Dexmedetomidine and IV Acetaminophen for the Prevention of Postoperative Delirium Following Cardiac Surgery

This is a prospective, randomized, placebo-controlled, triple-blinded, factorial design study
consisting of 120 patients who were randomized and received a study intervention. Intravenous
dexmedetomidine and acetaminophen will be compared to the standard sedation/analgesic
propofol and opioid regimen.

After obtaining informed consent, study subjects will be randomized by an unblinded
investigator and receive a specific combination of both sedatives and analgesic medications.
Sedatives will include either IV propofol or IV dexmedetomidine, and analgesics IV
acetaminophen or placebo (100 mL 0.9% NaCl equivalent to the administered volume of IV
acetaminophen). Subjects will be allocated in a 1:1:1:1 fashion into the following four
treatment arms: 1. IV acetaminophen with IV propofol, 2. IV acetaminophen with IV
dexmedetomidine, 3. IV propofol with placebo, or 4. IV dexmedetomidine with placebo. Sedation
and analgesia protocols will begin while patients are in the OR and continue as they are
transferred to the Cardiovascular Intensive Care Unit (CVICU). The medications for sedation
will be weight based (loading infusion of 0.5 - 1 µg/kg given over 10 minutes followed by a
maintenance infusion of 0.1-1.4 µg/kg/hr for IV dexmedetomidine, or 20-100 µg/kg/min for IV
propofol). Postoperative sedation is administrated 4-6 hours before patients are woken up in
the CVICU. IV Acetaminophen (1g or 100mL) will be given every 6 hours for 48 hours to
patients randomized to this drug. The volume of the placebo will be administered in
respective groups in the same timeframe. Oral acetaminophen will be continued until discharge
in all patients. All groups will also receive bolus doses of opioids (IV morphine or
hydromorphone) as needed for breakthrough pain.

Patients will be administered a preoperative (baseline) and a series of post-operative
evaluations to assess delirium by a blinded investigator. Baseline assessments will include
the Montreal Cognitive Assessment (MoCA), days of the week (DOW), months of the year (MOY),
Delirium Symptom Interview (DSI), the Geriatric Depression Scale (GDS) and the Confusion
Assessment Method (CAM). Daily cognitive assessments will include the DSI, CAM, and a
standard cognitive assessment. At discharge, the MoCA, DOW, MOY, DSI, and CAM will be given.
Follow-up assessments will be conducted at 1 month and 1 year post-discharge and will include
the telephonic MoCA, DSI, GDS and CAM. The delirium research assessments will not be provided
to the treating clinicians. Treating clinicians will assess and treat delirium as usual,
including assessment and correction of reversible causes, behavioral management, and use of
IV haloperidol as needed for agitation. Rescue doses of haloperidol will be recorded in the
study.

Blood will be collected from all subjects at the time of the baseline assessment,
post-operation day 1 (POD1) while in ICU, POD 2 in the ICU, and within 48 hours of discharge.
Two sets of 10 mL will be collected at each time point, with a total of 80mL of blood per
patient. Efforts will be made to efficiently draw blood through the patient's arterial line
at baseline or add onto to scheduled draws with phlebotomy. The plasma and buffy coat will be
separated from the blood, aliquotted into labeled vials, and stored in a biomarker bank at
-80°C for future use.

Inclusion Criteria:

- Patients ≥ 60 years of age

- Undergoing CABG with/without valve (aortic and/or mitral) procedure requiring bypass

Exclusion Criteria:

- Pre-operative Left Ventricular Ejection Fraction (LVEF) < 30%

- Emergent or urgent procedures, aortic surgery

- Pre-existing cognitive impairment (defined based on a short screening assessment),
Parkinson's disease, Alzheimer's disease, recent seizures (<3 months)

- Prophylactic medications for cognitive decline

- Serum creatinine > 2 mg/dl

- Liver dysfunction (liver enzymes > 4x the baseline, since patients will have a
baseline liver function tests), history and exam suggestive of jaundice

- Known history of alcohol or drug abuse (>10 drinks per week)

- Hypersensitivity to any of the study drug and percutaneous procedures

- Non-English speaking