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

• ClinicalTrials.gov Identifier: NCT04289142
• Recruitment Status: Recruiting
• First Posted: February 28, 2020
• Last Update Posted: March 15, 2022
• Sponsor: Sunnybrook Health Sciences Centre
• 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: October 9, 2019
• First Posted Date: February 28, 2020
• Last Update Posted Date: March 15, 2022
• Actual Study Start Date: December 1, 2019
• Estimated Primary Completion Date: March 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients
• Official Title: 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: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Prevention

Condition

• 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

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

• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 27, 2020): 2400
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2026
• Estimated Primary Completion Date: March 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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: Canada

Administrative Information

• NCT Number: NCT04289142
• Other Study ID Numbers: 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

• 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: Sunnybrook Health Sciences Centre
• Original Study Sponsor: Same as current

Collaborators

• London Health Sciences Centre
• University Health Network, Toronto
• McMaster University

Investigators

• Principal Investigator: Stephen Choi, MD,MSc,FRCPC; Sunnybrook Health Sciences Centre

• PRS Account: Sunnybrook Health Sciences Centre
• Verification Date: March 2022