Non-opioid pharmacologic interventions for the prevention of delirium after cardiac surgery in adults: systematic review and network meta analysis

Abstract Background Postoperative delirium (POD) is a more common complication of cognitive dysfunction in adults following cardiac surgery, which leads to higher mortality, poor prognosis and increased hospital resource utilization. Given the established correlation between opioid administration and an increased risk of POD, there is an imperative need to compare the effects of non-opioid pharmacologic interventions on delirium occurrence in adults undergoing cardiac surgery. Materials and methods We searched the following databases up to 12 January 2026: MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials, www.controlled-trials.com., and reference lists of retrieved studies. Results A total of 39 RCTs with 8019 participants (mean age, 65.1 years; 33.1% female) compared the incidence of POD were included. A network meta-analysis demonstrated that risperidone (risk ratio [RR], 0.37; 95% confidence interval [CI], 0.14 to 0.93), esketamine (RR, 0.47; 95% CI, 0.22 to 0.98), and dexmedetomidine (RR, 0.67; 95% CI, 0.44 to 0.98) might decrease the incidence of POD compared with placebo. Acetaminophen may reduce the duration of POD (mean difference [MD], –1.0; 95% CI, –1.7 to –0.27), whereas melatonin (MD, 1.0; 95% CI, 0.26 to 1.7), clonidine (MD, 2.2; 95% CI, 1.4 to 2.9), and midazolam (MD, 3.3; 95% CI, 0.70 to 5.7) may increase the duration of POD. Conclusion Based on low-certainty evidence, esketamine may lower the incidence of POD in adult cardiac surgery patients, while it is uncertain whether risperidone and dexmedetomidine prevent POD due to very low-certainty evidence. Acetaminophen may reduce the duration of POD, whereas melatonin, clonidine, and midazolam may be associated with an extended duration of POD.