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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04341844
Recruitment Status : Completed
First Posted : April 10, 2020
Last Update Posted : October 27, 2020
Sponsor:
Information provided by (Responsible Party):
Jun Zhang, Huashan Hospital

Brief 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.

Condition or disease Intervention/treatment Phase
Postoperative Delirium Postoperative Cognitive Dysfunction Drug: Methylene Blue Drug: Placebo Not Applicable

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 248 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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
Actual Study Start Date : January 14, 2019
Actual Primary Completion Date : April 30, 2020
Actual Study Completion Date : July 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Delirium

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




Primary Outcome Measures :
  1. Incidence of postoperative delirium(POD) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 days. ]
    the effectiveness of MB in reducing the incidence of POD compared with placebo in elderly patients undergoing major elective non-cardiac surgery.


Secondary Outcome Measures :
  1. Incidence of postoperative cognitive dysfunction (POCD) [ Time Frame: Up to 3 month after surgery ]
    the effectiveness of MB in reducing the incidence of POCD compared with placebo in elderly patients undergoing major elective non-cardiac surgery.

  2. Safety Assessments: incidence of perioperative adverse events [ Time Frame: the whole perioperative period ]
    the incidence of perioperative adverse events to reflect safety of intraoperative intravenous 2mg/kg MB administration

  3. Oxidative Stress Biomarkers [ Time Frame: the day before surgery and postoperative one day ]
    the Changes in levels of oxidative stress biomarkers( superoxide dismutase(SOD) and homocysteine(HCY) )



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Ages Eligible for Study:   60 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04341844


Locations
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China, Shanghai
Huashan Hospital
Shanghai, Shanghai, China, 200040
Sponsors and Collaborators
Fudan University
Investigators
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Principal Investigator: Jun Zhang, PhD Huashan Hospital
Publications of Results:

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Responsible Party: Jun Zhang, Principal Investigator, Huashan Hospital
ClinicalTrials.gov Identifier: NCT04341844    
Other Study ID Numbers: KY2019-274
First Posted: April 10, 2020    Key Record Dates
Last Update Posted: October 27, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Delirium
Cognitive Dysfunction
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Methylene Blue
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action