Methylene Blue and Postoperative Neurocognitive Disorders

Postoperative Delirium Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04529265
• Other study ID #: 2008222-Exps
• Status: Completed
• Phase: N/A
• Start date: May 1, 2021
• Est. completion date: October 30, 2023

Study information

• Verified date: February 2024
• Source: Fudan University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 314
• Est. completion date: October 30, 2023
• Est. primary completion date: April 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Emergence Delirium
• Neurocognitive Disorders
• Postoperative Cognitive Complications
• Postoperative Cognitive Dysfunction
• Postoperative Delirium

Intervention

Drug:
• Methylene Blue
Intraoperative infusion of 2mg/kg MB after induction of anesthesia and 1mg/kg MB at the end of surgery
• Placebo
Equal volume of normal saline after induction of anesthesia and at the end of surgery

Locations

Country	Name	City	State
China	Shanghai Cancer Center, Fudan University	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Fudan University

Country where clinical trial is conducted

China, 

References & Publications (5)

Avidan MS, Maybrier HR, Abdallah AB, Jacobsohn E, Vlisides PE, Pryor KO, Veselis RA, Grocott HP, Emmert DA, Rogers EM, Downey RJ, Yulico H, Noh GJ, Lee YH, Waszynski CM, Arya VK, Pagel PS, Hudetz JA, Muench MR, Fritz BA, Waberski W, Inouye SK, Mashour GA; — View Citation

Deiner S, Luo X, Lin HM, Sessler DI, Saager L, Sieber FE, Lee HB, Sano M; and the Dexlirium Writing Group; Jankowski C, Bergese SD, Candiotti K, Flaherty JH, Arora H, Shander A, Rock P. Intraoperative Infusion of Dexmedetomidine for Prevention of Postoper — View Citation

Gonzalez-Lima F, Barksdale BR, Rojas JC. Mitochondrial respiration as a target for neuroprotection and cognitive enhancement. Biochem Pharmacol. 2014 Apr 15;88(4):584-93. doi: 10.1016/j.bcp.2013.11.010. Epub 2013 Dec 4. — View Citation

Tucker D, Lu Y, Zhang Q. From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue. Mol Neurobiol. 2018 Jun;55(6):5137-5153. doi: 10.1007/s12035-017-0712-2. Epub 2017 Aug 24. — View Citation

Wischik CM, Staff RT, Wischik DJ, Bentham P, Murray AD, Storey JM, Kook KA, Harrington CR. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimers Dis. 2015;44(2):705-20. doi: 10.3233/JAD-14287 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of postoperative delirium(POD)	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	Incidence of postoperative cognitive dysfunction (POCD)	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
Secondary	Safety Assessments: incidence of perioperative adverse events	the incidence of perioperative adverse events to reflect safety of MB administration	the whole perioperative period
Secondary	disease-free survival	the effectiveness of MB on disease-free survival compared with placebo in patients undergoing pancreatic tumor surgery.	up to 3 years after surgery
Secondary	progression-free survival	the effectiveness of MB on progression-free survival compared with placebo in patients undergoing pancreatic tumor surgery.	up to 3 years after surgery
Secondary	overall survival	the effectiveness of MB on overall survival compared with placebo in patients undergoing pancreatic tumor surgery.	up to 3 years after surgery
Secondary	nerve damage biomarkers	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
Secondary	neuroinflammation biomarkers	the changes in levels of neuroinflammation biomarkers (IL-1ß, 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
Secondary	melatonin	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