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

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ClinicalTrials.gov Identifier: NCT04093219
Recruitment Status : Recruiting
First Posted : September 17, 2019
Last Update Posted : June 16, 2022
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Balachundhar Subramaniam, Beth Israel Deaconess Medical Center

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Delirium in Old Age Delirium Coronary Artery Disease Drug: IV acetaminophen Other: Placebo Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Prevention
Official Title: PANDORA: Scheduled Prophylactic 6-hourly Intravenous Acetaminophen to Prevent Postoperative Delirium in Older Cardiac Surgical Patients
Actual Study Start Date : August 11, 2020
Estimated Primary Completion Date : October 2024
Estimated Study Completion Date : October 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Delirium

Arms and Interventions
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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 Name: 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


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of postoperative delirium [ Time Frame: Participants will be followed for the duration of the hospital stay, an average of 5 days ]
    Occurrence of delirium on any postoperative day, as assessed using the CAM, 3D CAM, CAM Only, or CAM-ICU daily until hospital discharge.


Secondary Outcome Measures :
  1. Incidence of Charted Delirium [ Time Frame: Participants will be followed for the duration of the hospital stay, an average of 5 days ]
    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

  2. Duration of delirium [ Time Frame: 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 ]
    Total number of in-hospital postoperative days in which delirium is present

  3. Severity of delirium [ Time Frame: Participants will be followed for the duration of the hospital stay, an average of 5 days ]
    Delirium severity is evaluated both as the peak (highest) and sum CAM-S score over all hospital days

  4. Time to onset of delirium [ Time Frame: Participants will be followed for the duration of the hospital stay, an average of 5 days ]
    Measured in days

  5. Additional postoperative analgesic requirements [ Time Frame: First 48 hours postoperatively ]
    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).

  6. Worst daily pain scores with exertion (deep breathing and cough) [ Time Frame: Participants will be followed for the duration of the hospital stay, an average of 5 days ]
    Pain scores will be collected three times daily using a numeric rating scale (0, no pain, to 10, worst possible pain).

  7. Length of stay in the Intensive Care Unit (ICU) [ Time Frame: Measured in days admitted in the ICU, an average of 2 days ]
    Defined by the number of days admitted in the ICU prior to transfer to the general cardiac surgical floor

  8. Worst daily pain scores at rest [ Time Frame: Participants will be followed for the duration of the hospital stay, an average of 5 days ]
    Pain scores will be collected three times daily using a numeric rating scale (0, no pain, to 10, worst possible pain).

  9. Length of hospital stay [ Time Frame: Measured in days admitted in the hospital, an average of 6 days ]
    Defined by the number of days admitted in the hospital following the completion of surgery.

  10. Trajectory of cognitive function over time [ Time Frame: 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 ]
    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.

  11. Trajectory of physical function over time. [ Time Frame: Participants will be followed at 1 month, 6 month and 1- year following the date of surgery ]
    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.

  12. Trajectory of functional outcomes over time [ Time Frame: Participants will be followed at 1 month, 6 month and 1- year following the date of surgery ]
    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.

  13. Trajectory of chronic pain over time [ Time Frame: Participants will be followed at 6 month and 1- year following the date of surgery ]
    Chronic sternal pain will be assessed using the Numerical Pain Rating Scale (NPRS) at six and twelve months postoperatively assessed over the phone.


Other Outcome Measures:
  1. Need for additional liver function tests [ Time Frame: Participants will be followed for the duration of the hospital stay, an average of 5 days ]
    Clinical request for liver function test monitoring and reported ALT and AST values will be reported as safety outcomes

  2. Discontinuation of study drug [ Time Frame: 48 hours postoperatively ]
    Rates of clinician discontinuation of study drug.


Eligibility Criteria
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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04093219


Contacts
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Contact: Balachundhar Subramaniam, MD, MPH 617-754-2721 bsubrama@bidmc.harvard.edu

Locations
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United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35233
Contact: Jean-Francois Pittet, MD    205-996-4755    jpittet@uabmc.edu   
United States, California
University of California Los Angeles Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Maxime Cannesson, MD, PhD    310-267-8626    mcannesson@mednet.ucla.edu   
United States, Connecticut
Yale University/Yale New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
Contact: Amit Bardia, MD    203-785-2802    amit.bardia@yale.edu   
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Oluwaseun Johnson-Akeju, MD    617-726-3030    oluwaseun.akeju@mgh.harvard.edu   
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Jochen D. Muehlschlegel, MD    617-732-7330    jmuehlschlegel@bwh.harvard.edu   
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Brian O'Gara, MD    617-754-3189    bpogara@bidmc.harvard.edu   
United States, New York
Albert Einstein College of Medicine- Montefiore Not yet recruiting
Bronx, New York, United States, 10467
Contact: Matthias Eikermann, MD PhD    718-920-2802    meikermann@montefiore.org   
United States, Pennsylvania
University of Pittsburgh Medical Center Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Kathirvel Subramaniam, MD, MPH    412-647-6616    subramaniamk@upmc.edu   
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Balachundhar Subramaniam, MD, MPH Beth Israel Deaconess Medical Center
More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Balachundhar Subramaniam, Associate Professor of Anesthesia, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT04093219    
Other Study ID Numbers: 2019-P-000758
R01AG065554 ( U.S. NIH Grant/Contract )
First Posted: September 17, 2019    Key Record Dates
Last Update Posted: June 16, 2022
Last Verified: June 2022

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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
Keywords provided by Balachundhar Subramaniam, Beth Israel Deaconess Medical Center:
Acetaminophen
Postoperative
Delirium
Cardiac Surgery
Additional relevant MeSH terms:
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Delirium
Coronary Artery Disease
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Confusion
Neurobehavioral Manifestations
 Neurologic Manifestations
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Acetaminophen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics