Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients

Study Overview
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Brief Summary
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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
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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).

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

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

Intervention / Treatment
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* Drug: Dexmedetomidine Hydrochloride Group


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dexmedetomidine Hydrochloride Group<br>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<br>* 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.<br>* Other names: Dexmedetomidine Hydrochloride;|
| No Intervention: Standard of Care Group<br>Standard sedation protocols will be followed at the discretion of the attending physician. | |

What is the study measuring?
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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 |