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

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

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.

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.

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.

Occurrence of delirium on any postoperative day, as assessed using the CAM, 3D CAM, CAM Only, or CAM-ICU daily until hospital discharge.

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 6 days, and at 1 month, 6 month and 1- year following the date of surgery

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).

Pain scores will be collected three times daily using a numeric rating scale (0, no pain, to 10, worst possible pain).

Defined by the number of days admitted in the ICU prior to transfer to the general cardiac surgical floor

Pain scores will be collected three times daily using a numeric rating scale (0, no pain, to 10, worst possible pain).

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

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.

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.

Chronic sternal pain will be assessed using the Numerical Pain Rating Scale (NPRS) at six and twelve months postoperatively assessed over the phone.

Clinical request for liver function test monitoring and reported ALT and AST values will be reported as safety outcomes

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

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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.