CODEX: Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients

Sponsor

Sunnybrook Health Sciences Centre (Other)

Overall Status

Recruiting

CT.gov ID

NCT04289142

Collaborator

London Health Sciences Centre (Other), University Health Network, Toronto (Other), McMaster University (Other)

2,400

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Dexmedetomidine Hydrochloride Group	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

2400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Dec 1, 2019

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Mar 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
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).	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 Names: Dexmedetomidine Hydrochloride
No Intervention: Standard of Care Group Standard sedation protocols will be followed at the discretion of the attending physician.

Arm

Intervention/Treatment

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).

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 Names:

Dexmedetomidine Hydrochloride

No Intervention: Standard of Care Group

Standard sedation protocols will be followed at the discretion of the attending physician.

Outcome Measures

Primary Outcome Measures

Post-operative cognitive dysfunction [3 months]
Presence of POCD assessed by CogState Brief Battery (CBB)

Secondary Outcome Measures

Post-operative cognitive dysfunction (POCD) at 1 week, 6 months, 12 months after surgery [1 week, 6 and 12 months]
POCD assessed by CogState Brief Battery (CBB)
Delirium [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 [An average of 5 -14 days]
ICU and total hospital stay
Depressive symptoms [3, 6, and 12 months]
Evaluated by PHQ-9 (Patient Health Questionnaire, scale 0-27, higher score is worse outcome)
Persistent Surgical Site Pain [3, 6, and 12 months]
Evaluated by Brief Pain Inventory
Quality of Surgical Recovery [3, 6, 12 months]
Evaluated by QoR- (Quality of Recovery) 40 questionnaire (scale: 0-200, higher is better outcome)
Mild Cognitive Impairment [3, 6, and 12 months]
Presence of MCI assessed by CogState Brief Battery (CBB)
In-hospital mortality for index surgery [through initial inpatient admission, average of 1 week]
death before hospital discharge after surgery
Opioid consumption to POD 4 [4 days]
Cumulative opioid consumption
Time to extubation [through ICU stay, average of 12 hours]
Time from ICU arrival to cessation of mechanical ventilation

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)