PANDORA: Delirium Prevention After Cardiac Surgery Using IV Acetaminophen to Prevent Postoperative Delirium in Older Cardiac Surgical Patients

Coronary Artery Disease Clinical Trial

— PANDORA  

Official title:

PANDORA: Scheduled Prophylactic 6-hourly Intravenous Acetaminophen to Prevent Postoperative Delirium in Older Cardiac Surgical Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04093219
• Other study ID #: 2019-P-000758
• Secondary ID: R01AG065554
• Status: Recruiting
• Phase: Phase 3
• Start date: August 11, 2020
• Est. completion date: October 2024

Study information

• Verified date: September 2023
• Source: Beth Israel Deaconess Medical Center
• Contact: Balachundhar Subramaniam, MD, MPH
• Phone: 617-754-2721
• Email: bsubrama[@]bidmc.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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;

1. the incidence, duration, and severity of postoperative delirium,

2. the use of opioids and other rescue analgesics in the first 48 postoperative hours, daily pain scores at rest and exertion, and length of stay in the Intensive Care Unit and overall hospital length of stay

3. longer-term (one, six, 12 months) cognitive, physical, and self-care functional recovery after surgery.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 900
• Est. completion date: October 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

1. = 60 years of age

2. Patients undergoing cardiac surgery [coronary artery bypass grafting (CABG) with or without valve, isolated valve surgery] requiring cardiopulmonary bypass

Exclusion Criteria:

1. Pre-operative left ventricular ejection fraction (LVEF) < than 30%

2. Emergent procedures

3. Isolated aortic surgery

4. Liver dysfunction (liver enzymes > 3 times the baseline, all patients will have a baseline liver function test information), history and exam suggestive of jaundice

5. Hypersensitivity to the study drugs

6. Active (in the past year) history of alcohol abuse (=5 drinks per day for men or = 4 drinks per day for women)

7. Any history of alcohol withdrawal or delirium tremens

8. Delirium at baseline

9. Non-English speaking

10. Prisoners

11. Physician Refusal

12. COVID-19 Positive, symptomatic

13. Co-enrollment with non-approved interventional trial

Related Conditions & MeSH terms

• Coronary Artery Disease
• Delirium
• Delirium in Old Age
• Emergence Delirium

Intervention

Drug:
• IV acetaminophen
use of IV tylenol for pain

Other:
• Placebo
Volume of the placebo (saline) will match that of IV acetaminophen at 100ml 0.9% NaCl

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Albert Einstein College of Medicine- Montefiore	Bronx	New York
United States	University of California Irvine	Irvine	California
United States	University of California Los Angeles	Los Angeles	California
United States	Yale University/Yale New Haven Hospital	New Haven	Connecticut
United States	Columbia University Irving Medical Center	New York	New York
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

References & Publications (9)

Gallagher R. Opioid-induced neurotoxicity. Can Fam Physician. 2007 Mar;53(3):426-7. No abstract available. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: JAMA. 2019 Jul 16;322(3):276. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Discontinuation of study drug	Rates of clinician discontinuation of study drug.	48 hours postoperatively
Primary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Time to onset of delirium	Measured in days	Participants will be followed for the duration of the hospital stay, an average of 5 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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