International Substudy Enigma2 on Postoperative Cognitive Disorders

Study Overview
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Brief Summary
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The study is a substudy of the Enigma2 trial (NCT00430989) which aims at investigating the effectiveness and safety of nitrous oxide (N2O) in anaesthesia.The substudy focus is on postoperative cognitive disorders. Substudy Hypothesis: In patients undergoing anaesthesia for major surgery, administration of N2O will reduce postoperative cognitive disorders when compared with otherwise identically managed surgical patients not receiving N2O as a component of their anaesthesia.

Detailed Description
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Numerous studies questioned the routine use of nitrous oxide (N2O), the oldest anaesthetic agent used since the development of anaesthesia care. Despite its wide use, there is sufficient doubt as to the risk-benefit profile. There is strong evidence that N2O is a major risk factor for postoperative nausea and vomiting. It is clear that (even) brief exposure to N2O impairs methionine synthetase, an enzyme required for DNA production, red and white blood cell formation. Tissue hypoxia may be more common. These adverse effects are enhanced in sick patients (ie. those at highest risk, with increased hospital length of stay and healthcare expenditure), and will be more likely in longer surgery. At the same time, observational studies and subgroup analysis of published trials suggest that N2O may have beneficial effects in preventing pain and postoperative cognitive disorders Outcome trial data on postoperative cognitive disorders are lacking in this area for an anaesthetic gas used in more than 90% of all surgery around the world. The enigma2 substudy as a nested study of the large Enigma2 randomised controlled trial aims at answering this question. The investigators aim at recruiting 420 patients in 2 of the 25 centres participating to the Enigma 2 trials, who are undergoing major surgery.

Official Title
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Evaluating the Incidence and Association Between Nitrous Oxide and Postoperative Cognitive Disorders in Anaesthesia

Conditions
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Anesthesia, Delirium, Dementia, Amnestic, Cognitive Disorders

Intervention / Treatment
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* Drug: Nitrous Oxide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males and females aged ≥ 45 years, undergoing noncardiac surgery and general anaesthesia that exceeds two hours. At increased risk of cardiac events, defined as any of: history of coronary artery disease (angina, MI, Coronary revascularisation-Coronary Artery Bypass Graft (CABG) and Percutaneous Transluminal Coronary Angiography ( PTCA)-, positive stress testing, angiography/other imaging, Q waves on ECG) heart failure cerebrovascular disease due to atherothrombotic disease aortic or peripheral vascular disease OR three or more of the following risk factors: age ≥70 years, history of heart failure, diabetes (medicated), hypertension (medicated), preoperative serum creatinine >175 mmol/L, cholesterol ≥6.2 mmol/L, history of a transient ischemic attack (TIA), Exclusion Criteria: Dementia (MMS test≤24) Parkinson Disease Patients taking regularly (>2 weeks) tricyclic antidepressants or neuroleptics Patients suffering from Alcohol Dependency (WHO CRITERIA ) Patients suffering from severe hypoacusis or visual loss or any other reason hindering the CANTAB battery testing process Patients with untreated deficit in Vitamin B6, B12 and folic acid Patients with marked impairment of gas-exchange requiring Fi02> 0.5 intraoperatively Patients with specific circumstances where N2O is contraindicated (eg. volvulus, pulmonary hypertension, raised intracranial pressure) or the use of supplemental oxygen is planned (eg. colorectal surgery) N2O unavailable

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nitrous Oxide<br>Receives a mixture of 70% Nitrous Oxide in 30% Oxygen | Drug: Nitrous Oxide<br>* Administration of a concentration of 70% Nitrous Oxide with 30% Oxygen in the anaesthetic gas mixture<br>* Other names: N2O;|
| Placebo Comparator: Air/Oxygen (placebo)<br>Receives a mixture of 70% Air in 30% Oxygen | Other: Placebo<br>* Administration of a concentration of 70% Air with 30% Oxygen in the anaesthetic gas mixture<br>* Other names: Air/Oxygen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Memory, Executive function, Attention and psychomotor speed testing battery | Validated Computerized testing battery developed by the University of Cambridge for cognitive testing (CANTAB). Patients are tested for baseline cognitive function before surgery | Baseline before surgery | 
| Memory, Executive function, Attention and psychomotor speed using CANTAB Cognitive testing battery at 7days following surgery | Validated Computerized testing battery developed by the University of Cambridge for cognitive testing (CANTAB). Patients are tested for changes from the baseline cognitive function (before surgery) at 7 days after surgery | First assessment (7 days) | 
| Memory, Executive function, Attention and psychomotor speed using CANTAB Cognitive testing battery at 3 months following surgery | Validated Computerized testing battery developed by the University of Cambridge for cognitive testing (CANTAB). Patients are tested for changes from the baseline cognitive function (before surgery) at 3 months after surgery | Second assessment (3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU stay | Planned and unplanned admission to the ICU and ICU duration of stay; Follow up to be performed for the whole duration of hospital stay and up to a maximum of 3 months | up to a maximum of 3 months | 
| Hospital stay | Duration of stay in Hospital; Follow up to be performed for the whole duration of hospital stay and up to a maximum of 3 months | up to a maximum of 3 months | 
| Quality of life | Use of the validated EuroQol test (EQ-5D questionnaire http://www.euroqol.org/) | 3 months |