Clinical trial NCT04529265: Methylene Blue and Postoperative Neurocognitive Disorders
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Postoperative Delirium
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2020-08-27
Enrollment: 314
Sex: ALL
Minimum age (years): 55
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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 neuroinflammation may be linked to pathogensis of (postoperative delirium) POD and postoperative cognitive dysfunction (POCD). As Methylene blue(MB) has neuroprotective and anti-inflammatory properties, and it is a safe drug with long history of clinical use, we propose that inflammation-targeted interventions may be useful to prevent POD/POCD in surgical patients.

Detailed description: Pancreatic cancer is one of the most common incident cancers that causes cancer death in China. The patients undergoing pancreatic cancer surgery not only have a low survival rate, but also have 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 systemic inflammation plays a central role in neurodegenerative diseases, leading to neuronal death, metabolic disturbance, and excessive reactive oxidative species(ROS) production. Actually, recent experimental evidences have linked anesthesia/surgery-induced inflammation to POCD, and the available data support that restoration of neuroinflammation could reduce postoperative cognitive impairments in developing and aging animals. Therefore, we propose those inflammation-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 neuroprotection 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. And our experimental study also found that MB inhibited neuroinflammation and improved neurobehavioral deficits in lipopolysaccharide-treated mice via inhibiting the microglial Siah2/Morg1/PHD3 pathway. 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.

Eligibility criteria: Inclusion Criteria:

* aged 55-80 years old
* planning to undergo pancreatic tumor surgery.
* 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)
* MMSE\<24
* 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, hepatic and renal dysfunctions)
* severe language, visual or auditory deficiency
* other neoplastic diseases diagnosed in the past 5 years
* participated in other clinical trials within 3 months.

Primary outcomes:
measure: Incidence of postoperative delirium(POD)
timeFrame: Participants will be followed for the duration of hospital stay, an expected average of 7 days.
Secondary outcomes:
measure: type and duration of POD
timeFrame: Participants will be followed for the duration of hospital stay, an expected average of 7 days
measure: Safety Assessments: incidence of perioperative adverse events
timeFrame: the whole perioperative period
measure: neuroinflammation biomarkers
timeFrame: on the day of surgery (before anesthesia and at the end of surgery) and postoperative one day
measure: expressions of inflammatory and adhesion genes in cerebral endothelial cells
timeFrame: before anesthesia and at first day after surgery
measure: numbers of PBMCs adhesion to cerebral endothelial cells
timeFrame: before anesthesia and at first day after surgery
measure: Incidence of postoperative cognitive dysfunction (POCD)
timeFrame: Up to the 7th day after surgery
measure: overall survival
timeFrame: up to 3 years after surgery
measure: disease-free survival
timeFrame: up to 3 years after surgery
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai Cancer Center, Fudan University
Study officials:
affiliation: Fudan University
name: Jun Zhang, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Deng Y, Wang R, Li S, Zhu X, Wang T, Wu J, Zhang J. Methylene blue reduces incidence of early postoperative cognitive disorders in elderly patients undergoing major non-cardiac surgery: An open-label randomized controlled clinical trial. J Clin Anesth. 2021 Feb;68:110108. doi: 10.1016/j.jclinane.2020.110108. Epub 2020 Oct 19.
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 Postoperative Delirium and Cognitive Dysfunction in Elderly Patients Undergoing Major Elective Noncardiac Surgery: A Randomized Clinical Trial. JAMA Surg. 2017 Aug 16;152(8):e171505. doi: 10.1001/jamasurg.2017.1505. Epub 2017 Aug 16.
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