A systematic review and meta-analysis on ketamine use and postoperative delirium in older patients undergoing spine or orthopedic surgery

Abstract Purpose Postoperative delirium (POD) is common in older adults following major surgery. Ketamine has opioid-sparing properties and potential neuroprotective effects, yet whether intraoperative ketamine reduces the incidence of postoperative delirium remains uncertain. This systematic review aims to determine whether ketamine use is associated with a lower incidence of POD in older patients undergoing spine or orthopedic surgery. Methods We conducted comprehensive searches in PubMed, Web of Science, EMBASE, Cochrane CENTRAL, and CINAHL Complete from inception to June 26, 2025. Both keywords and index terms (Mesh/EMTREE) were used to develop broad and sensitive searches tailored to each database to retrieve all relevant articles. EMBASE results were limited to articles and articles in press. Eligible studies included patients aged ≥ 60 years undergoing surgery with intraoperative ketamine administration and reporting POD as an outcome. Two reviewers independently screened studies, extracted data, assessed risk of bias, and performed quality appraisal using RoB 2 for randomized controlled trials (RCTs) and ROBINS-I for observational studies. Random-effects meta-analyses were performed to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results We included 24 studies in the final analysis and five specifically studied patients undergoing spine or orthopedic surgery. The effect of ketamine on POD showed an OR of 1.50 (95% CI 0.38–5.91, P = 0.56 random effects model) for the two RCTs. Including the additional three cohort studies was marginally associated with an increase in the occurrence of postoperative delirium, OR 1.30 (95% CI 1.01–1.67), P = 0.0425. However, the imprecision of the studies was deemed to be serious due to small sample sizes, and only two were RCTs. Conclusions This systematic review and meta-analysis did not find a statistically significant association between intraoperative ketamine use and POD in older patients undergoing spine or orthopedic surgery in the RCTs. However, because of the small number of available studies together with imprecision, this conclusion should only be considered as preliminary. Larger, high-quality randomized trials are needed to determine whether ketamine influences POD risk and to assess different dosing strategies for their effects on postoperative cognitive outcomes in older adults.