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Trial details imported from

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Registration number
Ethics application status
Date submitted
Date registered
Date last updated

Titles & IDs
Public title
The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial
Scientific title
Large, Randomised, Parallel-group, Controlled Trial, With Patients Randomly Allocated to Either N2O-containing (70% N2O in Oxygen [FiO2 0.3]) or N2O-free (70% Nitrogen in Oxygen [FiO2 0.3]).
Secondary ID [1] 0 0
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coronary Artery Disease 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Study type
Description of intervention(s) / exposure
Other interventions - Nitrous Oxide
Other interventions - No Nitrous Oxide

Other: 70% Nitrous Oxide - General anaesthesia using 70% Nitrous Oxide with fraction of inspired oxygen at 30%

Other: No Nitrous Oxide - General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen at 30%

Other interventions: Nitrous Oxide
General anaesthesia with the inclusion of Nitrous Oxide at 70%

Other interventions: No Nitrous Oxide
General anaesthesia with no use of Nitrous Oxide

Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Primary outcome [1] 0 0
The Primary Endpoint is a Composite of Death and Cardiovascular Events (Clinical and Silent MI, Cardiac Failure, Cardiac Arrest, Pulmonary Embolism, and Stroke) Measured at 30 Days After Surgery.
Timepoint [1] 0 0
30 days post op
Secondary outcome [1] 0 0
Myocardial Infarction (MI)
Timepoint [1] 0 0
30 days post op
Secondary outcome [2] 0 0
Cardiac Arrest
Timepoint [2] 0 0
30 days
Secondary outcome [3] 0 0
Pulmonary Embolism
Timepoint [3] 0 0
30 Days Post op
Secondary outcome [4] 0 0
Timepoint [4] 0 0
30 Days Post op
Secondary outcome [5] 0 0
Wound Infection
Timepoint [5] 0 0
30 Days Post op
Secondary outcome [6] 0 0
Hospital Stay (Days)
Timepoint [6] 0 0
30 Days Post Op

Key inclusion criteria
Inclusion Criteria

1. Adult males and females age = 45 years, undergoing noncardiac surgery and general
anaesthesia expected to exceed two hours.

2. At increased risk of cardiac events, defined as any of

1. history of coronary artery disease as defined by a history of any one of the
following: i. angina ii. MI iii. segmental wall motion abnormality on
echocardiography or a fixed defect on radionuclide imaging iv. a positive
exercise stress test for cardiac ischaemia v. a positive radionuclide exercise,
echocardiographic exercise, or pharmacological cardiovascular stress test for
cardiac ischaemia vi. coronary revascularization (CABG or PTCA) vii. angiographic
evidence of atherosclerotic stenosis > 50% of the diameter of any coronary artery
viii. ECG with pathological Q waves in two contiguous leads

2. heart failure

3. cerebrovascular disease thought due to atherothrombotic disease

4. aortic or peripheral vascular disease

5. or three or more of the following risk factors:

- age =70 years

- any history of congestive heart failure

- diabetes and currently on an oral hypoglycaemic agent or insulin therapy

- current treatment for hypertension

- preoperative serum creatinine >175 micro mol/L (> 2.0 mg/dl)

- current or previous high cholesterol =6.2 mmol/L (> 240 mg/dl)

- history of a transient ischemic attack (TIA) (i.e. a transient focal
neurological deficit that lasted less than 24 hours and thought to be
vascular in origin)

- emergency/urgent surgery (i.e. surgery which must be undertaken within 24
hours of acute presentation to hospital)

- high-risk type of surgery (i.e. intrathoracic or intraperitoneal)
Minimum age
18 Years
Maximum age
No limit
Both males and females
Can healthy volunteers participate?
Key exclusion criteria
Exclusion Criteria

1. having cardiac surgery

2. marked impairment of gas-exchange expected to require Fi02> 0.5 intraoperatively

3. specific circumstances where N2O is contraindicated (eg. volvulus, pulmonary
hypertension, raised intracranial pressure) or the anaesthetist plans to use
supplemental oxygen (eg. colorectal surgery)

4. N2O unavailable for use.

Study design
Purpose of the study
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Other design features
Phase 4
Type of endpoint(s)
Statistical methods / analysis

Recruitment status
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Date of last participant enrolment
Date of last data collection
Sample size
Accrual to date
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Alfred Hosptial - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne

Funding & Sponsors
Primary sponsor type
Bayside Health
Other collaborator category [1] 0 0
Name [1] 0 0
National Health and Medical Research Council, Australia
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Brief summary
To investigate the safety of nitrous oxide (N2O) anaesthesia in patients with risk factors
for coronary artery disease undergoing major surgery.
Trial website
Trial related presentations / publications
Public notes

Principal investigator
Name 0 0
Paul S Myles, MBBS MPH MD
Address 0 0
The Alfred
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications