Analgesics, Analgesics, Non-Narcotic, Central Nervous System Depressants, Cognition Disorder, Cognitive Dysfunction, Confusion, Delirium, Dexmedetomidine, Hypnotics and Sedatives, Mental Disorders, Molecular Mechanisms of Pharmacological Action, Nervous System Diseases, Neurobehavioral Manifestations, Neurocognitive Disorders, Neurologic Manifestations, Physiological Effects of Drugs, Signs and Symptoms
Conditions
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 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).
Interventions
Dexmedetomidine will be initiated prior to transfer to the CVICU with loading dose of 1.2 ug/kg over approximately 20-60 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.
Sponsors
London Health Sciences Centre
University Health Network, Toronto
McMaster University
Canadian Institutes of Health Research (CIHR)
The Dana Foundation
Brain Canada
Alzheimer's Association
Hamilton Health Sciences Corporation
University of Saskatchewan
Fraser Health
Providence Health & Services
Sunnybrook Health Sciences Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post-operative cognitive dysfunction | 3 months | Presence of POCD assessed by CogState Brief Battery (CBB) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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) |
| 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 |
| Quality of Surgical Recovery | 3, 6, 12 months | Evaluated by QoR- (Quality of Recovery) 40 questionnaire (scale: 0-200, higher is better outcome) |
Countries
Canada
Contacts
Primary ContactStephen Choi, MD,MSc,FRCPC
Backup ContactLilia Kaustov, PhD
Outcome results
None listed