Methylene Blue and Postoperative Neurocognitive Disorders

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.

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.

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.

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.

Intraoperative infusion of 2mg/kg MB after induction of anesthesia and 1mg/kg MB at the end of surgery

the effectiveness of MB in reducing the incidence of POD compared with placebo in patients undergoing pancreatic tumor surgery.

the effectiveness of MB in reducing the incidence of POCD compared with placebo in patients undergoing pancreatic tumor surgery.

the effectiveness of MB on disease-free survival compared with placebo in patients undergoing pancreatic tumor surgery.

the effectiveness of MB on progression-free survival compared with placebo in patients undergoing pancreatic tumor surgery.

the effectiveness of MB on overall survival compared with placebo in patients undergoing pancreatic tumor surgery.

the changes in levels of neuroinflammation biomarkers (IL-1β, IL-6 and CRP)between MB group and control group

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.

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