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Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients (CODEX)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04289142
Recruitment Status : Recruiting
First Posted : February 28, 2020
Last Update Posted : March 15, 2022
Sponsor:
Collaborators:
London Health Sciences Centre
University Health Network, Toronto
McMaster University
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre

Tracking Information
First Submitted Date  ICMJE October 9, 2019
First Posted Date  ICMJE February 28, 2020
Last Update Posted Date March 15, 2022
Actual Study Start Date  ICMJE December 1, 2019
Estimated Primary Completion Date March 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 27, 2020)
Post-operative cognitive dysfunction [ Time Frame: 3 months ]
Presence of POCD assessed by CogState Brief Battery (CBB)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 27, 2020)
  • Post-operative cognitive dysfunction (POCD) at 1 week, 6 months, 12 months after surgery [ Time Frame: 1 week, 6 and 12 months ]
    POCD assessed by CogState Brief Battery (CBB)
  • Delirium [ Time Frame: Anytime up to post-operative day 10 ]
    Confusion Assessment Method (CAM/CAM-ICU) or Intensive Care Delirium Screening Checklist (ICDSC), binary scale to determine if delirium is present or absent
  • Length of stay [ Time Frame: An average of 5 -14 days ]
    ICU and total hospital stay
  • Depressive symptoms [ Time Frame: 3, 6, and 12 months ]
    Evaluated by PHQ-9 (Patient Health Questionnaire, scale 0-27, higher score is worse outcome)
  • Persistent Surgical Site Pain [ Time Frame: 3, 6, and 12 months ]
    Evaluated by Brief Pain Inventory
  • Quality of Surgical Recovery [ Time Frame: 3, 6, 12 months ]
    Evaluated by QoR- (Quality of Recovery) 40 questionnaire (scale: 0-200, higher is better outcome)
  • Mild Cognitive Impairment [ Time Frame: 3, 6, and 12 months ]
    Presence of MCI assessed by CogState Brief Battery (CBB)
  • In-hospital mortality for index surgery [ Time Frame: through initial inpatient admission, average of 1 week ]
    death before hospital discharge after surgery
  • Opioid consumption to POD 4 [ Time Frame: 4 days ]
    Cumulative opioid consumption
  • Time to extubation [ Time Frame: through ICU stay, average of 12 hours ]
    Time from ICU arrival to cessation of mechanical ventilation
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients
Official Title  ICMJE Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients: CODEX Trial
Brief Summary Anesthesia is a drug induced, reversible, comatose state that facilitates surgery and it is widely assumed that cognition returns to baseline after anesthetics have been eliminated. However, many patients have persistent memory impairment for weeks to months after surgery. Cardiac surgery appears to carry the highest risk of postoperative cognitive dysfunction (POCD). These cognitive deficits are associated with increased mortality, prolonged hospital stay and loss of independence. The investigators propose to investigate the role of Dexmedetomidine (DEX) in preventing long-term POCD after cardiac surgery and enhancing early postoperative recovery. It is anticipated that DEX will be the first effective preventative therapy for POCD, improve patient outcomes, and reduce length of stay and healthcare costs.
Detailed Description

Dexmedetomidine (DEX), a highly potent and selective α2-adrenoceptors (α2R) agonist used in clinical practice for sedation, analgesia, and anxiolysis, was recently shown to have beneficial effects on early cognitive changes by reducing delirium in humans. It also reduced memory impairment after surgery and isoflurane anesthesia, both in elderly mice (20-22 months) and in pups exposed to anesthesia in the early postnatal period. Importantly, co-treatment with DEX has been shown to restore learning and memory function in rats exposed to propofol in utero. Therefore, the investigators set out to investigate whether DEX has an effect on cognitive dysfunction months after surgery and whether it accelerates cognitive recovery from anesthesia and surgery.

This is a multi-site trial facilitated by Clinical Trials Ontario (CTO). Participants will be randomized 1:1 in permuted blocks of 4 to 8. The randomization sequence will be computer generated and stratified by 2 factors, planned procedure (CABG/CABG + valve or valve only procedure) and study site.

In hospital outcomes include delirium (assessed twice daily post-operative day (POD) 0-10, death, hemodynamic instability requiring vasopressors, time to extubation, re-intubation (and reason), length of stay (in Cardiovascular Intensive Care Unit and total hospital), POCD, depressive symptoms between POD 4-10, post-operative complications (infection [surgical site, sepsis, pneumonia], myocardial infarction, renal replacement therapy, re-operation, cumulative opioid consumption (to POD 5), in-hospital mortality.

Post-operative outcomes include POCD (3/6/12 months), depression (3/6/12 months), mild cognitive impairment (MCI) at 3/6/12 months (defined as 1-2 standard deviations below age matched controls), persistent surgical site pain at sternotomy/thoracotomy/graft harvest site (Brief Pain Inventory, 3/6/12 months), recovery (3,6, 12 months).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Delirium
  • Cognitive Dysfunction
  • Cognition Disorder
  • Neurocognitive Disorders
  • Mental Disorders
  • Confusion
  • Neurobehavioral Manifestations
  • Neurologic Manifestations
  • Nervous System Diseases
  • Signs and Symptoms
  • Dexmedetomidine
  • Hypnotics and Sedatives
  • Central Nervous System Depressants
  • Physiological Effects of Drugs
  • Analgesics, Non-Narcotic
  • Analgesics
  • Molecular Mechanisms of Pharmacological Action
Intervention  ICMJE Drug: Dexmedetomidine Hydrochloride Group
Dexmedetomidine will be initiated prior to transfer to the CVICU with loading dose of 1.2 ug kg-1 over approximately 20 minutes. This will be followed by an infusion at 0.1-1.2 ug kg-1h-1 in CVICU for up to 24 hours from the time DEX infusion started or until the patient is ready for discharge from the CVICU (whichever is earlier).
Other Name: Dexmedetomidine Hydrochloride
Study Arms  ICMJE
  • Active Comparator: Dexmedetomidine Hydrochloride Group
    Patients will receive a loading dose of 1.2 μg/kg dexmedetomidine prior to transfer to CVICU over 20 min immediately postoperative, followed by continuous infusion of 0.1- 1.2 μg/kg/h for up to 24 hours or until patient is ready for discharge from CVICU (whichever is earlier).
    Intervention: Drug: Dexmedetomidine Hydrochloride Group
  • No Intervention: Standard of Care Group
    Standard sedation protocols will be followed at the discretion of the attending physician.
Publications * Choi S, Jerath A, Jones P, Avramescu S, Djaiani G, Syed S, Saha T, Kaustov L, Kiss A, D'Aragon F, Hedlin P, Rajamohan R, Couture EJ, Singh A, Mapplebeck JC, Wong S, Orser BA. Cognitive Outcomes after DEXmedetomidine sedation in cardiac surgery: CODEX randomised controlled trial protocol. BMJ Open. 2021 Apr 13;11(4):e046851. doi: 10.1136/bmjopen-2020-046851.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 27, 2020)
2400
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2026
Estimated Primary Completion Date March 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Planned CABG (+/- valve, including off-pump) or valve replacement via sternotomy/thoracotomy, with initial recovery in the Cardiovascular Intensive Care Unit (CVICU)
  • Age ≥60

Exclusion Criteria:

  • Lack of patient consent
  • Pre-operative major cognitive dysfunction (CogState Brief Battery score < 80)
  • Aortic arch replacement/re-implantation (Bentalls)
  • Allergy/contraindication to dexmedetomidine (untreated 2nd degree type 2 or 3rd degree heart block (pacemaker), cirrhosis, HR < 50 , grade 4 LV, renal failure or on renal replacement therapy)
  • Unlikely to comply with study assessments (e.g. no fixed address, cannot complete cognitive tests at the 3, 6, and 12 month time points)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Stephen Choi, MD,MSc,FRCPC 416-480-6100 ext 1711 stephen.choi@sunnybrook.ca
Contact: Lilia Kaustov, PhD 416-480-6100 ext 89607 lilia.kaustov@sunnybrook.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04289142
Other Study ID Numbers  ICMJE 1743
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All de-identified participants data collected during this trial that underlie the results reported in the publication(s) will be available upon request after publication of the primary results.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data will be available upon request immediately after publication of the primary results. No end date.
Access Criteria: Direct request to PI. Anyone who wishes to access the data.
Current Responsible Party Sunnybrook Health Sciences Centre
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Sunnybrook Health Sciences Centre
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • London Health Sciences Centre
  • University Health Network, Toronto
  • McMaster University
Investigators  ICMJE
Principal Investigator: Stephen Choi, MD,MSc,FRCPC Sunnybrook Health Sciences Centre
PRS Account Sunnybrook Health Sciences Centre
Verification Date March 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP