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

Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients: CODEX Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Delirium; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognitive Dysfunction; Dexmedetomidine; Molecular Mechanisms of Pharmacological Action; Signs and Symptoms; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Cognition Disorder; Central Nervous System Depressants; Analgesics; Hypnotics and Sedatives
• Intervention / Treatment: Drug: Dexmedetomidine Hydrochloride Group

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
• Enrollment (Estimated): 2400
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Stephen Choi, MD,MSc,FRCPC; Phone Number: 1711 416-480-6100; Email: stephen.choi@sunnybrook.ca
• Study Contact Backup: Name: Lilia Kaustov, PhD; Phone Number: 89607 416-480-6100; Email: lilia.kaustov@sunnybrook.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Principal Investigator: Sinziana Avramescu, MD,FRCPC,PhD
      • Sub-Investigator: Angela Jerath, MD,FRCPC
      • Sub-Investigator: George Djaiani, MD,FRCPC
      • Sub-Investigator: Philip Jones, MD,FRCPC
      • Sub-Investigator: Summer Syed, MD,FRCPC,MSc
      • Sub-Investigator: David Mazer, MD,FRCPC,PhD
      • Sub-Investigator: Tarit Saha, MD,FRCPC
      • Sub-Investigator: Beverley A Orser, MD,PhD,FRCPC
      • Contact: Lilia Kaustov, PhD; Phone Number: 89607 416-480-6100; Email: lilia.kaustov@sunnybrook.ca
      • Principal Investigator: Stephen Choi, MD,FRCPC,MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard of Care Group; Standard sedation protocols will be followed at the discretion of the attending physician.
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 0.3 μg/kg/h for up to 12 hours or until patient is ready for discharge from CVICU (whichever is earlier). Any additional sedatives necessary at the discretion of ICU.	Drug: Dexmedetomidine Hydrochloride Group; Dexmedetomidine will be initiated prior to transfer to the CVICU with loading dose of 1.2 ug/kg over approximately 20 minutes. This will be followed by an infusion at 0.3 ug/kg/h in CVICU for up to 12 hours from the time DEX infusion started or until the patient is ready for discharge from the CVICU (whichever is earlier). Any additional sedatives necessary at the discretion of ICU.; Other Names: Dexmedetomidine Hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-operative cognitive dysfunction	Presence of POCD assessed by CogState Brief Battery (CBB)	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-operative cognitive dysfunction (POCD) at 1 week, 6 months, 12 months after surgery	POCD assessed by CogState Brief Battery (CBB)	1 week, 6 and 12 months
Delirium	Confusion Assessment Method (CAM/CAM-ICU) or Intensive Care Delirium Screening Checklist (ICDSC), binary scale to determine if delirium is present or absent	Anytime up to post-operative day 10
Length of stay	ICU and total hospital stay	An average of 5 -14 days
Depressive symptoms	Evaluated by PHQ-9 (Patient Health Questionnaire, scale 0-27, higher score is worse outcome)	3, 6, and 12 months
Persistent Surgical Site Pain	Evaluated by Brief Pain Inventory	3, 6, and 12 months
Quality of Surgical Recovery	Evaluated by QoR- (Quality of Recovery) 40 questionnaire (scale: 0-200, higher is better outcome)	3, 6, 12 months
Mild Cognitive Impairment	Presence of MCI assessed by CogState Brief Battery (CBB)	3, 6, and 12 months
In-hospital mortality for index surgery	death before hospital discharge after surgery	through initial inpatient admission, average of 1 week
Opioid consumption to POD 4	Cumulative opioid consumption	4 days
Time to extubation	Time from ICU arrival to cessation of mechanical ventilation	through ICU stay, average of 12 hours

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Collaborators: University Health Network, Toronto; McMaster University; London Health Sciences Centre
• Investigators: Principal Investigator: Stephen Choi, MD,MSc,FRCPC, Sunnybrook Health Sciences Centre

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2019
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: October 9, 2019
• First Submitted That Met QC Criteria: February 27, 2020
• First Posted (Actual): February 28, 2020

Study Record Updates

• Last Update Posted (Estimated): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Mental Disorders; Nervous System Diseases; Cognitive Dysfunction; Neurobehavioral Manifestations; Cognition Disorders; Confusion; Neurologic Manifestations; Neurocognitive Disorders; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: 1743

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: Data will be available upon request immediately after publication of the primary results. No end date.
• IPD Sharing Access Criteria: Direct request to PI. Anyone who wishes to access the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No