Methylene Blue and Postoperative Neurocognitive Disorders
Condition: Postoperative Delirium; Postoperative Cognitive Dysfunction
MeSH terms: Emergence Delirium; Postoperative Cognitive Complications; Cognitive Dysfunction; Neurocognitive Disorders
Study type: Interventional

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.
    

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.
    

Intervention name(s): Methylene Blue; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Intraoperative infusion of 2mg/kg MB after induction of anesthesia and 1mg/kg MB at the end of surgery; Equal volume of normal saline after induction of anesthesia and at the end of surgery
Intervention MeSH terms: Methylene Blue
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention