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Qingqing Huang,1,2 Xiao Wu,1,3 Ni Lei,1 Xin Chen,4 Sixun Yu,4 Xuemei Dai,1 Qin Shi,1,3 Gu Gong,1,* Hai-Feng Shu2,4,* 1Department of Anesthesiology, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 2College of Medicine, Southwest Jiaotong University, Chengdu, People’s Republic of China; 3Department of Anesthesiology, North Sichuan Medical College, Nanchong, People’s Republic of China; 4Department of Neurosurgery, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gu Gong, Department of Anesthesiology, The General Hospital of Western Theater Command, 270 Tianhui Road, Rongdu Avenue, Jinniu District, Chengdu, Sichuan, 610083, People’s Republic of China, Tel +8617360137572, Fax +86 028571770, Email gonggu68@163.comBackground: Postoperative delirium (POD) is a common neurological complication associated with valve replacement. Preoperative sleep disturbance is a risk factor for POD development, and nasal insulin modulates the sleep-wake cycle. This study investigated the beneficial effects of intranasal insulin pretreatment on preoperative sleep quality and reducing POD in patients undergoing valve replacement for rheumatic heart disease.Patients and Methods: This prospective, single-center, randomized controlled trial (RCT) included 76 adult patients aged 18– 65 years undergoing valve surgery with cardiopulmonary bypass who were randomly allocated to receive intranasal insulin or normal saline interventions two days before surgery. POD incidence was on postoperative days 1 (T3), 2 (T4), and 3 (T5). Before the first intervention (T0), 1 d before surgery (T1), and before anesthesia on the day of surgery (T2), sleep quality was assessed and serum cortisol concentrations were measured. At T1 and T2, sleep quality related indicators monitored by sleep monitoring watches from the previous night were recorded.Results: Compared with the normal saline group, 3 days after surgery, the insulin group showed a significantly reduced incidence of POD; significantly increased deep sleep, REM sleep, deep sleep continuity, and total sleep quality scores at T1 and T2; and significantly reduced serum cortisol concentration, PSQI scale, light sleep ratio, and wakefulness at T1 and T2.Conclusion: The administration of 20 U of intranasal insulin twice daily, from 2 days preoperatively until 10 minutes preanesthesia on the day of surgery, can improved preoperative sleep quality significantly and reduced POD incidence in patients with rheumatic heart disease undergoing valve replacement.Clinical Trial Registration: This study was registered with the Chinese Clinical Trial Registry (www.chictr.org.cn, with the unique identifier ChiCTR2100048515; July 9, 2021).Keywords: postoperative delirium, rheumatic heart disease, valve replacement, preoperative sleep quality, intranasal insulin