Esketamine/dexmedetomidine-based opioid-free anesthesia modulates perioperative neuro-inflammatory biomarkers and enhances postoperative cognitive recovery in patients undergoing total laparoscopic hysterectomy

BACKGROUND: Surgery-triggered neuro-inflammation is a recognized driver of early postoperative cognitive dysfunction (POCD). Whether an opioid-free anesthesia (OFA) regimen combining esketamine and dexmedetomidine can blunt this response during total laparoscopic hysterectomy (TLH) remains uncertain. METHODS: This pre-planned secondary analysis draws on the same prospective TLH cohort whose clinical outcomes were reported previously (total N.=114). Women received esketamine/dexmedetomidine-based OFA (N.=59) or conventional opioid-based anesthesia (OBA; N.=55). Serum interleukin-6 (IL-6), neuron-specific enolase (NSE) and S100β were sampled at baseline, 1 h after incision, skin closure and 24 h. The primary endpoint was the 0-24 h area-under-the-curve (AUC) for IL-6 and NSE. Secondary analyses examined the relation between biomarker surges and POCD, defined as a ≥2-point fall in Montreal Cognitive Assessment score on postoperative day 3. RESULTS: Baseline variables were comparable. OFA reduced IL-6 AUC by 32% (median 795 vs. 1172 pg·h/mL; difference -377, 95% CI -452 to -305; q<0.001) and NSE AUC by 28% (220 vs. 306 µg·h/L; difference -86, 95% CI -112 to -58; q<0.001). At 24 h, mean IL-6 was 34±5 vs. 54±5 pg/mL and NSE 16.6±1.8 vs. 22.5±2.0 µg/L (both q<0.001). S100β differences were non-significant (q>0.10). POCD occurred in 20/59 (34%) OFA versus 31/55 (56%) OBA patients (relative risk 0.60, 95% CI 0.40-0.90; q=0.022). Mediation analysis showed IL-6 and NSE reductions explained 42% and 35% of this association, respectively. CONCLUSIONS: Esketamine/dexmedetomidine-based OFA markedly attenuates peri-operative IL-6 and NSE surges and is associated with a lower incidence of early POCD after TLH. These mechanistic findings warrant confirmation in a definitive randomized trial.