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| ID | Type | Description | Link |
|---|---|---|---|
| R01AG065554 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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Our objective is to find an effective prophylactic intervention by evaluating IV acetaminophen's impact in reducing the frequency of postoperative delirium, one of the most common and detrimental complications of cardiac surgery in older adults.
This project will study the impact of scheduled administration of IV acetaminophen on the incidence, duration, and severity of postoperative delirium and other important hospital outcomes. Additionally, this trial will evaluate the effects of IV acetaminophen on longer-term postoperative cognitive dysfunction and functional status and develop a biorepository of perioperative samples as a future resource to probe the mechanisms of postoperative delirium.
The investigators propose three specific aims by conducting a randomized, triple-blind clinical trial that enrolls 900 patients 60 years of age or older undergoing cardiac surgery. Through this trial, the investigators will determine the effect of IV acetaminophen on;
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IV Acetaminophen | Experimental | 1 g IV acetaminophen every 6 hours for 48 hours during the first 2 days postoperatively |
|
| Placebo | Placebo Comparator | Volume of the placebo (saline) will match that of IV acetaminophen at 100ml 0.9% NaCl |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IV acetaminophen | Drug | use of IV tylenol for pain |
|
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| Measure | Description | Time Frame |
|---|---|---|
| Incidence of postoperative delirium | Occurrence of delirium on any postoperative day, as assessed using the CAM, 3D CAM, CAM Only, or CAM-ICU daily until hospital discharge. | Participants will be followed for the duration of the hospital stay, an average of 5 days |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Charted Delirium | Charted Delirium will be used as a key secondary outcome in addition to the CAM diagnosis. Incidence in patient's chart for diagnoses synonymous with delirium or a change to the patient's baseline mental status as indicated by trigger words associated with a predictive value for delirium | Participants will be followed for the duration of the hospital stay, an average of 5 days |
| Measure | Description | Time Frame |
|---|---|---|
| Need for additional liver function tests | Clinical request for liver function test monitoring and reported ALT and AST values will be reported as safety outcomes | Participants will be followed for the duration of the hospital stay, an average of 5 days |
| Discontinuation of study drug |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Balachundhar Subramaniam, MD, MPH | Beth Israel Deaconess Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35233 | United States | ||
| University of California Irvine |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21474660 | Background | Rudolph JL, Marcantonio ER. Review articles: postoperative delirium: acute change with long-term implications. Anesth Analg. 2011 May;112(5):1202-11. doi: 10.1213/ANE.0b013e3182147f6d. Epub 2011 Apr 7. | |
| 23992774 | Background | Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet. 2014 Mar 8;383(9920):911-22. doi: 10.1016/S0140-6736(13)60688-1. Epub 2013 Aug 28. |
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The research pharmacists at each institution will prepare the placebo and will dispense the study drug according to treatment allocation. Treatment allocation will otherwise remain concealed from all others involved in the conduct and analysis of the trial, including those performing statistical analysis. Study participants will remain blinded throughout.
| Placebo | Other | Volume of the placebo (saline) will match that of IV acetaminophen at 100ml 0.9% NaCl |
|
| Duration of delirium | Total number of in-hospital postoperative days in which delirium is present | Participants will be followed for the duration of the hospital stay, an average of 6 days, and at 1 month, 6 month and 1- year following the date of surgery |
| Severity of delirium | Delirium severity is evaluated both as the peak (highest) and sum CAM-S score over all hospital days | Participants will be followed for the duration of the hospital stay, an average of 5 days |
| Time to onset of delirium | Measured in days | Participants will be followed for the duration of the hospital stay, an average of 5 days |
| Additional postoperative analgesic requirements | Amount of opioid (IV morphine or hydromorphone) and oral analgesics required for pain control, reported as overall morphine equivalents. Total Morphine Equivalent is calculated as the sum of (fentanyl dose × 2.4) + (hydromorphone dose × 4) + morphine dose + (oxycodone dose × 1.5). | First 48 hours postoperatively |
| Worst daily pain scores with exertion (deep breathing and cough) | Pain scores will be collected three times daily using a numeric rating scale (0, no pain, to 10, worst possible pain). | Participants will be followed for the duration of the hospital stay, an average of 5 days |
| Length of stay in the Intensive Care Unit (ICU) | Defined by the number of days admitted in the ICU prior to transfer to the general cardiac surgical floor | Measured in days admitted in the ICU, an average of 2 days |
| Worst daily pain scores at rest | Pain scores will be collected three times daily using a numeric rating scale (0, no pain, to 10, worst possible pain). | Participants will be followed for the duration of the hospital stay, an average of 5 days |
| Length of hospital stay | Defined by the number of days admitted in the hospital following the completion of surgery. | Measured in days admitted in the hospital, an average of 6 days |
| Trajectory of cognitive function over time | Neurocognition will be reported using the Montreal Cognitive Assessment (MoCA) score that ranges from zero (worst possible score) to 30 (best). At one, six, and twelve months postoperatively a telephonic MoCA will be assessed over the phone. The t-MoCA scores range from zero [worst] to 22 [best]. A hierarchical linear regression model will be used to characterize the trajectory of t-MoCA scores over time. | Participants will be followed for the duration of the hospital stay, an average of 6 days, and at 1 month, 6 month and 1- year following the date of surgery |
| Trajectory of physical function over time. | Physical function will be assessed using the Medical Outcomes Study Short Form 12 questionnaire (SF-12) physical composite score at one, six, and twelve months postoperatively assessed over the phone. A hierarchical linear regression model will be used to characterize the trajectory of SF-12 scores over time. | Participants will be followed at 1 month, 6 month and 1- year following the date of surgery |
| Trajectory of functional outcomes over time | Functional status (self care) will be assessed using the FuncAQ and FRAIL scale at one, six, and twelve months postoperatively assessed over the phone. A hierarchical linear regression model will be used to characterize the trajectory of FuncAQ and FRAIL scores over time. | Participants will be followed at 1 month, 6 month and 1- year following the date of surgery |
| Trajectory of chronic pain over time | Chronic sternal pain will be assessed using the Numerical Pain Rating Scale (NPRS) at six and twelve months postoperatively assessed over the phone. | Participants will be followed at 6 month and 1- year following the date of surgery |
Rates of clinician discontinuation of study drug. |
| 48 hours postoperatively |
| Irvine |
| California |
| 92697 |
| United States |
| University of California Los Angeles | Los Angeles | California | 90095 | United States |
| Yale University/Yale New Haven Hospital | New Haven | Connecticut | 06510 | United States |
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| Columbia University Irving Medical Center | New York | New York | 10032 | United States |
| Albert Einstein College of Medicine- Montefiore | The Bronx | New York | 10467 | United States |
| University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | 15213 | United States |
| 20373345 | Background | Gottesman RF, Grega MA, Bailey MM, Pham LD, Zeger SL, Baumgartner WA, Selnes OA, McKhann GM. Delirium after coronary artery bypass graft surgery and late mortality. Ann Neurol. 2010 Mar;67(3):338-44. doi: 10.1002/ana.21899. |
| 22762316 | Background | Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012 Jul 5;367(1):30-9. doi: 10.1056/NEJMoa1112923. |
| 22206727 | Background | van den Boogaard M, Kox M, Quinn KL, van Achterberg T, van der Hoeven JG, Schoonhoven L, Pickkers P. Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients. Crit Care. 2011;15(6):R297. doi: 10.1186/cc10598. Epub 2011 Dec 29. |
| 17872676 | Background | Gallagher R. Opioid-induced neurotoxicity. Can Fam Physician. 2007 Mar;53(3):426-7. No abstract available. |
| 24350194 | Background | O'Neal JB. The utility of intravenous acetaminophen in the perioperative period. Front Public Health. 2013 Aug 6;1:25. doi: 10.3389/fpubh.2013.00025. |
| 30778597 | Background | Subramaniam B, Shankar P, Shaefi S, Mueller A, O'Gara B, Banner-Goodspeed V, Gallagher J, Gasangwa D, Patxot M, Packiasabapathy S, Mathur P, Eikermann M, Talmor D, Marcantonio ER. Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial. JAMA. 2019 Feb 19;321(7):686-696. doi: 10.1001/jama.2019.0234. |
| 24733193 | Background | Inouye SK, Kosar CM, Tommet D, Schmitt EM, Puelle MR, Saczynski JS, Marcantonio ER, Jones RN. The CAM-S: development and validation of a new scoring system for delirium severity in 2 cohorts. Ann Intern Med. 2014 Apr 15;160(8):526-533. doi: 10.7326/M13-1927. |
| 41980267 | Derived | Behera A, Ramachandran RV, Hussain Z, Ihalainen RJ, Orui H, Peck J, Ananthakrishnan A, Mathur P, Muehlschlegel JD, Pittet JF, Bardia A, Schonberger RB, Kveraga K, Subramaniam B. The Association of Preoperative Cognitive Dysfunction to Common Intraoperative Electroencephalographic Parameters and Cerebral Hypoxia During Cardiac Surgery. Anesth Analg. 2026 May 1;142(5):964-974. doi: 10.1213/ANE.0000000000007724. Epub 2026 Apr 14. |
| 39446661 | Derived | Ramachandran RV, Behera A, Hussain Z, Peck J, Ananthakrishanan A, Mathur P, Banner-Goodspeed V, Muehlschlegel JD, Pittet JF, Bardia A, Schonberger R, Marcantonio ER, Kveraga K, Subramaniam B. Incidence of Concurrent Cerebral Desaturation and Electroencephalographic Burst Suppression in Cardiac Surgery Patients. Anesth Analg. 2025 May 1;140(5):1086-1092. doi: 10.1213/ANE.0000000000007209. |
| 38883767 | Derived | Ramachandran RV, Ananthakrishnan A, Orui H, Kveraga K, Subramaniam B. The Influence of Preoperative Physical Activity on Intraoperative Brain Function in Cardiac Surgical patients. Res Sq [Preprint]. 2024 Jun 7:rs.3.rs-4427122. doi: 10.21203/rs.3.rs-4427122/v1. |
| 33692183 | Derived | Khera T, Mathur PA, Banner-Goodspeed VM, Narayanan S, Mcgourty M, Kelly L, Palihnich K, Novack L, Davis R, Talmor D, Marcantonio ER, Subramaniam B. Scheduled Prophylactic 6-Hourly IV AcetaminopheN to Prevent Postoperative Delirium in Older CaRdiac SurgicAl Patients (PANDORA): protocol for a multicentre randomised controlled trial. BMJ Open. 2021 Mar 10;11(3):e044346. doi: 10.1136/bmjopen-2020-044346. |
| ID | Term |
|---|---|
| D003693 | Delirium |
| D003324 | Coronary Artery Disease |
| ID | Term |
|---|---|
| D003221 | Confusion |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D003327 | Coronary Disease |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
| D000588 | Amines |
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