Effect of ketamine/esketamine on postoperative delirium and cognitive dysfunctions: A systematic review and meta-analysis of randomised trials

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.

Figure 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) flowchart

Figure 2

Risk of bias summary

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

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

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

Figure 6

Forest plot for subgroup analysis of outcome events according to structure of ketamine. (a) Postoperative delirium (POD). (b) Postoperative neurocognitive disorders (POND)

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)

Figure 8

Forest plot for subgroup analysis of outcome events according to evaluation score. (a) Postoperative delirium (POD). (b) Postoperative neurocognitive disorders (POND)