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

Beth Israel Lahey Health

Status and phase: Completed; Phase 4

Conditions: Delirium

Treatments: Drug: IV dexmedetomidine & placebo; Drug: IV acetaminophen & IV propofol; Drug: IV acetaminophen & IV dexmedetomidine; Drug: IV propofol & placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02546765

2014P000413

Details and patient eligibility

About

Investigators will assess the incidence and duration of postoperative delirium in patients ≥60 years old undergoing coronary artery bypass grafting (CABG), with/without valve surgery (aortic and/or mitral) based on different regimens for postoperative sedation and analgesia. Patients will receive either intravenous (IV) dexmedetomidine and IV acetaminophen or standard postoperative management using IV propofol with morphine or hydromorphone. The Confusion Assessment Method (CAM) will be used to assess delirium in these patients. Investigators also seek to compare postoperative (48 hours) analgesic requirements in patients with or without IV acetaminophen. Investigators will finally assess postoperative cognition in post-surgical patients up to one year post-discharge using a cognitive assessment scale.

Full description

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, aliquoted into labeled vials, and stored in a biomarker bank at -80°C for future use.

Enrollment: 140 patients

Sex: All

Ages: 60+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Triple Blind

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140 participants in 4 patient groups

IV acetaminophen & IV propofol

Experimental group

Description:

20-100 µg/kg/min IV propofol given for 4-6 hours before the patients are woken up in the ICU 1g IV acetaminophen every 6 hours for 48 hours during the first 2 days postoperatively

Treatment:

Drug: IV acetaminophen & IV propofol

IV acetaminophen & IV dexmedetomidine

Experimental group

Description:

A loading infusion of 0.5 - 1 µg/kg given over 10 minutes will be administered. After the loading infusion, a maintenance infusion of 0.1-1.4 µg/kg/hr will be initiated. 1 g IV acetaminophen every 6 hours for 48 hours during the first 2 days postoperatively

Treatment:

Drug: IV acetaminophen & IV dexmedetomidine

IV propofol & placebo

Active Comparator group

Description:

20-100 µg/kg/min IV propofol given for 4-6 hours before the patients are woken up in the ICU Volume of the placebo (saline) will match that of IV acetaminophen at 100ml 0.9% NaCl.

Treatment:

Drug: IV propofol & placebo

IV dexmedetomidine & placebo

Active Comparator group

Description:

0.1-1.0 µg/kg/hour IV dexmedetomidine given for 4-6 hours before the patients are woken up in the ICU Volume of the placebo (saline) will match that of i.v. acetaminophen at 100ml 0.9% NaCl.

Treatment:

Drug: IV dexmedetomidine & placebo