Remimazolam and Postoperative Delirium in Patients with Hyperlipidemia: A Retrospective Cohort Study with Target Trial Emulation Analysis

Purpose: Hyperlipidemia increases postoperative delirium (POD) risk via neuroinflammation; however, effective pharmacological interventions to mitigate POD in this population remain limited. Remimazolam has been reported to reduce perioperative stress and modulate neuroinflammatory responses. We investigated the effect of remimazolam on POD incidence in surgical patients with hyperlipidemia. Patients and Methods: In this retrospective cohort study, we enrolled 1123 patients with hyperlipidemia who underwent surgery under general anesthesia with or without remimazolam at a single institution. The primary outcome measure was POD incidence within 3 days postoperatively. To assess the impact of remimazolam on POD, a target trial emulation framework was applied to enhance control of confounders and strengthen causal inference. We additionally investigated the dose–response relationship between remimazolam exposure and POD. Results: POD incidence in the remimazolam group was 13.8%, which was 7.2% lower than that in the non-remimazolam group (P< 0.01). Additionally, delirium severity (median score: 9 vs 10, P< 0.01) and cognitive impairment incidence at 6 months postoperatively (4.4% vs 8.3%, P< 0.05) were lower in the remimazolam group. The target trial emulation further confirmed the protective effects of remimazolam on POD (adjusted risk difference [aRD]: − 5.3%, P=0.016), delirium severity (aRD: − 2.238, P< 0.001), and cognitive dysfunction incidence at 6 months postoperatively (aRD: − 3.97%, P=0.019). Dose–response analysis showed a significant reduction in POD incidence when the total remimazolam dose was ≥ 10.29 mg or the maintenance rate was ≥ 0.51 mg kg − 1 h − 1 . Conclusion: Remimazolam significantly reduced POD incidence and severity in patients with hyperlipidemia and improved cognitive function at 6 months postoperatively. However, prospective studies are needed to confirm these findings. Keywords: remimazolam, postoperative delirium, hyperlipidemia, target trial emulation, dose–response, neuroprotection