Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients

Delirium Clinical Trial

— CODEX  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04289142
• Other study ID #: 1743
• Status: Recruiting
• Phase: Phase 4
• Start date: December 1, 2019
• Est. completion date: March 2026

Study information

• Verified date: November 2023
• Source: Sunnybrook Health Sciences Centre
• Contact: Stephen Choi, MD,MSc,FRCPC
• Phone: 416-480-6100
• Email: stephen.choi[@]sunnybrook.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2400
• Est. completion date: March 2026
• Est. primary completion date: March 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Analgesics
• Analgesics, Non-Narcotic
• Central Nervous System Depressants
• Cognition Disorder
• Cognition Disorders
• 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

Intervention

Drug:
• Dexmedetomidine Hydrochloride Group
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.

Locations

Country	Name	City	State
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario

Sponsors (4)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre	London Health Sciences Centre, McMaster University, University Health Network, Toronto

Country where clinical trial is conducted

Canada, 

Outcome

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