative neurocognitive dysfunction: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"19","author":[{"given":"Xuelei","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linlin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianchun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Longyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linji","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e031212","DOI":"10.1136\/bmjopen-2019-031212","article-title":"Cholinesterase alterations in delirium after cardiosurgery: a German monocentric prospective study","volume":"10","author":"Adam","year":"2020","journal-title":"BMJ Open"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1080\/13607860903421011","article-title":"Delirium scales: a review of current evidence","volume":"14","author":"Adamis","year":"2010","journal-title":"Aging Ment. Health"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1177\/0310057X1704500508","article-title":"Effect of sugammadex versus neostigmine\/atropine combination on postoperative cognitive dysfunction after elective surgery","volume":"45","author":"Batistaki","year":"2017","journal-title":"Anaesth. Intensive Care"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/jrsm.12","article-title":"A basic introduction to fixed-effect and random-effects models for meta-analysis","volume":"1","author":"Borenstein","year":"2010","journal-title":"Res. Synth. Methods"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1093\/bja\/aev104","article-title":"Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study","volume":"115","author":"Brueckmann","year":"2015","journal-title":"Br. J. Anaesth."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1186\/s12871-023-02233-7","article-title":"Optimal dose of neostigmine antagonizing cisatracurium-induced shallow neuromuscular block in elderly patients: a randomized control study","volume":"23","author":"Cao","year":"2023","journal-title":"BMC Anesthesiol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1093\/ageing\/afr053","article-title":"Low preoperative plasma cholinesterase activity as a risk marker of postoperative delirium in elderly patients","volume":"40","author":"Cerejeira","year":"2011","journal-title":"Age Ageing"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1111\/j.1532-5415.2011.03883.x","article-title":"The cholinergic system and inflammation: common pathways in delirium pathophysiology","volume":"60","author":"Cerejeira","year":"2012","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1213\/01.ANE.0000180992.76743.C9","article-title":"Does neostigmine administration produce a clinically important increase in postoperative nausea and vomiting?","volume":"101","author":"Cheng","year":"2005","journal-title":"Anesth. Analg."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1186\/s12974-022-02656-y","article-title":"Targeting neuroinflammation as a preventive and therapeutic approach for perioperative neurocognitive disorders","volume":"19","author":"Cheng","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1056\/NEJM200006223422507","article-title":"Randomized, controlled trials, observational studies, and the hierarchy of research designs","volume":"342","author":"Concato","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"Ed000142","DOI":"10.1002\/14651858.ED000142","article-title":"Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions","volume":"10","author":"Cumpston","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"153007","DOI":"10.1016\/j.phymed.2019.153007","article-title":"Ameliorative effect of deoxyvasicine on scopolamine-induced cognitive dysfunction by restoration of cholinergic function in mice","volume":"63","author":"Deng","year":"2019","journal-title":"Phytomedicine"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1213\/ANE.00000000000006687","article-title":"Influence of neostigmine on early postoperative cognitive dysfunction in older adult patients undergoing noncardiac surgery: a double-blind, placebo-controlled, randomized controlled trial","volume":"138","author":"Deng","year":"2024","journal-title":"Anesth. Analg."},{"key":"ref15","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1213\/00000539-199403000-00005","article-title":"Use of mivacurium during laparoscopic surgery: effect of reversal drugs on postoperative recovery","volume":"78","author":"Ding","year":"1994","journal-title":"Anesth. Analg."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.ijsu.2020.07.017","article-title":"Trauma of major surgery: a global problem that is not going away","volume":"81","author":"Dobson","year":"2020","journal-title":"Int. J. Surg."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.ydbio.2004.02.027","article-title":"Acetylcholinesterase function is dispensable for sensory neurite growth but is critical for neuromuscular synapse stability","volume":"270","author":"Downes","year":"2004","journal-title":"Dev. Biol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1097\/ALN.0000000000002334","article-title":"Recommendations for the nomenclature of cognitive change associated with Anaesthesia and Surgery-2018","volume":"129","author":"Evered","year":"2018","journal-title":"Anesthesiology"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e1001026","DOI":"10.1371\/journal.pmed.1001026","article-title":"Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: methodological overview","volume":"8","author":"Golder","year":"2011","journal-title":"PLoS Med."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.19296\/j.cnki.1008-2409.2023-06-017","article-title":"Application effects of neostigmine in elderly laparoscopic surgery anesthesia","volume":"36","author":"Hang","year":"2023","journal-title":"Acta Med. Sinica"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1213\/00000539-199712000-00032","article-title":"Reversal of neuromuscular blockade with neostigmine has no effect on the incidence or severity of postoperative nausea and vomiting","volume":"85","author":"Hovorka","year":"1997","journal-title":"Anesth. Analg."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/S0140-6736(13)60688-1","article-title":"Delirium in elderly people","volume":"383","author":"Inouye","year":"2014","journal-title":"Lancet"},{"key":"ref23","article-title":"Effects of neostigmine on postoperative cognitive status and gastrointestinal function recovery in convalescent patients undergoing laparoscopic cholecystectomy under general anesthesia","volume":"38","author":"Jing","year":"2016","journal-title":"Hebei Med. J."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s40560-017-0224-1","article-title":"Acetylcholinesterase and butyrylcholinesterase in cardiosurgical patients with postoperative delirium","volume":"5","author":"John","year":"2017","journal-title":"J. Intensive Care"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1007\/s10072-019-3730-1","article-title":"Comprehensive risk factor evaluation of postoperative delirium following major surgery: clinical data warehouse analysis","volume":"40","author":"Kang","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"110408","DOI":"10.1016\/j.jclinane.2021.110408","article-title":"Development and validation of a risk score for predicting postoperative delirium after major abdominal surgery by incorporating preoperative risk factors and surgical Apgar score","volume":"75","author":"Li","year":"2021","journal-title":"J. Clin. Anesth."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1111\/cns.13794","article-title":"Neuroinflammation in perioperative neurocognitive disorders: from bench to the bedside","volume":"28","author":"Liu","year":"2022","journal-title":"CNS Neurosci. Ther."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/j.bja.2019.07.004","article-title":"State of the clinical science of perioperative brain health: report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018","volume":"123","author":"Mahanna-Gabrielli","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/jrsm.1411","article-title":"Risk-of-bias VISualization (robvis): an R package and shiny web app for visualizing risk-of-bias assessments","volume":"12","author":"McGuinness","year":"2020","journal-title":"Res. Synth. Methods"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/1054597","article-title":"Postoperative delirium in elderly patients undergoing hip fracture surgery in the Sugammadex era: a retrospective study","volume":"2016","author":"Oh","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1007\/s00134-017-4860-7","article-title":"The intensive care delirium research agenda: a multinational, interprofessional perspective","volume":"43","author":"Pandharipande","year":"2017","journal-title":"Intensive Care Med."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/S1470-2045(20)30675-6","article-title":"Global demand for cancer surgery and an estimate of the optimal surgical and anaesthesia workforce between 2018 and 2040: a population-based modelling study","volume":"22","author":"Perera","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.bjane.2014.10.003","article-title":"The effect of sugammadex on postoperative cognitive function and recovery","volume":"66","author":"Piskin","year":"2016","journal-title":"Braz. J. Anesthesiol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1186\/s12871-022-01804-4","article-title":"The effect of neostigmine on postoperative delirium after colon carcinoma surgery: a randomized, double-blind, controlled trial","volume":"22","author":"Purohit","year":"2022","journal-title":"BMC Anesthesiol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"S13","DOI":"10.1016\/S2214-109X(15)70087-2","article-title":"Estimated need for surgery worldwide based on prevalence of diseases: a modelling strategy for the WHO Global Health estimate","volume":"3","author":"Rose","year":"2015","journal-title":"Lancet Glob. Health"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1213\/ANE.0000000000006939","article-title":"Association of Intravenous Neostigmine and Anticholinergics or Sugammadex with postoperative delirium: a retrospective cohort study","volume":"140","author":"R\u00f6ssler","year":"2024","journal-title":"Anesth. Analg."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"e73","DOI":"10.1016\/j.lpm.2018.03.011","article-title":"Impact on the brain of the inflammatory response to surgery","volume":"47","author":"Saxena","year":"2018","journal-title":"Presse Med."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"n1864","DOI":"10.1136\/bmj.n1864","article-title":"Evaluating agreement between bodies of evidence from randomised controlled trials and cohort studies in nutrition research: meta-epidemiological study","volume":"374","author":"Schwingshackl","year":"2021","journal-title":"BMJ"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"51","DOI":"10.16252\/j.cnki.issn1004-0501-2015.01.016","article-title":"Clinical observation of small dose of Naloxonesynergistic with neostigmine used for infants and young children under general anesthesia recovery","volume":"36","author":"Shuai","year":"2015","journal-title":"Sichuan Med. J."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1097\/ALN.0000000000000671","article-title":"Preexisting cognitive impairment is associated with postoperative cognitive dysfunction after hip joint replacement surgery","volume":"122","author":"Silbert","year":"2015","journal-title":"Anesthesiology"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1097\/EJA.0000000000001456","article-title":"Physostigmine for prevention of postoperative delirium and long-term cognitive dysfunction in liver surgery: a double-blinded randomised controlled trial","volume":"38","author":"Spies","year":"2021","journal-title":"Eur. J. Anaesthesiol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/anae.12493","article-title":"Should general anaesthesia be avoided in the elderly?","volume":"69","author":"Str\u00f8m","year":"2014","journal-title":"Anaesthesia"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1111\/anae.15607","article-title":"Evidence-based strategies to reduce the incidence of postoperative delirium: a narrative review","volume":"77","author":"Swarbrick","year":"2022","journal-title":"Anaesthesia"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.bja.2022.01.005","article-title":"Postoperative delirium and changes in the blood-brain barrier, neuroinflammation, and cerebrospinal fluid lactate: a prospective cohort study","volume":"129","author":"Taylor","year":"2022","journal-title":"Br. J. Anaesth."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1080\/08820139.2017.1373898","article-title":"Anesthetic immunomodulation of the neuroinflammation in postoperative cognitive dysfunction","volume":"46","author":"Umholtz","year":"2017","journal-title":"Immunol. Investig."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/1471-2288-14-135","article-title":"Estimating the sample mean and standard deviation from the sample size, median, range and\/or interquartile range","volume":"14","author":"Wan","year":"2014","journal-title":"BMC Med. Res. Methodol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/s41572-020-00223-4","article-title":"Delirium","volume":"6","author":"Wilson","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1001\/jama.2010.1182","article-title":"Does this patient have delirium?: value of bedside instruments","volume":"304","author":"Wong","year":"2010","journal-title":"JAMA"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.biopha.2018.12.100","article-title":"CGY-1, a biflavonoid isolated from cardiocrinum giganteum seeds, improves memory deficits by modulating the cholinergic system in scopolamine-treated mice","volume":"111","author":"Zhang","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref53","article-title":"The effect of postoperative intravenous neostigmine administration antagonizing Residual neuromuscular blockade on early postoperative cognitive dysfunction morbidity in elderly patients","volume":"38","author":"Zhu","year":"2017","journal-title":"Med. Philos."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1186\/s13063-021-05648-0","article-title":"Efficiency of donepezil in elderly patients undergoing orthopaedic surgery due to underlying post-operative cognitive dysfunction: study protocol for a multicentre randomised controlled trial","volume":"22","author":"Zhu","year":"2021","journal-title":"Trials"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1186\/s12877-020-01793-4","article-title":"The effects of neostigmine on postoperative cognitive function and inflammatory factors in elderly patients - a randomized trial","volume":"20","author":"Zhu","year":"2020","journal-title":"BMC Geriatr."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1464272\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T06:48:04Z","timestamp":1741330084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1464272\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,7]]},"references-count":55,"alternative-id":["10.3389\/fnins.2025.1464272"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2025.1464272","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,7]]},"article-number":"1464272"}}