International Substudy Enigma2 on Postoperative Cognitive Disorders

Anesthesia Clinical Trial

— ISEP  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02489097
• Other study ID #: NAC 08-021
• Secondary ID: Enigma II nested
• Status: Terminated
• Phase: Phase 4
• Start date: September 2013
• Est. completion date: May 2016

Study information

• Verified date: December 2020
• Source: University Hospital, Geneva
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 140
• Est. completion date: May 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Anesthesia
• Cognition Disorders
• Delirium
• Delirium, Dementia, Amnestic, Cognitive Disorders
• Neurocognitive Disorders

Intervention

Drug:
• Nitrous Oxide
Administration of a concentration of 70% Nitrous Oxide with 30% Oxygen in the anaesthetic gas mixture

Other:
• Placebo
Administration of a concentration of 70% Air with 30% Oxygen in the anaesthetic gas mixture

Locations

Country	Name	City	State
China	The Chinese University of Hong Kong Prince of Wales Hospital	Hong Kong	Hong Kong
Switzerland	Geneva University Hospitals	Geneva

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital, Geneva	Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong

Countries where clinical trial is conducted

China,  Switzerland, 

References & Publications (3)

Chan MT, Wan AC, Gin T, Leslie K, Myles PS. Chronic postsurgical pain after nitrous oxide anesthesia. Pain. 2011 Nov;152(11):2514-20. doi: 10.1016/j.pain.2011.07.015. Epub 2011 Sep 1. — View 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. — View 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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)
Primary	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	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
Secondary	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
Secondary	Quality of life	Use of the validated EuroQol test (EQ-5D questionnaire http://www.euroqol.org/)	3 months