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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methylene Blue | Experimental | 2mg/kg MB diluted with normal saline into total 50 ml volume intravenous administration after induction of anesthesia within one hour. |
|
| Control | Placebo Comparator | normal saline in total 50 ml volume intravenous administration after induction of anesthesia within one hour. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methylene Blue | Drug | 2mg/kg MB diluted with normal saline into total 50 ml volume intravenous administration after induction of anesthesia within one hour. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Safety Assessments: incidence of perioperative adverse events |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jun Zhang, PhD | Huashan Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Huashan Hospital | Shanghai | Shanghai Municipality | 200040 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28593326 | Result | 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. | |
| 28576285 |
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| Placebo | Drug | normal saline in total 50 ml volume intravenous administration after induction of anesthesia within one hour. |
|
the incidence of perioperative adverse events to reflect safety of intraoperative intravenous 2mg/kg MB administration |
| the whole perioperative period |
| 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 |
| Result |
| 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; PODCAST Research Group. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet. 2017 Jul 15;390(10091):267-275. doi: 10.1016/S0140-6736(17)31467-8. Epub 2017 May 30. |
| 28840449 | Result | 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. |
| 24316434 | Result | 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. |
| ID | Term |
|---|---|
| D000071257 | Emergence Delirium |
| D000079690 | Postoperative Cognitive Complications |
| ID | Term |
|---|---|
| D003693 | Delirium |
| D003221 | Confusion |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012816 | Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D060825 | Cognitive Dysfunction |
| D003072 | Cognition Disorders |
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| ID | Term |
|---|---|
| D008751 | Methylene Blue |
| ID | Term |
|---|---|
| D010640 | Phenothiazines |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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