Postoperative delirium (POD) remains a significant complication following cardiopulmonary bypass (CPB) surgery, particularly in middle-aged patients who constitute the majority of this surgical population. While intranasal insulin (INI) has shown neuroprotective potential in aging cohorts, its efficacy in younger surgical patients and its underlying mechanisms remain under explored. This study investigates whether INI mitigates POD through sleep-wake cycle modulation.

It is a single-center prospective randomized, double-blinded controlled trial from March 4, 2024 to October 18, 2024. 76 middle-aged patients (45–65 years) undergoing elective CPB surgery were randomized to receive INI (20 IU) or placebo preoperatively and on postoperative days 1–2. The primary outcome was POD incidence (CAM-ICU criteria). Secondary outcomes included Mini-Mental State Examination (MMSE) scores, actigraphy-derived sleep metrics (sleep efficiency [SE], total sleep time [TST]). Analyses followed intention-to-treat principles.

INI significantly reduced POD incidence (17.1 % vs. 38.9 %, RR = 3.45, p = 0.037) and improved cognitive recovery, as evidenced by higher MMSE scores at postoperative day 5 with a difference of 1.71 (95 % CI, 0.19 to 3.23; p = 0.027). Sleep analysis revealed robust improvements in the INI group: SE increased by 21.3 % (78.2 ± 12.1 % vs. 64.5 ± 15.3 %, p = 0.031), and TST extended by 27.1 % (6.1 ± 1.2h vs. 4.8 ± 1.5h, p = 0.033) on postoperative day 1. No significant differences were observed in hospital length of stay (p = 0.893), highlighting the specificity of INI’s sleep-mediated effects.

This trial demonstrates that INI stabilizes postoperative sleep architecture, leading to reduced POD incidence and enhanced cognitive recovery in middle-aged CPB patients. These findings position INI as a targeted intervention for perioperative neurocognitive protection, particularly in populations vulnerable to circadian disruption.