Dou_2026_PLoS.One_21_e0346523

BACKGROUND: Postoperative delirium (POD) is an acute disturbance of attention and awareness in older adults undergoing surgery. It is associated with prolonged hospital stay and increased morbidity and mortality. Recent studies suggested that neostigmine, an acetylcholinesterase inhibitor used to reverse neuromuscular blockade, may reduce POD risk. We aim to evaluate whether neuromuscular blockade reversal with neostigmine/glycopyrrolate reduces POD compared with sugammadex. METHODS: This single-center, triple-masked, randomized, controlled superiority trial will enroll 320 older adults scheduled for major non-cardiac and non-neurosurgical surgery. Patients will be randomized (1:1) to receive either neostigmine 40 microg/kg plus glycopyrrolate 8 microg/kg or sugammadex 2 mg/kg for neuromuscular blockade reversal at the end of surgery. The primary outcome is the incidence of POD within postoperative 7 days or until discharge, assessed twice daily with the validated Chinese version of 3-min Diagnostic Interview for Confusion Assessment Method. Secondary outcomes include days with POD and proportion of hospital days affected; POD severity assessed using the highest score and the sum scores of Confusion Assessment Method Severity; and 30-day cognitive function assessed using the 10-item Telephone Interview of Cognitive Status. DISCUSSION: Results of this study will determine whether neostigmine/glycopyrrolate offers a simple, low-cost strategy to prevent POD and will inform evidence-based selection of neuromuscular reversal agents in older surgical patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2400093158).