Abstract
Background and Aims:
Postoperative delirium (POD) and postoperative neurocognitive dysfunction (POND) are common neurological complications after general anaesthesia. This study aimed to evaluate the effect of perioperative ketamine or esketamine on POD and POND.
Methods:
We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library for randomised controlled trials investigating perioperative use of ketamine or esketamine versus placebo or no treatment. The primary outcomes included the incidence of POD and POND. Secondary outcomes included postoperative nausea and vomiting, pain scores, length of hospital stay, extubation time, and psychological adverse effects. The pooled estimates were quantified using odds ratios (ORs) and 95% confidence intervals (CIs), and between-study variability was quantified by the I² index, and sensitivity, subgroup analyses, and meta-regression were used to explore effect modifiers.
Results:
Sixteen studies (2536 patients) demonstrated that ketamine significantly reduced POD risk (OR = 0.62, 95% CI: 0.42, 0.92; I² =51%), while seven studies (453 patients) showed no significant effect on POND (OR = 0.41, 95% CI: 0.14, 1.21; I² =74%). (es)ketamine administration was associated with increased psychological adverse effects (OR = 1.72, 95% CI: 1.24, 2.37; I² =0%). Subgroup analyses revealed that esketamine reduced delirium risk (OR = 0.68, 95% CI: 0.47, 0.98), whereas ketamine prevented neurocognitive disorder (OR = 0.35, 95% CI: 0.20, 0.61). No significant differences were observed in secondary outcomes including nausea/vomiting, pain intensity, hospital stay, or extubation time.
Conclusion:
Perioperative (es)ketamine significantly reduces POD risk but not POND. Subgroup analyses reveal esketamine excels in delirium prevention, while racemic ketamine shows better cognitive protection.
Keywords: Anaesthesia, delirium, esketamine, general, ketamine, metanalysis, neurocognitive disorders, postoperative, randomised controlled trials
INTRODUCTION
Due to demographic shifts towards an older population and ongoing progress in medical care, more elderly patients are being exposed to anaesthesia and surgery.[1] Perioperative neurocognitive disorders, particularly postoperative delirium (POD) and postoperative neurocognitive dysfunction (POND), are major complications after surgery.[2] Cognitive impairment in clinical settings is often reflected in deficits of learning, memory, language, executive function, mood, and emotional regulation. Such dysfunction is associated with prolonged hospital stays, increased medical expenses, heavier societal burden, and, in severe cases, elevated mortality. Reported incidence rates of POD and POND range between 10% and 26%, depending on diagnostic criteria, assessment tools, and timing of evaluation.[3] Although older patients are at higher risk, these complications are not limited to them and can occur in adults of all ages undergoing surgery.
Minimising the occurrence of POD and POND primarily depends on preventive measures, including the proactive identification and management of perioperative risk contributors.[4] Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is an intravenous anaesthetic with diverse therapeutic effects.[5] Its S-enantiomer, esketamine, has higher receptor affinity and similar neuroprotective functions, such as reducing excitotoxic neuronal injury, attenuating neuroinflammation, and modulating microglial reactivity.[6,7] These mechanisms suggest a potential role in preventing perioperative cognitive impairment. However, in relation to perioperative neurocognitive dysfunctions, there is still no consensus.
Conflicting results exist on whether ketamine or esketamine provides protection against POD and POND, with some studies showing benefit[8,9] and others not.[10,11] Fellous et al.[12] reported in their meta-analysis that perioperative ketamine had no preventive effect on POD or POND. Subsequent randomised trials have yielded inconsistent results, highlighting the necessity for an updated review.
The primary objective of the study was to assess the effectiveness of perioperative ketamine or esketamine in reducing the incidence of POD and POND. The secondary objectives included assessing their effects on postoperative nausea and vomiting, pain intensity, extubation time, hospital stay, and psychological adverse effects.
METHODS
The conduct of this study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations.[13] A pre-defined protocol was registered at the PROSPERO (ID: CRD42024571712).
Search strategy
Relevant articles were retrieved from PubMed, Embase, Web of Science, and the Cochrane Library published before 2 October, 2025 [Figure 1]. The keyword search terms were ketamine, esketamine, delirium, cognitive dysfunction, and general anaesthesia (detailed search strategy in Supplementary Table 1). Duplicates were first removed automatically in EndNote, and residual duplicates were screened and removed manually. In addition, citation tracking of the included studies and relevant reviews was conducted to identify additional eligible trials. Grey literature, including conference abstracts and trial registry records (ClinicalTrials.gov), was also screened. The manuscript excluded has been summarised in Supplementary Table 2.
Figure 1.
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) flowchart
Supplementary Table 1.
Search strategies
| Electronic databases | Search | Search strategy | Results |
|---|---|---|---|
| PUBMED | ((“ketamine”[MeSH Terms] OR “ketamine”[Title/Abstract] OR “keta*”[Title/Abstract]) AND (“delirium”[MeSH Terms] OR “delirium”[Title/Abstract] OR “postoperative delirium”[Title/ Abstract] OR “postoperative confusion”[Title/Abstract] OR “emergence delirium”[Title/ Abstract] OR “emergence agitation”[Title/Abstract] OR “postoperative neurocognitive disorder”[Title/Abstract] OR “cogniti*”[Title/Abstract] OR “cognitive dysfunction”[Title/ Abstract] OR “cognitive decline”[Title/Abstract] OR “POD”[Title/Abstract] OR “POCD”[Title/ Abstract]) AND (“anesthesia, general”[MeSH Terms] OR “general anesthesia”[Title/ Abstract] OR ((“analysis”[MeSH Subheading] OR “analysis”[All Fields] OR “an”[All Fields]) AND “esthe”[Title/Abstract]))) AND ((adaptiveclinicaltrial[Filter] OR classicalarticle[Filter] OR clinicalstudy[Filter] OR clinicaltrial[Filter] OR controlledclinicaltrial[Filter] OR multicenterstudy[Filter] OR randomizedcontrolledtrial[Filter]) AND (humans[Filter])) | 36 | |
| EMBASE | #1 | ‘ketamine'/exp OR ketamine:ab,ti OR keta*:ab,ti | 91632 |
| #2 | ‘delirium'/exp OR delirium:ab,ti | 59929 | |
| #3 | ‘cognitive dysfunction'/exp OR ‘cognitive dysfunction':ab,ti OR ‘cognitive defect':ab,ti OR ‘cognitive disorder':ab,ti OR ‘cognitive decline':ab,ti OR pod:ab,ti OR pocd:ab,ti | 784745 | |
| #4 | ‘anesthesia'/exp OR an?esthesia:ab,ti OR anesthesia:ab,ti | 744701 | |
| #5 | ‘general anesthesia'/exp OR ‘general an?esthesia':ab,ti OR ‘general anesthesia':ab,ti | 181407 | |
| #6 | #2 OR #3 | 828377 | |
| #7 | #4 OR #5 | 744701 | |
| #8 | #1 AND #6 AND #7 | 1677 | |
| #9 | #8 AND ‘human'/de AND ‘Article'/it | 633 | |
| Cochrane Library | #1 | MeSH descriptor:[Ketamine]explode all trees | 3321 |
| #2 | (ketamine)ti,ab,kw OR(keta*)ti,ab,kw | 9169 | |
| #3 | #1 OR #2 | 9169 | |
| #4 | MeSH descriptor:[Delirium]explode all trees | 1781 | |
| #5 | (delirium):ti,ab,kw OR(Postoperative delirium)ti,ab,kw OR(Emergence delirium).ti,ab,kw | 7263 | |
| #6 | MeSH descriptor:[Cognitive Dysfunction]explode all trees | 4807 | |
| #7 | (cognitive dysfunction)ti,ab,kw | 10845 | |
| #8 | (Cognitive Impairment) ti,ab.kw OR (Mental Deteriorations):ti,ab,kw OR(Cognitive Decline):ti,ab,kw OR(Cognitive Deterioration):ti,ab,kw OR (Cognitive Disorder):ti,ab,kw | 47119 | |
| #9 | #4 or#5 or#6 or#7 or#8 | 57316 | |
| #10 | MeSH descriptor:[Anesthesia]explode all trees | 25244 | |
| #11 | (Anesthesia):ti,ab,kw OR(an?esthesia):ti,ab,kw OR (general anaesthesia):ti,ab,kw OR (General an?esthe):ti,ab,kw | 103373 | |
| #12 | #10 or #11 | 106899 | |
| #13 | #3 and #9 and #12 | 336 | |
| Web Of Science | #1 | ketamine (Topic) OR keta* (Topic) | 47388 |
| #2 | general anaesthesia (Topic) OR general an?esthe (Topic) OR an?esthe (Topic) | 21128 | |
| #3 | delirium (Topic) OR Postoperative delirium (Topic) OR Postoperative confusion (Topic) OR Emergence delirium (Topic) OR Emergence agitation (Topic) OR cognitive dysfunction (Topic) OR cognitive defect (Topic) OR cognitive disorder (Topic) OR cognitive decline (Topic) OR POD (Topic) OR POCD (Topic) | 404391 | |
| #4 | #3 AND #2 AND #1 | 49 | |
| #5 | #1 AND #2 AND #5 and English (Languages) and Article (Document Types) | 39 |
Supplementary Table 2.
List of Excluded Full-Text Articles with Reasons
| First Author (Year) | Title | Reason for Exclusion |
|---|---|---|
| Nct (2025) | Effect of Low-dose EsketaMine on dElirium in High-risk Elderly Patients uNdergoing elecTive Surgery (ELEMENT) | In progress |
| Chictr (2025) | Study on the effect of ketamine on postoperative cognitive dysfunction in elderly patients with colorectal cancer | In progress |
| Ctri (2025) | TO STUDY THE EFFECT OF PAIN USING KETAMINE IN PATIENTS UNDERGOING ELECTIVE SURGERIES | In progress |
| Chictr (2025) | The Impact of Continuous Infusion of Esketamine on Postoperative Cognitive Function in Elderly Malnourished Patients Undergoing Total Hip Arthroplasty and the Relationship Between Perioperative Gut Microbiota Characteristics and Postoperative Cognitive Dysfunction | In progress |
| Nct (2025) | Subanesthetic Esketamine for Hemodynamic Stability and Recovery in Elderly Thoracic Surgery Patients | In progress |
| Chictr (2024) | The relationship between blood concentration and clinical efficacy of ketamine in protecting postoperative cognitive function in elderly patients | In progress |
| IRCT N (2024) | The effect of prescribing intravenous Ketamine in the anesthesia of patients undergoing coronary artery bypass surgery | In progress |
| Chictr (2024) | The effect of different administration methods of ketamine on postoperative pain hypersensitivity | In progress |
| Chictr (2024) | Comparison of the effects of different administration methods of ketamine on the early postoperative recovery quality of patients with colorectal cancer surgery INTERVENTION: Group A:Induction with 0.8mg/kg esketamine administered intranasally in combination with endotracheal intubation for general anesthesia | In progress |
| Actrn (2024) | Ketamine when compared to usual care as induction drugs for tracheal intubation of critically ill patients: a prospective, blinded, parallel-group, randomised, feasibility trial | In progress |
| Chictr (2023) | Effects of S-ketamine on postoperative delirium and pain in patients after breast surgery under general anesthesia | In progress |
| Ctri (2023) | Effect of ketamine (study drug) on delirium after surgery | In progress |
| Chictr (2023) | Effect of intraoperative use of S-ketamine on postoperative pain in patients with anxiety after thoracoscopic pneumonectomy | In progress |
| Chictr (2023) | Effect of es-ketamine for postoperative analgesia on postoperative gastrointestinal dysfunction in elderly colorectal cancer: a prospective, single-center, randomized, controlled study | In progress |
| Chictr (2023) | Effects of S-ketamine on postoperative delirium in elderly patients undergoing video-assisted thoracoscopic pulmonary resection | In progress |
| Chictr (2023) | Effect of S-ketamine on Postoperative Delirium in Patients undergoing Total Hip or Knee Arthroplasty under Intraspinal Anesthesia: a Single-Center, Randomized, Double-Blind, Placebo-Controlled, Pragmatic Study | In progress |
| IRCT N (2023) | postoperative delirium in patients with colorectal cancer | In progress |
| Chictr (2022) | Effect of nocturnal S-ketamine for prevention of postoperative delirium in elderly patients after major surgery: a randomized controlled trial | In progress |
| Chictr (2022) | Dex-ketamine combined with dexmedetomidine on combined COPD pulmonary function preservation during one-lung ventilation in surgical patients of protect | In progress |
| Nct (2021) | Effect of S-ketamine Anesthetic on Inflammatory Response in Septic Patients Undergoing Abdominal Surgery | In progress |
| Chictr (2021) | The effect of s-ketamine on the emergence time of sevoflurane anesthesia: a randomized double-blind controlled trial | In progress |
| Chictr (2021) | Safety and efficacy evaluation of S(+)-ketamine for Postoperative acute pain in adults in perioperative settings: a multicenter, randomized, open-label, active controlled pragmatic clinical trial (SAFE-SK-A) | In progress |
| Nct (2020) | Ketamine Versus Magnesium Sulfate in the Time and Awakening Quality of General Anesthesia | In progress |
| EUCTR FR (2020) | Evaluation of ketamine on opiods consumption in traumatic patient | In progress |
| Chictr (2020) | Effect of low-dose esketamine in gynecological surgery on postoperative cognitive impairment | In progress |
| Actrn (2017) | Reduction Of Chronic Post-surgical Pain with Ketamine - ROCKet Trial | In progress |
| Hallikeri et al. (2024) | Effect of Low-dose Ketamine on Inflammatory Markers, Perioperative Analgesia, and Chronic Pain in Patients Undergoing Laparoscopic Inguinal Hernia Surgery: A Prospective, Randomized, Double-blind, Comparative Study | No relevant outcomes (POD/POND) reported |
| Bartoc, C. et al. (2006) | A randomized, double-blind, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients | No relevant outcomes (POD/POND) reported |
| Abitagaoglu, S. (2021) | Effect of ketamine on emergence agitation following septoplasty | No relevant outcomes (POD/POND) reported |
| Demir, C.Y. & Yuzkat, N. (2018) | Prevention of Emergence Agitation with Ketamine in Rhinoplasty | No relevant outcomes (POD/POND) reported |
| Barreto, C.O. et al. (2022) | Ketamine-Associated Intraoperative Electroencephalographic Signatures of Elderly Patients With and Without Preoperative Cognitive Impairment | No relevant outcomes (POD/POND) reported |
| Table | Single-Dose of Postoperative Ketamine for Postoperative Pain After Mastectomy: A Pilot Randomized Controlled Trial | No relevant outcomes (POD/POND) reported |
| Almajali, H.A. et al. (2023) | Intramuscular Ketamine Effect on Postnasal Surgery Agitation | No relevant outcomes (POD/POND) reported |
| Zhao, Z. et al. (2021) | The effect of low-dose ketamine on postoperative quality of recovery in patients undergoing breast cancer surgery | No relevant outcomes (POD/POND) reported |
| Köse, E.A. et al. (2012) | Efficacy of prophylactic ketamine in preventing postoperative shivering | No relevant outcomes (POD/POND) reported |
| Dualé, C. et al. (2009) | Perioperative ketamine does not prevent chronic pain after thoracotomy | No relevant outcomes (POD/POND) reported |
| Deng, G.F. et al. (2009) | Remifentanil combined with low-dose ketamine for postoperative analgesia of lower limb fracture | No relevant outcomes (POD/POND) reported |
| Katz, J. et al. (2004) | Pre-emptive analgesia using intravenous fentanyl plus low-dose ketamine for radical prostatectomy | No relevant outcomes (POD/POND) reported |
| NCT (2007) | Ketamine In Thoracic Surgery (KITS) Trial | No relevant outcomes (POD/POND) reported |
| NCT (2008) | Ketamine as an Anaesthetic Agent in Electroconvulsive Therapy (ECT) | No relevant outcomes (POD/POND) reported |
| NCT (2021) | Prophylactic Effects of Esketamine in Surgical Patients | No relevant outcomes (POD/POND) reported |
| Moll, V. et al. (2019) | Single-dose ketamine has long-lasting effects on EEG | No relevant outcomes (POD/POND) reported |
| CTRI (2021) | The effect of administration of a very minimal amount of ketamine on mood changes after surgery in spinal cord compression patients | No relevant outcomes (POD/POND) reported |
| NCT (2021) | Effect of Low-dose Esketamine on Postoperative Depression in Patients With Breast Cancer | No relevant outcomes (POD/POND) reported |
| Wang, M., et al (2024) | Effect of low-dose esketamine on postoperative cognitive function in elderly patients undergoing non-cardiac surgery | Not in english |
| Park, H.J (2004) | The Effect of Intravenous Ketamine on the Recovery from Total Intravenous Anesthesia with Propofol | Not in english |
| Ma, P.P. (2013) | Influence of dexmedetomidine and sub-anesthetic dose of ketamine on postoperative delirium in elderly orthopedic patients under total intravenous anesthesia | Not in english |
| Hu, S., et al. (2025) | Effect of low-dose esketamine on intraoperative electroencephalographic burst suppression under general anesthesia in elderly patients | Not in english |
| Wittwer, E., et al. (2023) | Impact of ketamine versus propofol for anesthetic induction on cognitive dysfunction, delirium, and acute kidney injury following cardiac surgery in elderly, high-risk patients. | Comparator not placebo or no intervention |
| Zhang, J., et al. (2023) | General anesthesia with S-ketamine improves the early recovery and cognitive function in patients undergoing modified radical mastectomy: a prospective randomized controlled trial. | Comparator not placebo or no intervention |
| Qi, Y., et al. (2024) | Effect of S-Ketamine on Postoperative Nausea and Vomiting in Patients Undergoing Video- Assisted Thoracic Surgery: A Randomized Controlled Trial. | Comparator not placebo or no intervention |
| Pretto, G., et al. (2014) | Clonidine for reduction of hemodynamic and psychological effects of S+ ketamine anesthesia for dressing changes in patients with major burns: An RCT. | Comparator not placebo or no intervention |
| Siripoonyothai, S. and W. Sindhvananda (2021) | Comparison of postoperative delirium within 24 hours between ketamine and propofol infusion during cardiopulmonary bypass machine: A randomized controlled trial | Comparator not placebo or no intervention |
| Ezz, H.A.A. (2017) | Preoperative intranasal dexmedetomidine versus intranasal ketamine for prevention of emergence agitation after sevoflurane in myringotomy patients: A randomized clinical trial. | Comparator not placebo or no intervention |
| Lin, L., et al. (2016) | Effect of ketamine combined with butorphanol on emergence agitation of postoperative patients with gastric cancer. | Comparator not placebo or no intervention |
| Zhang, X.D., et al. (2013) | Influence of sub-anesthetic dose of ketamine and dexmedetomidine on early postoperative cognitive function in elderly orthopedic patients under total intravenous anesthesia. | Comparator not placebo or no intervention |
| Chazan, S., et al. (2010) | Low-Dose Ketamine via Intravenous Patient-Controlled Analgesia Device after Various Transthoracic Procedures Improves Analgesia and Patient and Family Satisfaction | Comparator not placebo or no intervention |
| Liu, T., et al. (2023) | Effects of intraoperative administration of subanesthetic s-ketamine on emergence from sevoflurane anesthesia: a randomized double-blind placebo-controlled study. | Double-zero studies |
Inclusion criteria
The meta-analysis included studies as per the following criteria: 1. population: adult patients (≥18 years) scheduled for general anaesthesia and without a history of mental or neurological disorders; 2. intervention group: ketamine or esketamine administration; 3. control group: placebo administration or non-intervention; 4. outcome: POD or POND; 5—design: randomised controlled trials; 6. articles published in English.
Outcomes
This analysis aimed to assess whether the perioperative use of ketamine or esketamine influences the occurrence of POD and POND. These two outcomes were assessed and analysed separately to determine their respective associations with the interventions. The secondary outcomes included nausea and vomiting, psychological adverse effects including agitation, visual or auditory misperceptions, anxious states, and nightmare episodes, postoperative pain, duration of hospitalisation, and duration of extubation.
Data extraction and statistical methods
Study characteristics (author, country, year, group, sample size, intervention, and outcomes) were independently extracted into Excel by two reviewers. Any discrepancies were addressed through discussion or resolved by a third reviewer. Inter-rater agreement for the risk of bias ratings across the included studies was quantified using Cohen’s kappa statistic, where κ >0.75 indicates excellent agreement, 0.40–0.75 reflects moderate to good agreement, and κ <0.40 denotes poor agreement.
Statistical analyses were performed using RevMan 5.4 (Cochrane IMS, Oxford, United Kingdom) and STATA 17.0 (College Station, Texas 77845 USA). A random-effects model (DerSimonian–Laird) was used because clinical and methodological heterogeneity across studies was expected. We interpreted heterogeneity using the I² statistic, considering I² >50% as moderate and I² >75% as high. In cases of high heterogeneity, sensitivity testing and subgroup assessments were undertaken to identify contributors to variability. Dichotomous outcomes were summarised as odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). For continuous variables, since pain was reported with diverse scales across studies, standardised mean differences (SMDs) were derived; for the remaining variables, mean differences (MDs) were applied. Univariable meta-regression was performed using restricted maximum likelihood (REML) to assess whether the treatment effect was influenced by patient- or study-level predictors. Variables selected for analysis included ketamine dose (per 0.1 mg/kg), age (per year), and duration of surgery (minutes), based on completeness and consistency of reporting across studies. Outcome evaluation scores were excluded from regression modelling due to heterogeneity in tools used and reporting limitations [Supplementary Table 3]. A subgroup analysis was done based on the predictors found to be significant in the meta-regression, as well as the various outcome evaluation methods used across the included studies. For inherently dichotomous variables [ketamine type (ketamine vs. esketamine) and administration mode (bolus vs. continuous infusion)], pre-specified subgroup analyses to assess potential effect modification wad done. These categorical variables were analysed as originally defined in the included studies without post-hoc categorisation. We evaluated publication bias through the Egger test[14] and visual examination of funnel plots with contours.[15] To assess the size of the data and the benefits of treatment, trial sequential analysis (TSA) was employed.
Supplementary Table 3.
Baseline Characteristics of Predictor Variables for Meta-Regression
| Study | Dose (mg/kg) | Age (year) C/K | Surgery (min) C/K | Ketamine Type | Administration | Evaluation score |
|---|---|---|---|---|---|---|
| Avidan 2017 | 0.5, 1 | 70 (6.9)/70 (7.2), 70 (7.3) | / | ketamine | bolus injection | CAM |
| Farhadi 2025 | 50mg | 60.78 (11.33)/52.83 (12.12) | 220.24 (77.14)/234.83 (77.56) | ketamine | bolus injection | CAM-ICU |
| Gecaj 2010 | 0.5 | 29.2 (13.2)/32.0 (15.3) | / | ketamine | bolus injection | UNSURE |
| Ghazaly 2023 | 1 | 69.41 (4.7)/71.15 (3.9) | 95.40 (20.1)/69.01 (16.3) | ketamine | bolus injection | DOS |
| Hollinger 2021 | 1 | 74.8 (6.6)/73.4 (6.1) | 153.1 (83.4)/ 165.4 (78.8) | ketamine | bolus injection | DOS, Nu-DESC , ICDSC |
| Ju 2025 | 0.25 | 62.6 (8.32)/65.0 (7.47) | 255 (230-280) /245 (210-270) | esketamine | continuous injection | CAM-ICU, 3D-CAM |
| Li 2022 | 0.2 | 69.2 (5.4)/68.8 (3.6) | 109.1 (31.2) /105.2 (26.3) | esketamine | bolus injection | CAM |
| Ma 2024 | 0.2, 0.125/h, 0.5 | 68.6 (4.1)/69.0 (5.4) | 96.8 (13.0)/94.1 (15.2) | esketamine | continuous injection | D-CAM |
| Pereira 2023 | 0.5 | 46.6 | / | ketamine | bolus injection | Nu-DESC |
| Urban 2008 | 0.2 | 50.5 | 270 (54)/288 () | ketamine | continuous injection | CAM |
| Wang 2024 | 0.2 | 42.05 | 102.6 (32.9) /106.0 (31.9) | esketamine | bolus injection | UNSURE |
| Xiong 2024 | 0.25 | 51.5 (47.2- 56.0)/52.5 (44.0-57.0) | 240 (210- 324)/246 (210-300) | esketamine | bolus injection | CAM, CAM-ICU |
| Zhou 2023 | 0.3 | 47.82 | / | esketamine | bolus injection | UNSURE |
| Zhang 2024 | 0.2 | 71.00 (5.24)/70.84 (4.83) | / | esketamine | bolus injection | 3D-CAM |
| Hudetz 2009 | 0.5 | 64 (7)/67 (8) /68 (7) | 391 (69)/372 (77) | ketamine | bolus injection | a neuropsychological test battery |
| Hudetz 2009 | 0.5 | 60 (8)/68 (8) | 386 (68)/364 (79) | ketamine | bolus injection | ICDSC |
| Huang 2024 | 0.5 (Intraoperative) and 2 (postoperative) low-dose | 63.0 (62.0, 66.0)/63.0 (62.0, 66.0) | / | Esketamine | bolus injection + continuous injection | confusion assessment method |
| Kornilov 2024 | 0.25 | 69 (64.25-74.5)/67 (57.75-74) | 243 (210.5- 287)/244 (215.5-268.75) | ketamine | continuous injection | UNSURE |
| Lee 2015 | 0.5 | 68.38 (6.54)/68.32 (5.34) | 125.19 (70) /139.60 (67.85) | ketamine | bolus injection | MMSE, TMT, DST |
| Luo 2024 | 0.2, 0.5 | 55.86 (10.60)/55.95 (9.08), 55.20 (9.23) | 143.50 (43.88) /145.10 (57.94), 161.80 (53.39) | esketamine | bolus injection | CAM MMSE |
| Oriby 2023 | 0.3 | 70.63 (5.63) /72.80 (5.33) | 20.53 (5.64) /19.83 (6.44) | ketamine | continuous injection | incorporating tests |
CAM=Confusion Assessment Method; MMSE=Mini-Mental State Examination; Nu-DESC=Nursing Delirium Screening Scale; TMT=Trail Making Test; DST=Digit Span Test; DOS=Delirium Observation Screening Scale; ICDSC=Intensive Care Delirium Screening Checklist
The quality of the methodology in the selected studies was evaluated with the Cochrane Risk of Bias Tool.[16] The evidence quality regarding the outcomes was evaluated with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method.[17] Supplementary Table 2 presents a list of excluded full-text articles along with the reasons for their exclusion.
RESULTS
We identified 1044 records by searching databases such as Embase, Cochrane, PubMed, and Web of Science. After eliminating 157 duplicates, 887 records were left for further screening. Out of these, 799 records were excluded after reviewing titles and abstracts. The remaining 88 full-text articles were evaluated for eligibility.
After evaluating the full texts, 21 studies (Avidan 2017[10]; Farhadi[18]; Gecaj 2010[19]; Ghazaly 2023[20]; Hollinger 2021[21]; Huang[22]; Hudetz 2009[23]; Hudetz 2009[24]; Ju[25]; Kornilov 2024[26]; Lee 2015[27]; Li 2022[28]; Luo 2024[29]; Ma[30]; Oriby 2023[31]; Pereira 2023[32]; Urban 2008[33]; Wang 2024[34]; Xiong[35]; Zhou 2023[36]; Zhang[37]) with 2878 patients were included [Figure 1 and Table 1].
Table 1.
Characteristics of the included studies
Figure 2 displays the Cochrane Risk of Bias, with most studies showing low or unclear risk of bias. The inter-rater agreement for assessing the risk of bias in the included studies was substantial (κ = 0.63; 95% CI: 0.26, 1.00), reflecting strong consistency among reviewers. Residual discrepancies were resolved by consensus.
Figure 2.
Risk of bias summary
Primary outcome
Sixteen studies[10,18,19,20,21,22,24,25,28,30,32,33,34,35,36,37] reported the incidence of POD. The overall model effect indicated that ketamine administration was associated with a statistically significant reduction in the risk of POD compared to the control group [odds ratio (OR) = 0.62, 95% CI: 0.42, 0.92, I2 = 51%, P = 0.02] [Figure 3a]. Supplementary Figure 1 (1.1MB, tif) displays the funnel plots for publication bias, and the Egger test indicated no evidence of publication bias regarding the incidence of POD in this meta-analysis (P = 0.072). Besides, Supplementary Figure 2 (1.1MB, tif) shows the results of the sensitivity analysis, which confirmed the models’ credibility. Meanwhile, TSA results revealed that the cumulative Z-curve crossed both the conventional boundary for statistical significance (P = 0.05) and the trial sequential monitoring boundary for benefit prior to reaching the pre-defined RIS of 325 participants. This demonstrates that the evidence for a significant treatment effect is firmly established and conclusive. The results suggest that no further trials are needed to reach a definitive conclusion on the efficacy of ketamine for this outcome [Figure 3b].
Figure 3.
Meta-analysis and Trial Sequential Analysis of (es)ketamine on postoperative delirium. (a) Forest plot summarising the effect of perioperative (es)ketamine compared to control (placebo or no intervention) on the incidence of postoperative delirium. (b) Trial Sequential Analysis evaluating the robustness of the pooled results
The incidence of POND was reported in seven studies.[20,21,23,26,27,29,31] The overall effect of the model shows no significant difference between ketamine/esketamine group and control group (OR = 0.41, 95% CI: 0.14, 1.21, I2 = 74%, P = 0.11) [Figure 4a]. Supplementary Figure 3 (1.1MB, tif) presents the funnel plots for publication bias, and the Egger test indicated no evidence of bias concerning POND incidence in this meta-analysis (P = 0.906). Besides, Supplementary Figure 4 (1.1MB, tif) shows that the sensitivity analysis validated the reliability of the models. TSA revealed that the cumulative z-score did not exceed the RIS line, indicating that the studies lacked sufficient evidence to demonstrate a significant difference in POND. Additionally, the studies did not cross trial sequential or traditional boundaries, suggesting inadequate evidence to declare futility for POND [Figure 4b].
Figure 4.
Meta-analysis and Trial Sequential Analysis of (es)ketamine on postoperative neurocognitive dysfunction. (a) Forest plot showing the effect of perioperative (es)ketamine on the incidence of postoperative neurocognitive dysfunction. (b) Trial Sequential Analysis evaluating the robustness of the pooled results
Secondary outcome
No notable difference was found in nausea and vomiting (OR = 1.06, 95% CI: 0.87, 1.29, I2 = 0%, P = 0.55)[10,19,22,28,29,30,31,32,33,34,35,36,37] [Figure 5a], pain intensity (OR = -0.50, 95% CI: -1.14, 0.15, I2 = 95%, P = 0.13)[10,20,22,31,33,34,36] [Figure 5b], hospital stay duration (OR = 0.37, 95% CI: -0.38, 1.11, I2 = 87%, P = 0.33)[18,20,26,29,35] [Figure 5c], and extubation time (OR = -0.29, 95% CI: -2.81, 2.22, I2 = 83%, P = 0.82)[20,21,29,30,34] [Figure 5d].
Figure 5.
Forest plot of incidence of postoperative side effects. (a) Nausea/vomiting. (b) Pain evaluation. (c) Length of hospital stay. (d) Duration of extubation. (e) Psychological adverse events
Psychological side effects like anxiety, restlessness, discomfort, purposeless movement/agitation, hallucinations, and nightmares were more commonly reported with ketamine/esketamine (OR = 1.72, 95% CI: 1.24, 2.37, I2 = 0%, P = 0.001)[10,19,22,27,28,29,30,35,36] [Figure 5e], with consistent point estimates in sensitivity analyses (OR range: 1.24, 2.37) [Supplementary Figure 5 (1.1MB, tif) ]. The lower precision when excluding Avidan 2017 (95% CI: 0.86, 4.14) suggests that additional research is required to validate this connection.
Subgroup analysis for true dichotomies (ketamine type/administration) and evaluation score
Based on the structure of ketamine
For POD: A significant reduction was observed with S-ketamine (OR = 0.68, 95% CI: 0.47, 0.98, P = 0.04) but not with racemic ketamine (OR = 0.49, 95% CI: 0.21,1.17, P = 0.11). The difference between subgroups was not statistically significant (P = 0.50) [Figure 6a].
Figure 6.
Forest plot for subgroup analysis of outcome events according to structure of ketamine. (a) Postoperative delirium (POD). (b) Postoperative neurocognitive disorders (POND)
For POND: A strong, significant reduction was found for racemic ketamine (OR = 0.35, 95% CI: 0.20, 0.61, P = 0.0002), while a single trial of S-ketamine showed no significant effect (OR = 0.83, 95% CI: 0.33, 2.06, P = 0.68). The difference between subgroups did not reach statistical significance (P = 0.12) [Figure 6b].
Based on the administration mode of ketamine
For POD: A significant reduction was observed with bolus injection (OR = 0.53, 95% CI: 0.31, 0.91, P = 0.02) but not with continuous infusion (OR = 0.74, 95% CI: 0.43,1.28, P = 0.28). The difference between subgroups was not statistically significant (P = 0.40) [Figure 7a].
Figure 7.
Forest plot for subgroup analysis of outcome events according to administration mode of ketamine. (a) Postoperative delirium (POD). (b) Postoperative neurocognitive disorders (POND)
For POND: A significant reduction was found for continuous infusion (OR = 0.15, 95% CI: 0.05, 0.47, P = 0.001), while bolus injection showed no significant effect (OR = 0.53, 95% CI: 0.16, 1.77, P = 0.30). The difference between subgroups did not reach statistical significance (P = 0.14) [Figure 7b].
Based on the evaluation score
For POD: In the analysis of 3-level diagnostic scales, studies using DOS/Nu-DESC/ICDSC showed significant POD reduction (OR = 0.22, 95% CI: 0.05, 0.98, P = 0.05), while CAM-based studies showed a non-significant trend (OR = 0.76, 95% CI: 0.57, 1.01, P = 0.06). The subgroup using other diagnostic methods (OR = 1.12, 95% CI: 0.48, 2.63, P = 0.80) showed no beneficial effect. The differences between these three diagnostic approaches were not statistically significant (P = 0.18) [Figure 8a].
Figure 8.
Forest plot for subgroup analysis of outcome events according to evaluation score. (a) Postoperative delirium (POD). (b) Postoperative neurocognitive disorders (POND)
For POND: In the analysis of 2-level diagnostic criteria, alternative methods showed a significant protective effect (OR = 0.14, 95% CI: 0.06, 0.32, P < 0.00001), while MMSE-based assessment showed no significant benefit (OR = 0.89, 95% CI: 0.36, 2.16, P = 0.79). The difference between these two diagnostic approaches was statistically significant (P = 0.002) [Figure 8b].
Meta-regression
For POD, none of the predictors showed significant association with treatment effect: ketamine dose (β = -1.15, 95% CI: -3.51, 1.21, P = 0.34), age (β = 0.00, 95% CI: -0.05, 0.05, P = 0.93), or surgery duration (β = 0.00, 95% CI: -0.01, 0.01, P = 0.98) [Table 2].
Table 2.
Meta-Regression of Evaluation Methods on POD
| Predictor | β (95% CI) | P |
|---|---|---|
| Ketamine dose (0.1 mg/kg) | -1.15 (-3.51-1.21) | 0.34 |
| Age (per year) | 0.00 (-0.05-0.05) | 0.93 |
| Surgery duration (min) | 0.00 (-0.01-0.01) | 0.98 |
*Note: Random-effects meta-regression using REML. POD=postoperative delirium; CI=Confidence interval; P-value represents statistical significance of meta-regression coefficients
For POND, none of the predictors showed significant association with treatment effect: ketamine dose (β = 1.15, 95% CI: -2.63, 4.92, P = 0.55), age (β = -0.02, 95% CI: -0.21, 0.17, P = 0.84), or surgery duration (β = 0.00, 95% CI: -0.02, 0.01, P = 0.91) [Table 3].
Table 3.
Meta-Regression of Evaluation Methods on POND
| Predictor | β (95% CI) | P |
|---|---|---|
| Ketamine dose (0.1 mg/kg) | 1.15 (-2.63-4.92) | 0.55 |
| Age (per year) | -0.02 (-0.21-0.17) | 0.84 |
| Surgery duration (min) | 0.00 (-0.02-0.01) | 0.91 |
*Note: Random-effects meta-regression using REML. POND=postoperative neurocognitive dysfunction; CI=Confidence interval; P-value represents statistical significance of meta-regression coefficients
Additionally, Table 4 presents the risk of bias and evidence ranking for each outcome in this meta-analysis.
Table 4.
Summary of findings table of primary and secondary outcomes by GRADE
| keta compared to con for delirium and cognitive dysfunctions | ||||||
|---|---|---|---|---|---|---|
| Patient or population: patients with delirium and cognitive dysfunctions Settings: Intervention: keta Comparison: con | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) |
Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
|
| ||||||
| Con | Keta | |||||
| Delirium | Study population | OR 0.62 (0.42 to 0.92) | 2536 (16 studies) | ⨁⨁⨁⊝moderate1,2 | ||
| 180 per 1000 | 120 per 1000 (84 to 168) | |||||
| Moderate | ||||||
| 83 per 1000 | 53 per 1000 (37 to 77) | |||||
| POND | Study population | OR 0.41 (0.14 to 1.21) | 453 (7 studies) | ⨁⨁⊝⊝ low2,3 | ||
| 310 per 1000 | 156 per 1000 (59 to 353) | |||||
| Moderate | ||||||
| 214 per 1000 | 100 per 1000 (37 to 248) | |||||
| Nausea/vomiting | Study population | OR 1.06 (0.87 to 1.29) | 2349 (13 studies) | ⨁⨁⨁⊝ moderate2 | ||
| 337 per 1000 | 350 per 1000 (307 to 396) | |||||
| Moderate | ||||||
| 134 per 1000 | 141 per 1000 (119 to 166) | |||||
| Psychological adverse events | Study population | OR 172 (1.24 to 2.37) | 1699 (9 studies) | ⨁⨁⨁⨁ high | ||
| 94 per 1000 | 947 per 1000 (114 to 198) | |||||
| Moderate | ||||||
| 13 per 1000 | 694 per 1000 (16 to 30) | |||||
| Pain evaluation | The mean pain evaluation in the intervention groups was 0.5 standard deviations lower (1.48 lower to 0.05 higher) | 1189 (7 studies) | ⨁⊝⊝⊝ very low2,4 | SMD -0.58 (-1.48 to 0.33) | ||
| Length of stay | The mean length of stay in the intervention groups was 0.37 higher (0.39 lower to 1.11 higher) | 364 (5 studies) | ⨁⊝⊝⊝ very low2,5,6 | |||
| Duration of extubation | The mean duration of extubation in the intervention groups was 0.29 lower (4.45 lower to 2.22 higher) | 584 (5 studies) | ⨁⊝⊝⊝ very low2,5 | |||
*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio; GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1I2=51 inconsistency. 2Crossing the equivalent line, imprecision. 3I2=74 inconsistency. 4I2=95 inconsistency. 5I2=87 inconsistency. 6sample size < 400, imprecision
DISCUSSION
This systematic review and meta-analysis provide a comprehensive evaluation of (es)ketamine’s neuroprotective effects in the perioperative setting. Our findings demonstrate that (es)ketamine administration significantly reduces the risk of POD, while its preventive effect on POND remains inconclusive. These results offer valuable insights for clinical decision-making regarding (es)ketamine use while highlighting the need for a better understanding of its mechanisms and influencing factors.
Methodological considerations and evidence strength
It should be noted that some included studies had methodological limitations, particularly concerning blinding procedures and allocation concealment. However, sensitivity analyses confirmed the robustness of our primary conclusions. Compared to previous meta-analyses focusing solely on delirium, our simultaneous evaluation of both POD and POND provides more comprehensive evidence for understanding ketamine’s neuroprotective effects.
Pharmacological characteristics and clinical implications
The observed differential efficacy between ketamine isomers presents a compelling area for clinical consideration. Esketamine’s superior performance in preventing POD may be attributed to its approximately fourfold greater affinity for NMDA receptors compared to R-ketamine, resulting in more potent glutamate-mediated excitotoxicity prevention—a key mechanism in delirium pathogenesis. This enhanced receptor binding capability potentially allows esketamine to more effectively modulate the glutamatergic hyperactivity associated with acute neuroinflammation following surgical stress.[38]
Conversely, the apparent advantage of racemic ketamine in reducing POND risk suggests the involvement of neuroprotective mechanisms extending beyond NMDA receptor antagonism. The R-enantiomer, once considered pharmacologically inactive at NMDA receptors, appears to contribute meaningfully to cognitive protection through alternative pathways. Emerging evidence indicates R-ketamine may exert effects through adenosine A1 and A2A receptors, in addition to modulating monoaminergic systems, including dopamine and serotonin transmission.[39] These complementary mechanisms potentially support synaptic plasticity and neural repair processes relevant to long-term cognitive function, possibly explaining the differential efficacy profile between isomers for distinct neurocognitive outcomes.
The method of administration further refined (es)ketamine’s therapeutic effects. The efficacy of bolus administration for POD prevention aligns with the clinical need for rapid intervention in acute neuroinflammatory cascades. By achieving high initial synaptic concentrations quickly, bolus dosing may effectively interrupt early pathological processes leading to delirium. This approach appears particularly relevant in the context of surgical stress, where the immediate post-operative period represents a critical window for neuroinflammatory modulation.
In contrast, the demonstrated superiority of continuous infusion for cognitive protection suggests that sustained receptor modulation better supports the extended processes of neural repair and synaptic re-organisation. The stable drug levels maintained through continuous infusion may provide consistent protection against the prolonged neuroinflammatory responses and metabolic disturbances that contribute to longer-term cognitive decline. This temporal relationship between administration method and therapeutic outcome underscores the importance of matching pharmacokinetic profiles to pathophysiological timelines.
These findings carry significant implications for clinical practice. Rather than employing a uniform approach to ketamine administration, clinicians might consider tailoring their strategy based on specific neurocognitive risks.
Safety profile and risk–benefit assessment
The side effects of ketamine were also analysed in our meta-analysis, and no significant differences were observed in the incidences of post-operative nausea and vomiting, pain level, hospital stay duration, or extubation time between the (es)ketamine administration group and the control group. These results align with those found in the previous meta-analysis.[12] However, our analysis suggests a consistent trend towards increased psychological adverse effects with ketamine or esketamine (OR range: 1.24, 2.37 across sensitivity analyses), though the statistical significance of this finding depends on the inclusion of the largest trial (Avidan 2017[10]). This signal warrants caution in clinical use and further investigation with standardised psychiatric assessments; meanwhile, Viderman, D.[40] reported in their meta-analysis also found that hallucinations were more commonly reported in the ketamine group, especially when ketamine was used for inducing rapid and sustaining antidepressant effects in patients with major depressive disorder and bipolar depression; hallucination also cannot be neglected.[41] Beck K[42] found that ketamine was linked to psychological adverse effects in healthy volunteers and recommended avoiding bolus doses in therapeutic ketamine use to reduce the risk of inducing transient positive (psychotic) symptoms. These results highlight the importance of caution when using ketamine and esketamine, especially in vulnerable populations.
This study has some limitations, such as the inclusion of studies with small sample sizes; the results of these studies are not entirely reliable; second, studies included in this meta-analysis exhibit significant heterogeneity regarding the types of surgery, the evaluation score, and evaluation timing on the diagnosis of POD and POND. Third, there is lack of baseline of some studies, like duration of anaesthesia and evaluation score. Fourth, inter-rater reliability was quantified only for risk-of-bias ratings of the included studies; we did not estimate agreement during the study selection stage, which may be considered in future reviews. Finally, most included studies were institutionally supported. No trial reported direct industry funding; however, several studies did not disclose funding sources, which may introduce unrecognised bias.
CONCLUSION
This study confirms ketamine’s efficacy in reducing postoperative delirium risk while emphasising the importance of isomer selection and administration protocol design. In clinical practice, careful balance between its neuroprotective benefits and potential psychiatric risks is essential, requiring implementation of individualised medication strategies. These findings provide important evidence for the rational use of ketamine in perioperative neuroprotection.
Study data availability
De-identified data may be requested with reasonable justification from the authors (email to the corresponding author) and shall be shared upon request.
Presentation at conferences/CMEs and abstract publication
Not applicable.
Disclosure of use of artificial intelligence (AI)-assistive or generative tools
The authors confirm that no AI tools or language models (LLMs) were used in the writing or editing of the manuscript, and no images were manipulated using AI.
Declaration of use of permitted tools
The scales, scores, figures, and tables used in this study are entirely original, created by the authors, and are not copyrighted. No permissions are required.
Authors contributions
QQG, ZHD and XYW provided the idea for the meta-analysis. QQG, NS, TW and BL contributed to the data extraction. NS and BL computed the pooled outcomes. QQG wrote the article. CSL revised the article.
Supplementary material
This article has supplementary material and can be accessed at this link. Supplementary Material at http://links.lww.com/IJOA/A57.
Conflicts of interest
There are no conflicts of interest.
Funnel plot for publication bias of postoperative delirium
Sensitivity analysis for the association with postoperative delirium
Funnel plot for publication bias of postoperative delirium
Sensitivity analysis for the association with postoperative neurocognitive dysfunction
Sensitivity analysis for psychological side effects
Acknowledgements
The authors have no acknowledgements to make.
Funding Statement
Nil.
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Associated Data
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Supplementary Materials
Funnel plot for publication bias of postoperative delirium
Sensitivity analysis for the association with postoperative delirium
Funnel plot for publication bias of postoperative delirium
Sensitivity analysis for the association with postoperative neurocognitive dysfunction
Sensitivity analysis for psychological side effects