BACKGROUND: Postoperative delirium is the most common complication in older patients and is associated with surgery-induced inflammation. Although inflammation plays a key role in delirium, the potential benefits of a comprehensive anti-inflammatory approach to managing perioperative systemic inflammation remain underexplored. This study evaluated whether a perioperative anti-inflammatory bundle strategy, combining dexmedetomidine, glucocorticoids, ulinastatin, and nonsteroidal anti-inflammatory drugs, reduces the risk of postoperative delirium in older patients undergoing hip fracture surgery. METHODS: This dual-center, double-blind, placebo-controlled, parallel-group, pilot study was conducted from August 2023 to January 2024 at two tertiary university hospitals. A total of 132 patients aged ≥ 65 years with an American Society of Anesthesiologists physical status of 2 or 3 scheduled for elective hip fracture surgery were screened and randomized to receive either an anti-inflammatory drug bundle or a placebo. The primary outcome was postoperative delirium, identified within the first three postoperative days. Postoperative blood inflammatory markers and acute pain were measured for mediation analysis. RESULTS: Of the 132 patients randomized, 123 (93%) completed the trial (mean age, 82 years
75% women). The prevalence of postoperative delirium was significantly lower in the anti-inflammatory bundle group (15%, 9/62) compared to the placebo group (44%, 27/61) (risk difference, - 30 percentage points [95% CI, - 45 to - 15]
relative risk [RR], 0.33 [95% CI, 0.17 to 0.64]
P = 0.001). No major adverse events were reported in either group. The postoperative CRP level in the anti-inflammatory bundle group was significantly lower (predicted mean difference: - 29.4 [95% CI: - 46.5, - 12.2] mg·L CONCLUSIONS: This study demonstrates that a perioperative anti-inflammatory bundle significantly reduces the prevalence of postoperative delirium in older patients undergoing hip fracture surgery, without major side effects. Systemic inflammation mediates the protective effect of the intervention. These findings provide preliminary evidence supporting the anti-inflammatory bundle strategy, paving the way for large-scale multicenter trials to optimize postoperative delirium prevention strategies. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (ChiCTR2300074303) by Ayixia Nawan on August 3, 2023, prior to patient enrollment.