Postoperative delirium (POD) is a common and distressing complication after thoracic surgery. S-ketamine has neuroprotective properties as a dissociative anesthetic. Emerging literature has indicated that S-ketamine can reduce cognitive impairment in depressed patients. However, the role of S-ketamine in preventing postoperative delirium is still unknown. Therefore, this study aims to evaluate the effect of intraoperatively prophylactic S-ketamine compared to dexmedetomidine on the incidence of postoperative delirium in elderly patients undergoing non-cardiac thoracic surgery.

Postoperative delirium (POD) is a common and distressing complication after thoracic surgery. S-ketamine has neuroprotective properties as a dissociative anesthetic. Emerging literature has indicated that S-ketamine can reduce cognitive impairment in depressed patients. However, the role of S-ketamine in preventing postoperative delirium is still unknown. Therefore, this study aims to evaluate the effect of intraoperatively prophylactic S-ketamine compared to dexmedetomidine on the incidence of postoperative delirium in elderly patients undergoing non-cardiac thoracic surgery. This will be a randomized, double-blinded, placebo-and positive-controlled, non-inferiority trial that enrolls patients aged 60 or over undergoing thoracic surgery. The primary outcome will be the incidence of postoperative delirium within 4 days after surgery and assessed using a 3-minute Diagnostic Confusion Assessment Method (3D-CAM) twice a day. Secondary outcomes included postoperative delirium severity, motroic subtypes, episodes, and duration. Additional prespecified outcomes were emergence delirium; time to delirium onset; time to extubation; postoperative pain intensity at rest and during cough at 4, 24, and 48 h postoperatively; postoperative opioid consumption and rescue analgesia requirements; subjective sleep quality within the initial 4 days after surgery; postoperative length of hospital stay; and cognitive function and mortality at 30- and 90-day follow-up.

Inclusion Criteria:

• Aged 60 years or over
• Both genders
• American anesthesiologist association (ASA) physical status classificationⅠ-Ⅲ
• Diagnosed with lung, esophagus, or mediastinum disorders
• Undergoing open or video-assisted thoracic surgery including lobectomy, segmentectomy, pneumonectomy, esophagectomy, or resection of mediastinal tumor
• General anesthesia with one-lung ventilation (OLV) or bronchial blocker.
• An expected operation duration of 2 hours or more.
• Voluntarily participate in the trial and sign informed consent.

Exclusion Criteria:

• History of psychiatric disease or severe depression
• History of glaucoma or hyperthyroidism
• History of severe hepatic (Child-Pugh grade C) or renal (requirement for renal replacement therapy) disorder.
• Body mass index (BMI) greater 35 kg/m2
• Dementia history or baseline Mini-Mental State Examination (MMSE) score less than 23
• Severe audio-visual impairments, or inability to speak Mandarin or Cantonese precluding communication
• Sinus bradycardia (heart rate < 50 beats per minutes, bpm), sick sinus or Wolff- Parkinson-White syndromes, or Ⅱ degree atrioventricular block and over
• Poorly controlled hypertension (resting systolic blood pressure over 180 mm Hg, or resting diastolic blood pressure over 100 mm Hg)
• Allergic to dexmedetomidine, S-ketamine or any of their formulation ingredients;
• Taking sedatives, antidepressants or glucocorticoids
• Alcohol or drug abuser
• Life expectancy of less than 2 months due to extensive tumor metastasis.

The labeled "Study medication" syringes (50ml) in identical appearance, and the infusion regimen formulated by the pharmacist based on the randomization, will be distributed to the attending anesthesiologists responsible for anesthetic management as soon as the research team informs the central pharmacy about the patient heading for surgery. To avoid anesthesiologists' speculation about the randomized assignment, the study drugs will be infused at a similar rate. The anesthesiologists, the patients, the investigators responsible for follow-up, and the statisticians are all masked to randomized allocations until the final statistical analyses are completed. The blindness will be unmasked by the primary investigator in a medical emergency including deterioration of patient's condition intraoperatively or adverse events postoperatively.