Intraoperative Infusion of Methylene Blue for Prevention of Postoperative Delirium and Cognitive Dysfunction in Elderly Patients Undergoing Major Elective Noncardiac Surgery

Postoperative Delirium Clinical Trial

Official title:

Intraoperative Infusion of Methylene Blue for Prevention of Postoperative Delirium and Cognitive Dysfunction in Elderly Patients Undergoing Major Elective Noncardiac and Nonneurosurgical Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04341844
• Other study ID #: KY2019-274
• Status: Completed
• Phase: N/A
• Start date: January 14, 2019
• Est. completion date: July 30, 2020

Study information

• Verified date: October 2020
• Source: Fudan University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Postoperative neurocognitive impairments often occur in elderly patients undergoing anesthesia and non-cardiac surgery, including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). These disorders are often associated with increased mortality and morbidity, prolonged length of hospital stay, functional and cognitive decline with nursing home or long-term care facility placement. Until now highly effective intervention has not been established yet. As a mitochondrial protective agent, the role of methylene blue(MB) in preventing elderly patients from POD/POCD is unknown.Therefore, investigators design this study to validate its prevention against POD/POCD and the aim of this study is to evaluate the efficacy and safety of perioperative administration of MB for POD/POCD prevention.

Description:

Postoperative neurocognitive impairments often occur in elderly patients undergoing major surgery, 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. POD and POCD are major complications that cause disability and distress for millions of patients annually.In 2004, there was an estimated 5-40% incidence in 7.9 million patients over 65 years who had a surgical procedure subsequently experiencing either POD or POCD.The underlying pathophysiology of Postoperative neurocognitive impairments is increasingly understood, implicating a prominent role of neuroinflammation, oxidative stress and mitochondrial dysfunction.Recent experimental evidences reveal that mitochondrial dysfunction is increasingly considered a significant contributor to the development of POD and POCD. Methylene blue(MB) is a diaminophenothiazine with a long history of clinical use due to its minimal side effect profiles. MB currently is used for treatment of methemoglobinemia, carbon monoxide poisoning, and vasoplegic syndrome as well as for surgical staining. MB could diffuse rapidly into brain and accumulate in the cytoplasm and mitochondria of neurons. In recent years its role as a mitochondrial protective agent has elicited much of its renewed interest, especially, studies have shown that MB has established its neuroprotective effects against ischemic stroke, post-chemotherapy-induced Encephalopathy and neurodegenerative diseases caused by Alzheimer's disease(AD) and psychoses.To date, there is no trials have examined the role of intraoperative MB administration in prevention of POD and POCD in elderly patients undergoing non-cardiac surgery, who have preoperative normal neurocognitive function. Therefore, investigators design this study to evaluate the efficacy and safety of perioperative administration of MB for POD/POCD prevention. It's an entirely novel therapy for postoperative neurocognitive disorders and will have high clinical translatable value if this intervention is found to be beneficial.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 248
• Est. completion date: July 30, 2020
• Est. primary completion date: April 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years to 80 Years

Eligibility

Inclusion Criteria:

• aged 60-80 years old
• planning to undergo non-cardiac and non-neurosurgical surgery (e.g..thoracic, orthopaedic, urologic and major abdominal surgeries) under general anesthesia
• MMSE>20
• Liver and kidney function are normal
• 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:

• Patients with personal history of allergy to methylene blue
• Emergency Surgery
• Patients have 6-phospho-glucose dehydrogenase deficiency (vicia faba disease)
• Patients have recent drug administration that may lead to drug interactions(e.g..SSRIs, SNRIs)
• Patient with a history of major head trauma
• Patients with a history of drug or alcohol abuse
• Patient has serious mental or neurological disorders
• Patients with severe language, hearing and visual impairment
• Patients have serious medical diseases(e.g..heart failure, acute stage of myocardial infarction or respiratory failure)
• Illiteracy
• Patients have participated in other clinical trials in the last 3 months.

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Delirium
• Postoperative Cognitive Dysfunction
• Postoperative Delirium

Intervention

Drug:
• Methylene Blue
2mg/kg MB diluted with normal saline into total 50 ml volume intravenous administration after induction of anesthesia within one hour.
• Placebo
normal saline in total 50 ml volume intravenous administration after induction of anesthesia within one hour.

Locations

Country	Name	City	State
China	Huashan Hospital	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Fudan University

Country where clinical trial is conducted

China, 

References & Publications (4)

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. Review. — 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. Review. — 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 elderly patients undergoing major elective non-cardiac surgery.	Participants will be followed for the duration of hospital stay, an expected average of 5 days.
Secondary	Incidence of postoperative cognitive dysfunction (POCD)	the effectiveness of MB in reducing the incidence of POCD compared with placebo in elderly patients undergoing major elective non-cardiac surgery.	Up to 3 month after surgery
Secondary	Safety Assessments: incidence of perioperative adverse events	the incidence of perioperative adverse events to reflect safety of intraoperative intravenous 2mg/kg MB administration	the whole perioperative period
Secondary	Oxidative Stress Biomarkers	the Changes in levels of oxidative stress biomarkers( superoxide dismutase(SOD) and homocysteine(HCY) )	the day before surgery and postoperative one day