Effects of perioperative continuous infusion of esketamine on postoperative delirium in older adults undergoing elective noncardiac surgery: a systematic review and meta-analysis of randomized controlled trials

Postoperative delirium (POD) is a common neurological complication in older adults following anesthesia and is associated with poor postoperative outcomes. Esketamine has been investigated for prevention of postoperative neurocognitive dysfunction such as POD. However, the effect of continuous perioperative esketamine infusion on POD in older adults undergoing non-cardiac surgery remains inconclusive. The purpose of this systematic review and meta-analysis is to explore the impact of continuous infusion of esketamine on POD in older adults undergoing elective non-cardiac surgery. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception to March 21, 2026, for eligible randomized controlled trials evaluating the effect of esketamine on postoperative delirium in older adults undergoing elective noncardiac surgery. PROSPERO registration number: CRD420261347602. The primary outcome was the overall incidence of POD within the first three days after surgery. The RevMan 5.4 software was used for data analysis. Meta-analysis was conducted to calculate risk ratio (RR) or mean difference (MD) with 95% CI, and Cochrane’s tool (RoB 2) was used to evaluate the risk of bias. We performed sensitivity analyses and subgroup analyses to assess the robustness of the results. Six randomized controlled trials involving 1096 patients were included. Compared with placebo, the esketamine group had a lower overall incidence of POD within the first three postoperative days (RR = 0.49, 95% CI [0.27, 0.88], P = 0.02); however, this reduction was not robust to the exclusion of one influential trial. In older adults undergoing non‑cardiac surgery, continuous infusion of esketamine significantly reduced VAS scores on the first postoperative day (MD = -0.32, 95% CI [-0.47, -0.16], P < 0.0001). Nevertheless, continuous esketamine infusion did not significantly reduce the incidence of POD on day one (RR = 0.71, 95% CI [0.31, 1.65], P = 0.43), day two (RR = 0.80, 95% CI [0.34, 1.90], P = 0.61), or day three (RR = 0.34, 95% CI [0.09, 1.31], P = 0.12) postoperatively. It also did not reduce the incidence of PONV (RR = 0.93, 95% CI [0.68, 1.26], P = 0.62), nor did it reduce VAS scores on day two (MD = -0.05, 95% CI [-0.16, 0.07], P = 0.42) or day three (MD = -0.16, 95% CI [-0.38, 0.07], P = 0.17). In older adults undergoing elective noncardiac surgery, continuous infusion of esketamine may have a beneficial effect on reducing POD. However, only three trials were included in the analysis of the total incidence of POD within three days after surgery, the moderate certainty and the loss of significance in the sensitivity analyses should not be underestimated, the apparent reduction was not robust to exclusion of one influential trial and should be considered hypothesis-generating, any overinterpretation of esketamine’s therapeutic effects should be avoided.