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

Sponsor

Beth Israel Deaconess Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04093219

Collaborator

National Institute on Aging (NIA) (NIH)

900

Enrollment

Locations

Arms

49.7

Anticipated Duration (Months)

112.5

Patients Per Site

2.3

Patients Per Site Per Month

Study Details

Study Description

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;

the incidence, duration, and severity of postoperative delirium,
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
longer-term (one, six, 12 months) cognitive, physical, and self-care functional recovery after surgery.

Study Design

Study Type:

Interventional

Anticipated 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 :

Aug 11, 2020

Anticipated Primary Completion Date :

Oct 1, 2024

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Incidence of postoperative delirium [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

Incidence of Charted Delirium [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
Duration of delirium [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
Severity of delirium [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
Time to onset of delirium [Participants will be followed for the duration of the hospital stay, an average of 5 days]
Measured in days
Additional postoperative analgesic requirements [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).
Worst daily pain scores with exertion (deep breathing and cough) [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).
Length of stay in the Intensive Care Unit (ICU) [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
Worst daily pain scores at rest [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).
Length of hospital stay [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.
Trajectory of cognitive function 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]
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.
Trajectory of physical function over time. [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.
Trajectory of functional outcomes over time [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.
Trajectory of chronic pain over time [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

Need for additional liver function tests [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
Discontinuation of study drug [48 hours postoperatively]
Rates of clinician discontinuation of study drug.

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

≥ 60 years of age
Patients undergoing cardiac surgery [coronary artery bypass grafting (CABG) with or without valve, isolated valve surgery] requiring cardiopulmonary bypass

Exclusion Criteria:

Pre-operative left ventricular ejection fraction (LVEF) < than 30%
Emergent procedures
Isolated aortic surgery
Liver dysfunction (liver enzymes > 3 times the baseline, all patients will have a baseline liver function test information), history and exam suggestive of jaundice
Hypersensitivity to the study drugs
Active (in the past year) history of alcohol abuse (≥5 drinks per day for men or ≥ 4 drinks per day for women)
Any history of alcohol withdrawal or delirium tremens
Delirium at baseline
Non-English speaking
Prisoners
Physician Refusal
COVID-19 Positive, symptomatic
Co-enrollment with non-approved interventional trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	University of California Los Angeles	Los Angeles	California	United States	90095
3	Yale University/Yale New Haven Hospital	New Haven	Connecticut	United States	06510
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
6	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
7	Albert Einstein College of Medicine- Montefiore	Bronx	New York	United States	10467
8	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213