International Substudy Enigma2 on Postoperative Cognitive Disorders (ISEP)

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

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.

Study Overview

• Status: Terminated
• Conditions: Anesthesia; Delirium, Dementia, Amnestic, Cognitive Disorders
• Intervention / Treatment: Drug: Nitrous Oxide; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Hong Kong
    • Hong Kong, Hong Kong, China
      • The Chinese University of Hong Kong Prince of Wales Hospital
• Switzerland
  • Geneva, Switzerland, 1203
    • Geneva University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Nitrous Oxide; Receives a mixture of 70% Nitrous Oxide in 30% Oxygen	Drug: Nitrous Oxide; Administration of a concentration of 70% Nitrous Oxide with 30% Oxygen in the anaesthetic gas mixture; Other Names: N2O
PLACEBO_COMPARATOR: Air/Oxygen (placebo); Receives a mixture of 70% Air in 30% Oxygen	Other: Placebo; Administration of a concentration of 70% Air with 30% Oxygen in the anaesthetic gas mixture; Other Names: Air/Oxygen

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Collaborators: Chinese University of Hong Kong; Prince of Wales Hospital, Shatin, Hong Kong
• Investigators: Study Chair: Myles Paul, MD, FANZCA, Bayside Health

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2013
• Primary Completion (ACTUAL): May 1, 2016
• Study Completion (ACTUAL): May 1, 2016

Study Registration Dates

• First Submitted: June 26, 2015
• First Submitted That Met QC Criteria: July 1, 2015
• First Posted (ESTIMATE): July 2, 2015

Study Record Updates

• Last Update Posted (ACTUAL): December 16, 2020
• Last Update Submitted That Met QC Criteria: December 12, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Cognition Disorders; Neurocognitive Disorders; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Anesthetics, Inhalation; Nitrous Oxide
• Other Study ID Numbers: NAC 08-021; Enigma II nested NCT00430989 (OTHER: ClinicalTrials.gov)