Ketamine and Esketamine for the Prevention of Delirium in Surgical Patients: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background Delirium is a common and serious complication in critically ill and surgical patients, associated with increased morbidity, prolonged hospitalization, and long-term cognitive impairment. Ketamine and esketamine have been proposed as potential protective agents due to their anti-inflammatory, analgesic, and NMDA receptor-blocking properties. Methods We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the use of ketamine or esketamine for the prevention of delirium in adult surgical patients, some of whom required postoperative Intensive Care Unit (ICU) level care. The primary outcome was the incidence of delirium. Secondary outcomes included pain assessment, opioid consumption, ICU and hospital length of stay, mortality, and neuropsychiatric adverse events. Risk of bias was assessed using the Cochrane RoB 2.0 tool. This review was registered in PROSPERO (CRD420251061137) and conducted according to PRISMA 2020 guidelines. Results Eight RCTs involving a total of 1645 patients were included. Ketamine or esketamine significantly reduced the incidence of delirium compared to placebo (odds ratio [OR] = 0. 50; 95% CI: 0.28-0.91; p = .02). Subgroup analysis revealed a significant benefit in older adults (mean age > 60 years), but not in younger populations. Neuropsychiatric adverse events—such as hallucinations and nightmares—were more frequent in the ketamine group (OR = 1.60; 95% CI: 1.15-2.21; p = .005). No consistent effects were observed on pain scores, opioid consumption, or length of stay. Conclusion Ketamine and esketamine may reduce the incidence of delirium in surgical patients, particularly in older adults, although this benefit must be weighed against a higher incidence of neuropsychiatric symptoms.