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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease; Delirium; Delirium in Old Age
• Intervention / Treatment: Drug: IV acetaminophen; Other: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 900
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Balachundhar Subramaniam, MD, MPH; Phone Number: 617-754-2721; Email: bsubrama@bidmc.harvard.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • University of Alabama at Birmingham
      • Contact: Jean-Francois Pittet, MD; Phone Number: 205-996-4755; Email: jpittet@uabmc.edu
  • California
    • Irvine, California, United States, 92697
      • Not yet recruiting
      • University of California Irvine
      • Contact: Jay Shen, MD; Email: jayys@hs.uci.edu
      • Contact: Bryan Robles; Email: bsrobles@hs.uci.edu
    • Los Angeles, California, United States, 90095
      • Not yet recruiting
      • University Of California Los Angeles
      • Contact: Maxime Cannesson, MD, PhD; Phone Number: 310-267-8626; Email: mcannesson@mednet.ucla.edu
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale University/Yale New Haven Hospital
      • Contact: Amit Bardia, MD; Phone Number: 203-785-2802; Email: amit.bardia@yale.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Jochen D. Muehlschlegel, MD; Phone Number: 617-732-7330; Email: jmuehlschlegel@bwh.harvard.edu
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Oluwaseun Johnson-Akeju, MD; Phone Number: 617-726-3030; Email: oluwaseun.akeju@mgh.harvard.edu
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Contact: Brian O'Gara, MD; Phone Number: 617-754-3189; Email: bpogara@bidmc.harvard.edu
  • New York
    • Bronx, New York, United States, 10467
      • Recruiting
      • Albert Einstein College of Medicine- Montefiore
      • Contact: Matthias Eikermann, MD PhD; Phone Number: 718-920-2802; Email: meikermann@montefiore.org
    • New York, New York, United States, 10032
      • Not yet recruiting
      • Columbia University Irving Medical Center
      • Contact: Marcos Vidal-Melo, MD; Email: "Vimv2869@cumc.columbia.edu
      • Contact: Vivek Moitra, MD; Email: vm2161@cumc.columbia.edu
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh Medical Center
      • Contact: Kathirvel Subramaniam, MD, MPH; Phone Number: 412-647-6616; Email: subramaniamk@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

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: IV Acetaminophen; 1 g IV acetaminophen every 6 hours for 48 hours during the first 2 days postoperatively	Drug: IV acetaminophen; use of IV tylenol for pain; Other Names: ofirmev
Placebo Comparator: Placebo; Volume of the placebo (saline) will match that of IV acetaminophen at 100ml 0.9% NaCl	Other: Placebo; Volume of the placebo (saline) will match that of IV acetaminophen at 100ml 0.9% NaCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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
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

Other Outcome Measures

Outcome Measure	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	Rates of clinician discontinuation of study drug.	48 hours postoperatively

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Balachundhar Subramaniam, MD, MPH, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

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

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2020
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: September 13, 2019
• First Submitted That Met QC Criteria: September 16, 2019
• First Posted (Actual): September 17, 2019

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 5, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Cardiac Surgery; Postoperative; Acetaminophen; Delirium
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Coronary Disease; Coronary Artery Disease; Delirium; Emergence Delirium; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: 2019-P-000758; R01AG065554 (U.S. NIH Grant/Contract)

Drug and device information, study documents

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