Methylene Blue and Postoperative Neurocognitive Disorders

February 10, 2024 updated by: Jun Zhang, Fudan University

Effectiveness and Safety of Methylene Blue for Prevention of Postoperative Neurocognitive Disorders in Patients Undergoing Pancreatic Tumor Surgery: A Prospective Randomized Controlled Clinical Trial

Postoperative Neurocognitive Disorders are the most common neurological complications after major surgery, which are associated with higher increased mortality and morbidity in elderly patients undergoing major surgery. Until now highly effective intervention has not been established yet. Recent preclinical studies suggest mithochiondrial dysfunction may be linked to pathogensis of (postoperative delirium) POD and postoperative cognitive dysfunction (POCD). As Methylene blue(MB) is a mitochondrial protective agent and a safe drug with long history of clinical use, we propose that mitochondrial-targeted interventions may be useful to prevent POD/POCD in surgical patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Pancreatic cancer is one of the most common incident cancers that causes cancer death in China. The patients of pancreatic cancer not only have a high proportion of vitality, but also high postoperative complications, including postoperative delirium(POD) characterized by an acute change in cognition with altered consciousness and impaired attention, and postoperative cognitive dysfunction(POCD) mainly manifested as reduced ability of learning and memory. It is reported that POD occurred in 10% - 60% of elderly surgical patients, varying by surgical procedure, while the incidence of POCD is approximately 25%-40%. Although it was reported that small dosage of intravenous dexmedetomidine maybe reduce the incidence of POD/POCD, a large number of studies had also shown that dexmedetomidine would promote breast cancer, liver cancer and lung cancer cells' proliferation and migration, which urged to find more effective and safer treatment strategies to reduce the incidence of postoperative neurocognitive dysfunction in elderly cancer patients.

The preclinical and clinical studies have demonstrated anesthesia/surgery-induced neuroinflammation and oxidative stress are strongly associated with postoperative neurocognitive disorders. The mitochondrial dysfunction plays a central role in neurodegenerative diseases, leading to neuronal death, neuroinflammation, metabolic disturbance, and excessive reactive oxidative species(ROS) production. Actually, recent experimental evidences have linked anesthesia/surgery-induced mitochondrial dysfunction to POCD, and the available data support that restoration of mitochondrial function could reduce postoperative cognitive impairments in developing and aging animals. Therefore, we propose those mitochondrial-targeted interventions may be useful to prevent POD/POCD in elderly surgical patients.

Methylene blue(MB) is a diaminophenothiazine with a long history of clinical use due to its safe profile. The studies have indicated that MB, as a redox mediator in the electron transfer chain (ETC), restores mitochondrial function and enhances brain metabolism. In recent years its role as a mitochondrial protective agent has elicited much of its renewed interest, especially its neuroprotective effects in clinical studies against ischemic stroke, chemotherapy-induced encephalopathy and neurodegenerative disorders associated with psychoses. MB has been proposed to protect selective regions of the brain, wherein memory is encoded and processed in various models of brain dysfunction-induced amnesia, and importantly, enhances learning and memory in patients with mental diseases and healthy human through its beneficial brain network effects. Now its emerging role as neuroprotectant and memory-enhancer makes this old drug become a promising cure for neurodegenerative diseases. Our previous clinical study ( NCT04341844) found that the single dosage of 2mg/kg MB was safe to the elderly patients undergoing non-cardiac surgery, and was effective to prevent of the incidence of POD and early POCD. However, whether the safety and effectiveness of MB could prevent postoperative cognitive impairments in pancreatic tumor patients needs further investigation. Therefore, we design this prospective randomized controlled clinical trial to test whether MB could decrease the incidence of POD/POCD in patients undergoing pancreatic tumor surgery.

Study Type

Interventional

Enrollment (Actual)

314

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
      • Shanghai, China
        • Shanghai Cancer Center, Fudan University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • aged 18-80 years old
  • planning to undergo pancreatic tumor surgery.
  • MMSE ≥ 24
  • Patients have the ability to act in full spirit, understand and sign the informed consent, and are willing to complete the whole research process.

Exclusion Criteria:

  • preexisted dementia, major depression or other serious mental or neurological disorders
  • history of allergy to MB or 6-phospho-glucose dehydrogenase deficiency (favism)
  • pregnant or lactating women
  • illiterate patients
  • patients diagnosed with rheumatoid diseases such as systemic lupus erythematosus, rheumatoid arthritis and ankylosing spondylitis
  • drug or alcohol abuse or recent drug administration that may lead to drug interactions, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)
  • history of major head trauma
  • serious medical diseases (ie. heart failure, pulmonary hypertension, acute stage of myocardial infarction or respiratory failure, liver and kidney dysfunctions)
  • severe language, visual or auditory deficiency
  • participated in other clinical trials within 3 months.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Methylene Blue group
The first dosage: 2mg/kg MB diluted with normal saline into total 50 ml volume intravenous administration after induction of anesthesia within one hour; The second dosage: 1mg/kg MB diluted with normal saline into total 50 ml volume intravenous administration before the end of surgery within 30 minutes.
Drug: Methylene Blue
Intraoperative infusion of 2mg/kg MB after induction of anesthesia and 1mg/kg MB at the end of surgery
Placebo Comparator: Control group
The first dosage: normal saline in total 50 ml volume intravenous administration after induction of anesthesia within one hour; The second dosage: normal saline in total 50 ml volume intravenous administration before the end of surgery within 30 minutes.
Drug: Placebo
Equal volume of normal saline after induction of anesthesia and at the end of surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of postoperative delirium(POD)
Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 7 days.
the effectiveness of MB in reducing the incidence of POD compared with placebo in patients undergoing pancreatic tumor surgery.
Participants will be followed for the duration of hospital stay, an expected average of 7 days.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of postoperative cognitive dysfunction (POCD)
Time Frame: Up to the 7th day after surgery
the effectiveness of MB in reducing the incidence of POCD compared with placebo in patients undergoing pancreatic tumor surgery.
Up to the 7th day after surgery
Safety Assessments: incidence of perioperative adverse events
Time Frame: the whole perioperative period
the incidence of perioperative adverse events to reflect safety of MB administration
the whole perioperative period
disease-free survival
Time Frame: up to 3 years after surgery
the effectiveness of MB on disease-free survival compared with placebo in patients undergoing pancreatic tumor surgery.
up to 3 years after surgery
progression-free survival
Time Frame: up to 3 years after surgery
the effectiveness of MB on progression-free survival compared with placebo in patients undergoing pancreatic tumor surgery.
up to 3 years after surgery
overall survival
Time Frame: up to 3 years after surgery
the effectiveness of MB on overall survival compared with placebo in patients undergoing pancreatic tumor surgery.
up to 3 years after surgery
nerve damage biomarkers
Time Frame: on the day of surgery (before surgery and at the end of surgery) and postoperative one day
the changes in levels of Neurofilament Light (NfL ) between MB group and control group
on the day of surgery (before surgery and at the end of surgery) and postoperative one day
neuroinflammation biomarkers
Time Frame: on the day of surgery (before surgery and at the end of surgery) and postoperative one day
the changes in levels of neuroinflammation biomarkers (IL-1β, IL-6 and CRP)between MB group and control group
on the day of surgery (before surgery and at the end of surgery) and postoperative one day
melatonin
Time Frame: on the day of surgery (before surgery and at the end of surgery) and postoperative one day
the changes in levels of melatonin between MB group and control group
on the day of surgery (before surgery and at the end of surgery) and postoperative one day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fudan University

Investigators

  • Principal Investigator: Jun Zhang, PhD, Fudan University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2021

Primary Completion (Actual)

April 30, 2023

Study Completion (Actual)

October 30, 2023

Study Registration Dates

First Submitted

August 22, 2020

First Submitted That Met QC Criteria

August 25, 2020

First Posted (Actual)

August 27, 2020

Study Record Updates

Last Update Posted (Estimated)

February 13, 2024

Last Update Submitted That Met QC Criteria

February 10, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2008222-Exps

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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