Clinical trial NCT02489097: International Substudy Enigma2 on Postoperative Cognitive Disorders
Official title: Evaluating the Incidence and Association Between Nitrous Oxide and Postoperative Cognitive Disorders in Anaesthesia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Anesthesia
Delirium, Dementia, Amnestic, Cognitive Disorders
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
Collaborators: name: Prince of Wales Hospital, Shatin, Hong Kong
name: Chinese University of Hong Kong
First posted: 2015-07-02
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

1. Dementia (MMS test≤24)
2. Parkinson Disease
3. Patients taking regularly (\>2 weeks) tricyclic antidepressants or neuroleptics
4. Patients suffering from Alcohol Dependency (WHO CRITERIA )
5. Patients suffering from severe hypoacusis or visual loss or any other reason hindering the CANTAB battery testing process
6. Patients with untreated deficit in Vitamin B6, B12 and folic acid
7. Patients with marked impairment of gas-exchange requiring Fi02\> 0.5 intraoperatively
8. 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)
9. N2O unavailable

Primary outcomes:
measure: Memory, Executive function, Attention and psychomotor speed testing battery
timeFrame: Baseline before surgery
measure: Memory, Executive function, Attention and psychomotor speed using CANTAB Cognitive testing battery at 7days following surgery
timeFrame: First assessment (7 days)
measure: Memory, Executive function, Attention and psychomotor speed using CANTAB Cognitive testing battery at 3 months following surgery
timeFrame: Second assessment (3 months)
Secondary outcomes:
measure: ICU stay
timeFrame: up to a maximum of 3 months
measure: Hospital stay
timeFrame: up to a maximum of 3 months
measure: Quality of life
timeFrame: 3 months
Other outcomes:
Locations:
city: Hong Kong
country: China
facility: The Chinese University of Hong Kong Prince of Wales Hospital
state: Hong Kong
city: Geneva
country: Switzerland
facility: Geneva University Hospitals
Study officials:
affiliation: Bayside Health
name: Myles Paul, MD, FANZCA
role: STUDY_CHAIR
References:
citation: Chan MTV, Wan ACM, Gin T, Leslie K, Myles PS. Chronic postsurgical pain after nitrous oxide anesthesia. Pain. 2011 Nov;152(11):2514-2520. doi: 10.1016/j.pain.2011.07.015. Epub 2011 Sep 1.
citation: Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology. 2008 Oct;109(4):707-22. doi: 10.1097/ALN.0b013e3181870a17.
citation: Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, Silbert BS, Pascoe E; ENIGMA Trial Group. Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. Anesthesiology. 2007 Aug;107(2):221-31. doi: 10.1097/01.anes.0000270723.30772.da.