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

Sunnybrook Health Sciences Centre

Status and phase: Enrolling; Phase 4

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

Treatments: Drug: Dexmedetomidine Hydrochloride Group

Study type: Interventional

Funder types: Other

Identifiers

NCT04289142

1743

Details and patient eligibility

About

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.

Full 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 double blinded, 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).

Enrollment: 2,400 estimated patients

Sex: All

Ages: 60+ years old

Volunteers: No 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) at screening
• Aortic arch replacement/re-implantation (surgery requiring hypothermic circulatory arrest, e.g. Bentall procedure)
• 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)

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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2,400 participants in 2 patient groups

Dexmedetomidine Hydrochloride Group

Active Comparator group

Description:

Patients will receive a loading dose of 1.2 μg/kg dexmedetomidine prior to transfer to CVICU over 20-60 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.

Treatment:

Drug: Dexmedetomidine Hydrochloride Group

Standard of Care Group

No Intervention group

Description:

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