Dose-dependent effects of dexmedetomidine on POCD: mediated by perioperative neuroimmune modulation in cholecystectomy patients

Background Postoperative cognitive dysfunction (POCD) remains a major clinical challenge, and perioperative neuroinflammation has been recognized as a key contributing factor. Although our previous trial confirmed that dexmedetomidine (DEX) reduces the incidence of POCD, the precise immunomodulatory mechanism underlying its neuroprotective effect and the corresponding dose–response relationship remain to be fully elucidated. This study was designed to test the hypothesis that DEX provides dose-dependent neuroprotection by alleviating systemic inflammation and the subsequent neuroimmune responses. Methods A retrospective cohort study nested within a prospective cohort was performed based on a previous prospective cohort. Patients undergoing elective laparoscopic cholecystectomy were allocated into four groups according to DEX dose: control group (C: 0 μg/kg), low-dose group (D1: 0.4 μg/kg), medium-dose group (D2: 0.6 μg/kg), and high-dose group (D3: 0.8 μg/kg). POCD cases and non-POCD controls were matched at a 1:2 ratio for age, sex, educational level, and operative duration. Serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), S100 calcium-binding protein β (S100β), neuron-specific enolase (NSE), and brain-derived neurotrophic factor (BDNF) were measured preoperatively, 24 h postoperatively (T1), and 48 h postoperatively (T2) using enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression and bootstrap mediation analysis were conducted. Results Among the initial cohort of 361 patients, 24 POCD cases were matched with 48 control subjects. There were no significant differences in preoperative biomarker levels between groups. At 24 and 48 h postoperatively, serum levels of IL-6, TNF-α, NSE, and S100β were significantly reduced in a DEX dose-dependent manner ( p < 0.01), whereas BDNF levels were significantly elevated ( p < 0.01). The high-dose DEX group showed the most significant changes, with biomarker levels significantly different from those in the control and low-dose groups ( p < 0.05). Multivariable regression confirmed that high-dose DEX was an independent protective factor against POCD (OR: 0.82 per 0.1 μg/kg; 95% CI: 0.74–0.91; p < 0.001). Mediation analysis revealed that the protective effect of DEX against POCD was mediated by inhibiting early postoperative IL-6 release. Conclusion This study demonstrates that DEX significantly reduces neuroinflammation and the incidence of POCD in a dose-dependent manner after laparoscopic cholecystectomy. The neuroprotective effect of DEX is mainly mediated by suppressing IL-6 release, indicating that inhibition of this key proinflammatory cytokine represents a critical mechanism underlying the beneficial effects of DEX. A DEX dose of 0.6 μg/kg or higher is recommended for optimal neuroprotection.