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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Delirium in Old Age, Delirium, Coronary Artery Disease

Intervention / Treatment
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* Drug: IV acetaminophen
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV Acetaminophen<br>1 g IV acetaminophen every 6 hours for 48 hours during the first 2 days postoperatively | Drug: IV acetaminophen<br>* use of IV tylenol for pain<br>* Other names: ofirmev;|
| Placebo Comparator: Placebo<br>Volume of the placebo (saline) will match that of IV acetaminophen at 100ml 0.9% NaCl | Other: Placebo<br>* Volume of the placebo (saline) will match that of IV acetaminophen at 100ml 0.9% NaCl<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acetaminophen, Postoperative, Delirium, Cardiac Surgery