Association of a routine dexmedetomidine-remifentanil anesthetic strategy with POD3 morning cortisol change in older patients undergoing radical esophagectomy

Background Older patients undergoing radical esophagectomy may experience marked postoperative endocrine stress, inflammation, pain, and short-term cognitive decline. We evaluated whether a routine anesthetic strategy combining dexmedetomidine with remifentanil was associated with a smaller POD3 serum cortisol increase than remifentanil- or dexmedetomidine-based strategies alone. Methods This single-center retrospective cohort screened 426 consecutive patients aged ≥65 years who underwent elective radical esophagectomy from January 2023 to December 2025. Of these, 347 had verifiable pathway-based POD3 biomarker and POD7 MoCA data after predefined clinical, laboratory, and follow-up exclusions. The primary analysis used a prespecified balanced common-support analytic cohort drawn from the naturally occurring REM (continuous remifentanil without dexmedetomidine), DEX (dexmedetomidine with non-remifentanil opioid analgesia and without continuous remifentanil), and Dex-REM (both infusions) exposure strata (100 patients each). The primary endpoint was morning serum cortisol change from preoperative day 1 to postoperative day 3 (POD3). Results POD7 screening-based cognitive decline occurred in 51 patients in the balanced common-support cohort. Mean cortisol change was +164.0 nmol/L in REM, + 126.0 nmol/L in DEX, and +86.0 nmol/L in Dex-REM. After adjustment, Dex-REM was associated with lower cortisol change than REM (adjusted mean difference, -78.4 nmol/L; 95% CI, -103.2 to -53.6; p<0.001) and DEX (-39.6 nmol/L; 95% CI, -64.1 to -15.1; p=0.002). Dex-REM also showed lower 24-h VAS AUC than REM (adjusted mean difference, -5.8 point-hours; 95% CI, -9.3 to -2.3; FDR q=0.006), while POD7 MoCA-decline risk was numerically lower but imprecise (12.0% vs. 22.0%; adjusted risk ratio, 0.52; 95% CI, 0.26 to 1.05; p=0.071). Conclusions The real-world Dex-REM anesthetic pathway was associated with a smaller POD3 morning serum cortisol increase. This pathway-level association does not establish an agent-specific effect, pharmacologic synergy, or attenuation of the complete surgical-stress trajectory. Clinical and screening-based cognitive secondary outcomes were exploratory and require prospective multicenter confirmation before causal or neuroprotective conclusions are drawn.