Effects of intranasal long-acting insulin pretreatment on postoperative delirium and the NLRP3/caspase-1/IL-1β pathway in older patients with esophageal cancer

BACKGROUND: Insulin exhibits neuroprotective and anti-inflammatory properties. Preoperative intranasal insulin preconditioning is a potential strategy to prevent postoperative delirium (POD), but prior studies mainly used rapid-acting formulations. This investigation focused on intranasal long-acting insulin, which ensures sustained central nervous system exposure, in elderly patients undergoing radical esophagectomy. We assessed its impact on POD incidence and the NLRP3/caspase-1/IL-1β pathway. METHODS: Sixty older patients scheduled for elective radical esophagectomy were randomized into two groups. The intervention group (n = 30) received a single intranasal dose of long-acting insulin (30 U) 1 day preoperatively, while the control group (n = 30) received an equivalent volume of physiological saline. POD was evaluated using the Confusion Assessment Method for the ICU on postoperative days 1, 2, and 3. Peripheral blood samples were collected before surgery and postoperatively to measure IL-1β concentrations and NLRP3/caspase-1 mRNA expression in mononuclear cells. RESULTS: Compared to controls, long-acting insulin pretreatment significantly reduced POD incidence (16.7% vs. 46.7%, P = 0.012) and suppressed the postoperative rise in peripheral IL-1β levels (P < 0.05). In addition, NLRP3 and caspase-1 mRNA expression were notably lower in the insulin group during the postoperative period (P < 0.05). Correlation analysis revealed that in the control group, increases in NLRP3 mRNA, caspase-1 mRNA, and IL-1β levels on postoperative day 1 were significantly associated with the development of POD (P < 0.05). In contrast, no such significant correlations were found in the insulin intervention group. CONCLUSION: Preoperative intranasal long-acting insulin effectively decreases POD incidence in the first 3 days after radical esophagectomy in older patients. This protective effect may be associated with the observed sustained downregulation of the peripheral NLRP3/caspase-1/IL-1β signaling pathway, which consequently weakens the link between early postoperative inflammation and delirium. This emphasizes the advantage of long-acting formulations for continuous neuroprotection during the critical postoperative phase.