Dexmedetomidine for Postoperative Cognitive Dysfunction

(CODEX Trial)

Overseen By Stephen Choi, MD,FRCPC,MSc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Sunnybrook Health Sciences Centre

Disqualifiers: Cognitive dysfunction, Heart block, Cirrhosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Up to 12 hours

2400 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Dexmedetomidine for postoperative cognitive dysfunction?

Research shows that Dexmedetomidine can reduce the risk of postoperative cognitive dysfunction (POCD) in elderly patients after surgery. It also improves cognitive test scores shortly after surgery, indicating better mental function. ^{1 2 3 4 5}

Is dexmedetomidine safe for humans?

Dexmedetomidine is generally considered safe for use in humans, but it can cause low blood pressure (hypotension) and slow heart rate (bradycardia), which can be managed with medication. ^{2 4 6 7 8}

How is the drug dexmedetomidine unique for treating postoperative cognitive dysfunction?

Dexmedetomidine is unique because it acts as a sedative with neuroprotective properties, which can help improve cognitive function after surgery. Unlike traditional pain medications, it is a non-opioid option that minimizes opioid-related side effects, making it particularly beneficial for elderly patients who are more susceptible to postoperative cognitive issues. ^{1 2 6 7 9}

Research Team

Stephen Choi, MD

Principal Investigator

Sunnybrook Health Sciences Centre

Eligibility Criteria

This trial is for cardiac surgery patients aged 60 or older who are recovering in the CVICU and can complete cognitive tests post-surgery. It's not for those with major pre-op cognitive issues, certain heart conditions, severe liver or kidney disease, or an allergy to dexmedetomidine.

Inclusion Criteria

I am scheduled for heart surgery that requires opening my chest, with initial recovery in the CVICU.

I am 60 years old or older.

Exclusion Criteria

I do not have severe allergies or conditions that dexmedetomidine could worsen.

Pre-operative major cognitive dysfunction (CogState Brief Battery score < 80)

I have had an aortic arch replacement or Bentall procedure.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive dexmedetomidine or standard sedation protocols post-surgery

Up to 12 hours

In-hospital stay

In-hospital Monitoring

Participants are monitored for delirium, hemodynamic stability, and other complications

10 days

Daily assessments

Follow-up

Participants are monitored for cognitive outcomes and other post-operative conditions

12 months

Assessments at 3, 6, and 12 months

Treatment Details

Interventions

• Dexmedetomidine Hydrochloride

Trial Overview The study is testing whether Dexmedetomidine (DEX) can prevent long-term memory and thinking problems after cardiac surgery. The goal is to see if DEX improves recovery and reduces hospital stay and healthcare costs.

Participant Groups

Group I: Dexmedetomidine Hydrochloride Group Active Control 1 Intervention

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.

Group II: Standard of Care Group Active Control 1 Intervention

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

Dexmedetomidine Hydrochloride is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Precedex for:

• Sedation for mechanically ventilated patients
• Procedural sedation
• Acute agitation associated with schizophrenia or bipolar disorder

Approved in European Union as Dexdor for:

• Sedation for mechanically ventilated patients
• Procedural sedation

Approved in Canada as Dexmedetomidine Hydrochloride for:

• Sedation for mechanically ventilated patients
• Procedural sedation

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

London Health Sciences Centre

Collaborator

Trials

151

Recruited

60,400+

McMaster University

Collaborator

Trials

936

Recruited

2,630,000+

University Health Network, Toronto

Collaborator

Trials

1,555

Recruited

526,000+

Findings from Research

In elderly patients undergoing major surgery, continuous infusion of dexmedetomidine (DEX) at doses of 200 μg or 400 μg significantly reduced the incidence of postoperative delirium (POD) and early postoperative cognitive dysfunction (POCD) compared to lower doses.

DEX 400 μg was particularly effective in reducing early POCD in patients who had open surgery, and this treatment did not lead to increased sedation, pain intensity, or side effects, indicating its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect and Optimal Dosage of Dexmedetomidine Plus Sufentanil for Postoperative Analgesia in Elderly Patients With Postoperative Delirium and Early Postoperative Cognitive Dysfunction: A Single-Center, Prospective, Randomized, Double-Blind, Controlled Trial. Zhao, W., Hu, Y., Chen, H., et al.[2022]

In a study of 148 aged surgical patients, dexmedetomidine significantly reduced the incidence of post-operative cognitive dysfunction (POCD) to 9.20% compared to 21.31% in the control group, indicating its efficacy in protecting cognitive function after surgery.

The mechanism behind this protective effect may involve the suppression of inflammatory markers, as dexmedetomidine inhibited the post-operative increase of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), which were positively correlated with the incidence of POCD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of dexmedetomidine on post-operative cognitive dysfunction and inflammatory factors in senile patients. Chen, W., Liu, B., Zhang, F., et al.[2022]

In a study of 80 elderly patients undergoing laparoscopic colorectal surgery, dexmedetomidine at doses of 0.5 and 0.8 µg/kg significantly reduced the incidence of postoperative cognitive dysfunction (POCD) compared to lower doses and a control group.

While higher doses of dexmedetomidine were effective in reducing POCD, they were also associated with increased rates of hypotension and bradycardia, particularly in the highest dose group, indicating a need for careful dose management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of different doses of dexmedetomidine on cognitive dysfunction in elderly patients early after laparoscopic surgery for colorectal cancer]. Zhang, Y., Xing, Z., Xu, Y., et al.[2018]

In a study of 83 pediatric patients undergoing inguinal hernia repair, intranasal administration of dexmedetomidine resulted in lower rates of emergence agitation (4.76%) compared to intravenous administration (21.95%), indicating a more favorable awakening experience.

Patients receiving intranasal dexmedetomidine also showed better cognitive, language, and motor scores three days post-surgery, with a significantly lower incidence of cognitive dysfunction (4.76% vs. 21.95% for IV), suggesting that this route of administration may enhance early cognitive recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of different routes of administration on early cognitive function following inguinal hernia repair. Huang, J., Deng, B., Shuai, J., et al.[2021]

Dexmedetomidine significantly reduces the incidence of postoperative cognitive dysfunction (POCD) in elderly adults after general anesthesia, with a relative risk of 0.59 based on 13 randomized controlled trials.

The use of dexmedetomidine also improves cognitive function as measured by the Mini-Mental State Examination (MMSE) score on the first postoperative day, indicating its potential benefits in enhancing recovery after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of dexmedetomidine on postoperative cognitive dysfunction in elderly patients after general anaesthesia: A meta-analysis. Zhou, C., Zhu, Y., Liu, Z., et al.[2022]

Dexmedetomidine (DEX) is an effective sedative with neuroprotective properties, showing improved outcomes in ICU patients and potential as a non-opioid analgesic, which is important for reducing opioid-related side effects.

While DEX has significant benefits for the nervous system, clinicians must be aware of potential adverse effects like hypotension and bradycardia, which can be managed with medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexmedetomidine as an Analgesic Agent with Neuroprotective Properties: Experimental and Clinical Aspects. Bozorgi, H., Zamani, M., Motaghi, E., et al.[2021]

A meta-analysis of 14 randomized controlled trials involving 1626 elderly adults showed that dexmedetomidine significantly reduces the incidence of postoperative cognitive dysfunction (POCD), with a risk ratio of 0.47, indicating nearly a 53% reduction in risk.

The most robust evidence for dexmedetomidine's effectiveness in preventing POCD came from studies using the Mini-Mental State Examination (MMSE) for diagnosis, suggesting it may be a valuable preventative treatment for cognitive issues after surgery in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of dexmedetomidine on postoperative cognitive dysfunction in the elderly: A meta-analysis of randomized controlled trials. Yu, H., Kang, H., Fan, J., et al.[2022]

In a study of 19 patients aged 65 on average who underwent various cardiac surgeries, continuous infusion of dexmedetomidine was found to effectively sedate patients without significantly affecting heart rate or other hemodynamic parameters, except for a decrease in blood pressure.

Dexmedetomidine caused a reduction in systemic vascular resistance and mixed venous oxygen saturation, indicating its vaso-dilating effects, which suggests it can be safely used as a sedative in the post-operative setting after cardiac surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic effects of dexmedetomidine in patients after cardiac surgery. Ishikawa, S., Kugawa, S., Neya, K., et al.[2006]

Dexmedetomidine hydrochloride (Dex) significantly lowers heart rate and arterial pressure during and after intracranial aneurysm surgery, indicating its effectiveness in stabilizing hemodynamics.

Patients receiving Dex showed improved cognitive protection and reduced postoperative pain compared to the control group, suggesting its beneficial role in recovery after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain protective effect and hemodynamics of dexmedetomidine hydrochloride in patients with intracranial aneurysm. Zheng, D., Zhao, S., Zhang, N., et al.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

The Effect and Optimal Dosage of Dexmedetomidine Plus Sufentanil for Postoperative Analgesia in Elderly Patients With Postoperative Delirium and Early Postoperative Cognitive Dysfunction: A Single-Center, Prospective, Randomized, Double-Blind, Controlled Trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

The effects of dexmedetomidine on post-operative cognitive dysfunction and inflammatory factors in senile patients. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Effects of different doses of dexmedetomidine on cognitive dysfunction in elderly patients early after laparoscopic surgery for colorectal cancer]. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of different routes of administration on early cognitive function following inguinal hernia repair. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Effect of dexmedetomidine on postoperative cognitive dysfunction in elderly patients after general anaesthesia: A meta-analysis. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Dexmedetomidine as an Analgesic Agent with Neuroprotective Properties: Experimental and Clinical Aspects. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Influence of dexmedetomidine on postoperative cognitive dysfunction in the elderly: A meta-analysis of randomized controlled trials. [2022]

8. Italy pubmed.ncbi.nlm.nih.gov

Hemodynamic effects of dexmedetomidine in patients after cardiac surgery. [2006]

9. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Brain protective effect and hemodynamics of dexmedetomidine hydrochloride in patients with intracranial aneurysm. [2020]