Investigators propose this multi-center randomised controlled study to test the preventive effect of intravenouse acetaminophen in delirium over 5 postoperative days among older patients recovering from major non-cardiac surgery.

Delirium is a common complication in elderly patients after major surgeries and can lead to poor outcomes such as neurocognitive decline. Acetaminophen is a widely used adjuvant for perioperative multimodal analgesia. It can effectively alleviate postoperative pain, promote opioid-sparing and exert anti-neuroinflammatory response, showing strong potential for preventing postoperative delirium. There is evidence that intravenous acetaminophen reduces delirium in older patients following cardiac surgery, but its effectiveness is inconclusive among non-cardiac surgical patients. Investigators propose this multi-center, randomized, placebo-controlled, parallel-group trial in patients aged >65 years old scheduled for non-cardiac major surgery with general anesthesia expected to last at least 2 h. A total of 1930 elderly patients will be enrolled and randomized at 1:1 ratio to acetaminophen or saline placebo groups, stratified by age, education level, and trial site with random-sized blocking. Acetaminophen or saline will be given when the surgical suture begin at the end of surgery and thereafter a total of 7 doses within 48h after surgery. The primary outcome will be the incidence of delirium, assessed twice daily, through the five postoperative days. Secondary outcomes will include pain scores with movement, opioid use within the first 48 postoperative hours, severity of delirium, ICU and hospital lengths of stay.

Inclusion Criteria:

1. Age ≥ 65 years.
2. Scheduled for non-cardiac major surgery with general anesthesia that is expected to last more than 2h.
3. ASA Physical Status I-III.
4. Weight >50 kg.
5. Written informed consent.

Exclusion Criteria:

1. Pre-existing neuropsychiatric diseases (Alzheimer's disease, Schizophrenia, Parkinson's Disease, Seizures, etc.).
2. Pre-existing cognitive impairment (MMSE<18).
3. Preoperative delirium.
4. Severe circulatory instability (preoperative left ventricular ejection fraction less than 30%, unstable angina, severe coronary artery disease, sick sinus syndrome, etc.).
5. Contraindication to the acetaminophen use, including serum creatinine > 177µmol/L or aminotransferses > 3 times the upper limit of normal.
6. Alcohol or drug abuse within a year before surgery.
7. Inability to communicate because of severe visual/auditory dysfunction or language barrier.

Study protocol and statistical analysis plan will be shared in peer-reviewed academic journals. Other IPD will be made available from the principal investigator upon reasonable request.