Transcutaneous Auricular Vagus Nerve Stimulation for Prevention of Postoperative Delirium in Older Adults Undergoing Total Knee Arthroplasty: A Multicenter Randomized Controlled Trial Protocol

Xincheng Liao,1,* Tongtong Zhang,2,* Jingxuan Zhang,3 Jialin Yang,3 Junyu Li,3 Lei Chen,4 Bin Qian4 1Department of Anesthesiology, The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China; 2Department of Anesthesiology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 3Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 4Department of Anesthesiology, People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junyu Li, Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, 134 Dongjie Street, Fuzhou, 350001, People’s Republic of China, Email [email protected] Lei Chen, Department of Anesthesiology, People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, 602 Bayiqi Road, Fuzhou, 350005, People’s Republic of China, Email [email protected]: Postoperative delirium affects up to 65% of elderly surgical patients, leading to increased mortality and cognitive decline. Current prevention strategies face implementation barriers, necessitating accessible, non-pharmacological interventions. Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive neuromodulation technique, reduces neuroinflammation and regulates autonomic function, offering potential for delirium prevention. This multicenter, randomized, double-blind, sham-controlled trial evaluates whether taVNS can prevent postoperative delirium in older adults undergoing total knee arthroplasty.Patients and Methods: We will enroll 1448 patients aged 65– 80 years undergoing elective knee replacement under general anesthesia at four hospitals in Fujian Province, China. Participants will be randomized equally to receive active taVNS (25 Hz, 250 μs targeting the cymba conchae and tragus) or sham stimulation (25 Hz, 250 μs targeting the earlobe and antihelix). Both groups will receive interventions at two timepoints: the afternoon before surgery and the morning of surgery before anesthesia. The primary outcome is delirium incidence within 72 hours postoperatively, assessed using the Confusion Assessment Method. Secondary outcomes include inflammatory markers (interleukin-1, interleukin-6, tumor necrosis factor-alpha), autonomic function (heart rate variability), cognitive trajectories, psychological status, sleep quality, pain scores, and recovery parameters. Safety monitoring will follow standardized adverse event reporting guidelines.Conclusion: If effective, taVNS could provide a practical, non-invasive method to reduce delirium incidence in elderly patients undergoing knee replacement, potentially improving postoperative outcomes and reducing healthcare costs.Keywords: neuromodulation, cognitive complications, orthopedic surgery, inflammation, autonomic regulation