Intravenous Acetaminophen for Postoperative Delirium in Older Patients Recovering From Major Noncardiac Surgery

Intravenous Acetaminophen for Postoperative Delirium in Older Patients Recovering From Major Noncardiac Surgery: a Randomised Controlled Study

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Delirium in Old Age
• Intervention / Treatment: Drug: Acetaminophen; Drug: Saline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 1930
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: LIQUN YANG, MD; Phone Number: 15921969001; Email: lqyang72721@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: intravenous aceteminophen group; 50 ml contains 500 mg of acetaminophen will be administered for the first dose when the surgical suture begin at the end of surgery and thereafter repeated every 6 hours for the following 7 doses using automatic intravenous pump (4g acetaminophen diluted with 0.9% saline to 400 ml), and every bolus of 50 ml will be finished within 10 minutes.	Drug: Acetaminophen; Acetaminophen, which has similarly effects with NSAIDs in terms of inhibition of cyclooxygenase COX1, COX2 and COX3, is widely used as adjuvant for perioperative multimodal analgesia.
Placebo Comparator: saline placebo group; 50 ml 0.9% saline will be administered for the first dose placebo when the surgical suture begin at the end of surgery and thereafter repeated every 6 hours for the following 7 doses using automatic intravenous pump (400ml 0.9% saline without acetaminophen), and every bolus of 50 ml will be finished within 10 minutes.	Drug: Saline; Saline, a kind of crystalloid widely used in clinical treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of postoperative delirium	Delirium will be assessed by the trained investigators twice daily, from 8-10 AM and from 5-7 PM, starting from postoperative day 1 using 3-minute Confusion Assessment Method (3D-CAM) or CAM-ICU for intubated patients. Immediately before assessing delirium, sedation or agitation was assessed using Richmond Agitation-Sedation Scale (RASS). If the patient was too deeply sedated or unarousable (RASS -4 or -5), delirium assessment was aborted and the patient was recorded as comatose.	Participants will be followed up during the first 5 postoperative days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain scores	Pain scores will be assessed using numerical rating scale (NRS) once daily, with 0 meaning "no pain" and 10 meaning "the worst pain imaginable".	Participants will be followed up during the first 5 postoperative days.
Total opioid consumption	Amount of intravenous and/or oral opioid consumption for analgesia will be recorded.	Participants will be followed up during the first 5 postoperative days.
Delirium duration	Time to onset of delirium.	Participants will be followed up during the first 5 postoperative days.
Delirium type	Patients with delirium were classified into three motoric subtypes. Hyperactive delirium was defined when RASS was consistently positive (+1 to +4); hypoactive delirium was defined when RASS was consistently neutral or negative (-3 to 0); and mixed delirium was defined when some RASS scores were positive (+1 to +4) and some RASS scores were neutral or negative (-3 to 0).	Participants will be followed up during the first 5 postoperative days.
Delirium severity	Delirium rating scale 98 revised (DRS-R-98) will be used to evaluate severity of delirium. DRS-R-98 consists of 16 items, including 13 items to assess severity of delirium and 3 diagnostic items. The total severity score range from zero (best) to 39 (worst).	Participants will be followed up during the first 5 postoperative days.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of days in ICU and hospital after surgery	Length of stay in ICU and hospital after surgery will be collected from electronic medical records.	one month
All cause mortality		one month
Cognitive function	Cognitive function will be evaluated with Mini-Mental State Examination (MMSE) score that ranges from zero (worst) to 30 (best).	Cognitive function will be evaluated on the fifth day after operation.

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Investigators: Principal Investigator: LIQUN YANG, MD, Anesthesiology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine Shanghai, China

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: October 20, 2024
• First Submitted That Met QC Criteria: October 20, 2024
• First Posted (Actual): October 22, 2024

Study Record Updates

• Last Update Posted (Actual): April 4, 2025
• Last Update Submitted That Met QC Criteria: April 1, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: acetaminophen; elderly patient; postoperative delirium
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Postoperative Complications; Pathologic Processes; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Emergence Delirium; Delirium; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Antipyretics; Acetaminophen
• Other Study ID Numbers: LY-2023-239

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No