Clinical trial NCT04289142: Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients
Official title: Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients: CODEX Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: 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
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
Collaborators: name: London Health Sciences Centre
name: University Health Network, Toronto
name: McMaster University
First posted: 2020-02-28
Enrollment: 2400
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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).

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)

Primary outcomes:
measure: Post-operative cognitive dysfunction
timeFrame: 3 months
Secondary outcomes:
measure: Post-operative cognitive dysfunction (POCD) at 1 week, 6 months, 12 months after surgery
timeFrame: 1 week, 6 and 12 months
measure: Delirium
timeFrame: Anytime up to post-operative day 10
measure: Length of stay
timeFrame: An average of 5 -14 days
measure: Depressive symptoms
timeFrame: 3, 6, and 12 months
measure: Persistent Surgical Site Pain
timeFrame: 3, 6, and 12 months
measure: Quality of Surgical Recovery
timeFrame: 3, 6, 12 months
measure: Mild Cognitive Impairment
timeFrame: 3, 6, and 12 months
measure: In-hospital mortality for index surgery
timeFrame: through initial inpatient admission, average of 1 week
measure: Opioid consumption to POD 4
timeFrame: 4 days
measure: Time to extubation
timeFrame: through ICU stay, average of 12 hours
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Stephen Choi, MD,MSc,FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.