Clinical trial NCT02546765: Dexmedetomidine and IV Acetaminophen for the Prevention of Postoperative Delirium Following Cardiac Surgery
Official title: Dexmedetomidine and IV Acetaminophen for the Prevention of Postoperative Delirium Following Cardiac Surgery in Adult Patients 60 Years of Age and Older
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Delirium
Keywords: analgesics
cardiac surgery
sedation
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
First posted: 2015-09-11
Enrollment: 140
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Delirium
timeFrame: Participants will be followed for the duration of the hospital stay, an average of 5 days
Secondary outcomes:
measure: Duration of Delirium
timeFrame: Participants will be followed for the duration of the hospital stay, an average of 6 days, and at 1 month and 1- year following the date of surgery
measure: Severity of Delirium
timeFrame: Participants will be followed for the duration of the hospital stay, an average of 6 days
measure: Postoperative Opioid Consumption in Morphine Equivalents
timeFrame: Participants will be followed for the first 48 hours postoperatively.
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: On the day of discharge, an average of 6 days
measure: Hospital Length of Stay
timeFrame: Measured in days admitted in the hospital, an average of 6 days
measure: ICU Length of Stay
timeFrame: Measured in days admitted in the ICU, an average of 2 days
measure: Follow up Incidence of Cognitive Dysfunction
timeFrame: Patients will be assessed for cognitive dysfunction with T-MOCA at 1 month following the date of surgery
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Balachundhar Subramaniam, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Subramaniam B, Shankar P, Shaefi S, Mueller A, O'Gara B, Banner-Goodspeed V, Gallagher J, Gasangwa D, Patxot M, Packiasabapathy S, Mathur P, Eikermann M, Talmor D, Marcantonio ER. Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial. JAMA. 2019 Feb 19;321(7):686-696. doi: 10.1001/jama.2019.0234.
citation: Shankar P, Mueller A, Packiasabapathy S, Gasangwa D, Patxot M, O'Gara B, Shaefi S, Marcantonio ER, Subramaniam B. Dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium following cardiac surgery (DEXACET trial): protocol for a prospective randomized controlled trial. Trials. 2018 Jun 22;19(1):326. doi: 10.1186/s13063-018-2718-0.