Objective To evaluate the clinical efficacy and safety of a perioperative lung protective protocol specifically adapted for minimally invasive esophagectomy (MIE) in high-altitude hypoxic environments, thereby providing evidence-based guidelines for MIE in high-altitude regions. Methods This retrospective study analyzed the clinical data of 69 patients (a study group) who underwent combined thoracoscopic and laparoscopic esophagectomy with a high-altitude-specific lung protective strategy at Qinghai Provincial People’s Hospital from March 2022 to November 2024. A historical control group comprised 67 patients (control group) who underwent the same surgery without this protocol from March 2020 to February 2022. Propensity score matching was employed to balance baseline covariates. The study group received a comprehensive lung protective protocol encompassing preoperative pulmonary function assessment and optimization, individualized lung protective ventilation and meticulous anesthesia management during surgery, and standardized enhanced recovery after surgery. Primary outcome measures included surgical duration, intraoperative blood loss, oxygenation index during one-lung ventilation, incidence of postoperative complications, pulmonary function recovery trajectory, and long-term disease-free survival. Results After propensity score matching, 58 patients [44 males, 14 females; mean age (62.3±8.5) years] were included in the study group, and 55 patients [41 males, 14 females; mean age (61.8±9.2) years] in the control group. Surgical duration was significantly shorter in the study group [ (289.7±26.1) min vs. (312.6±30.3) min, P<0.001], and intraoperative blood loss was significantly lower [ (187.0±12.6) mL vs. (215.4±18.5) mL, P<0.001]. During one-lung ventilation, the PaO₂/FiO₂ ratio was significantly higher in the study group [ (285.6±45.2) mm Hg] compared to the control group [ (210.3±39.7) mm Hg, P<0.001]. The incidence of overall postoperative complications (15.5% vs. 32.7%, P=0.031) and pulmonary complications (6.9% vs. 21.8%, P=0.012) was significantly lower in the study group. At 7 days postoperatively, forced vital capacity and forced expiratory volume in 1 second recovered to 85.6% and 83.2% of preoperative levels, respectively, and approached preoperative levels by 6 months. The 12-month disease-free survival rate was 91.4% in the study group, which was superior to 83.6% in the control group (log-rank χ²=4.521, P=0.033). Conclusion The perioperative lung protective protocol, specifically designed for high-altitude hypoxic environments, is safe and effective. It significantly improves intraoperative oxygenation, reduces postoperative complications, accelerates pulmonary function recovery, and does not compromise oncological radicality. This protocol offers a standardized practice guideline for minimally invasive esophagectomy in regions with altitudes ranging from 2 260 to 3 200 meters.

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