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

NCT ID: NCT02546765

Last Updated: 2020-04-09

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

140 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-10-31

Study Completion Date

2019-07-31

Brief Summary

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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

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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.

Conditions

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Delirium

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Outcome Assessors

Study Groups

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IV acetaminophen & IV propofol

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

Group Type EXPERIMENTAL

IV acetaminophen & IV propofol

Intervention Type DRUG

use of IV tylenol and IV propofol for pain and sedation (respectively)

IV acetaminophen & IV dexmedetomidine

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

Group Type EXPERIMENTAL

IV acetaminophen & IV dexmedetomidine

Intervention Type DRUG

use of IV tylenol and IV dexmedetomidine for pain and sedation (respectively)

IV propofol & placebo

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.

Group Type ACTIVE_COMPARATOR

IV propofol & placebo

Intervention Type DRUG

use of IV propofol for sedation and morphine, the drug of choice for cardiac pain

IV dexmedetomidine & placebo

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.

Group Type ACTIVE_COMPARATOR

IV dexmedetomidine & placebo

Intervention Type DRUG

use of IV dexmedetomidine for sedation and morphine, the drug of choice for cardiac pain

Interventions

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IV acetaminophen & IV propofol

use of IV tylenol and IV propofol for pain and sedation (respectively)

Intervention Type DRUG

IV acetaminophen & IV dexmedetomidine

use of IV tylenol and IV dexmedetomidine for pain and sedation (respectively)

Intervention Type DRUG

IV propofol & placebo

use of IV propofol for sedation and morphine, the drug of choice for cardiac pain

Intervention Type DRUG

IV dexmedetomidine & placebo

use of IV dexmedetomidine for sedation and morphine, the drug of choice for cardiac pain

Intervention Type DRUG

Other Intervention Names

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Ofirmev Diprivan Ofirmev Precedex Diprivan Precedex

Eligibility Criteria

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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
Minimum Eligible Age

60 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Beth Israel Deaconess Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Balachundhar Subramaniam

Anesthesiologist

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Balachundhar Subramaniam, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Beth Israel Deaconess Medical Center

Locations

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Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Site Status

Countries

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United States

References

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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.

Reference Type DERIVED
PMID: 29929533 (View on PubMed)

Rudolph JL, Jones RN, Levkoff SE, Rockett C, Inouye SK, Sellke FW, Khuri SF, Lipsitz LA, Ramlawi B, Levitsky S, Marcantonio ER. Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery. Circulation. 2009 Jan 20;119(2):229-36. doi: 10.1161/CIRCULATIONAHA.108.795260. Epub 2008 Dec 31.

Reference Type BACKGROUND
PMID: 19118253 (View on PubMed)

Inouye SK. Delirium in older persons. N Engl J Med. 2006 Mar 16;354(11):1157-65. doi: 10.1056/NEJMra052321. No abstract available.

Reference Type BACKGROUND
PMID: 16540616 (View on PubMed)

Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012 Jul 5;367(1):30-9. doi: 10.1056/NEJMoa1112923.

Reference Type BACKGROUND
PMID: 22762316 (View on PubMed)

Lin YY, He B, Chen J, Wang ZN. Can dexmedetomidine be a safe and efficacious sedative agent in post-cardiac surgery patients? a meta-analysis. Crit Care. 2012 Sep 27;16(5):R169. doi: 10.1186/cc11646.

Reference Type BACKGROUND
PMID: 23016926 (View on PubMed)

Corbett SM, Rebuck JA, Greene CM, Callas PW, Neale BW, Healey MA, Leavitt BJ. Dexmedetomidine does not improve patient satisfaction when compared with propofol during mechanical ventilation. Crit Care Med. 2005 May;33(5):940-5. doi: 10.1097/01.ccm.0000162565.18193.e5.

Reference Type BACKGROUND
PMID: 15891317 (View on PubMed)

Shehabi Y, Grant P, Wolfenden H, Hammond N, Bass F, Campbell M, Chen J. Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study). Anesthesiology. 2009 Nov;111(5):1075-84. doi: 10.1097/ALN.0b013e3181b6a783.

Reference Type BACKGROUND
PMID: 19786862 (View on PubMed)

Maldonado JR, Wysong A, van der Starre PJ, Block T, Miller C, Reitz BA. Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009 May-Jun;50(3):206-17. doi: 10.1176/appi.psy.50.3.206.

Reference Type BACKGROUND
PMID: 19567759 (View on PubMed)

Dasta JF, Jacobi J, Sesti AM, McLaughlin TP. Addition of dexmedetomidine to standard sedation regimens after cardiac surgery: an outcomes analysis. Pharmacotherapy. 2006 Jun;26(6):798-805. doi: 10.1592/phco.26.6.798.

Reference Type BACKGROUND
PMID: 16716133 (View on PubMed)

Holmer Pettersson P, Jakobsson J, Owall A. Plasma concentrations following repeated rectal or intravenous administration of paracetamol after heart surgery. Acta Anaesthesiol Scand. 2006 Jul;50(6):673-7. doi: 10.1111/j.1399-6576.2006.01043.x.

Reference Type BACKGROUND
PMID: 16987360 (View on PubMed)

Wiredu K, Mueller A, McKay TB, Behera A, Shaefi S, Akeju O. Sex Differences in the Incidence of Postoperative Delirium after Cardiac Surgery: A Pooled Analyses of Clinical Trials. Anesthesiology. 2023 Oct 1;139(4):540-542. doi: 10.1097/ALN.0000000000004656. No abstract available.

Reference Type DERIVED
PMID: 37535937 (View on PubMed)

Goncalves M, Khera T, Otu HH, Narayanan S, Dillon ST, Shanker A, Gu X, Jung Y, Ngo LH, Marcantonio ER, Libermann TA, Subramaniam B. Multivariable model of postoperative delirium in cardiac surgery patients: proteomic and demographic contributions. medRxiv [Preprint]. 2023 Oct 13:2023.05.30.23289741. doi: 10.1101/2023.05.30.23289741.

Reference Type DERIVED
PMID: 37333093 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30778597 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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2014P000413

Identifier Type: -

Identifier Source: org_study_id

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