The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial

NCT00430989 | Completed Phase 4 Results DMC

• 1 other identifier: 6/07
• Study Type: interventional
• Target: 7,112
• Locations: 1 country
• Sites: 1

Brief Summary

To investigate the safety of nitrous oxide (N2O) anaesthesia in patients with risk factors for coronary artery disease undergoing major surgery.

Conditions

Coronary Artery Disease

Keywords

Anaesthesia; Major Surgery; Coronary artery disease; Nitrous oxide; Effects of Nitrous Oxide following Anaesthesia; Anaesthesia and coronary artery disease

Outcome Measures

Primary Outcomes (1)

• 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.

  30 days post op

Secondary Outcomes (6)

• Myocardial Infarction (MI)

  30 days post op

• Cardiac Arrest

  30 days

• Pulmonary Embolism

  30 Days Post op

• Stroke

  30 Days Post op

• Wound Infection

  30 Days Post op

Study Arms (2)

70% Nitrous Oxide

OTHER

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

Other: Nitrous Oxide

No Nitrous Oxide

OTHER

General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen at 30%

Other: No Nitrous Oxide

Interventions

Nitrous Oxide OTHER

General anaesthesia with the inclusion of Nitrous Oxide at 70%

70% Nitrous Oxide

No Nitrous Oxide OTHER

General anaesthesia with no use of Nitrous Oxide

No Nitrous Oxide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult males and females age ≥ 45 years, undergoing noncardiac surgery and general anaesthesia expected to exceed two hours.
• At increased risk of cardiac events, defined as any of
• 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
• heart failure
• cerebrovascular disease thought due to atherothrombotic disease
• aortic or peripheral vascular disease
• 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)

You may not qualify if:

• having cardiac surgery
• marked impairment of gas-exchange expected to require Fi02\> 0.5 intraoperatively
• specific circumstances where N2O is contraindicated (eg. volvulus, pulmonary hypertension, raised intracranial pressure) or the anaesthetist plans to use supplemental oxygen (eg. colorectal surgery)
• N2O unavailable for use.

Sponsors & Collaborators

• Bayside Health: lead
• National Health and Medical Research Council, Australia: collaborator

Study Sites (1)

Alfred Hosptial

Melbourne, Victoria, 3004, Australia

Location

Related Publications (5)

• Beattie WS, Wijeysundera DN, Chan MTV, Peyton PJ, Leslie K, Paech MJ, Sessler DI, Wallace S, Myles PS, Galagher W, Farrington C, Ditoro A, Baulch S, Sidiropoulos S, Bulach R, Bryant D, O'Loughlin E, Mitteregger V, Bolsin S, Osborne C, McRae R, Backstrom M, Cotter R, March S, Silbert B, Said S, Halliwell R, Cope J, Fahlbusch D, Crump D, Thompson G, Jefferies A, Reeves M, Buckley N, Tidy T, Schricker T, Lattermann R, Iannuzzi D, Carroll J, Jacka M, Bryden C, Badner N, Tsang MWY, Cheng BCP, Fong ACM, Chu LCY, Koo EGY, Mohd N, Ming LE, Campbell D, McAllister D, Walker S, Olliff S, Kennedy R, Eldawlatly A, Alzahrani T, Chua N, Sneyd R, McMillan H, Parkinson I, Brennan A, Balaji P, Nightingale J, Kunst G, Dickinson M, Subramaniam B, Banner-Godspeed V, Liu J, Kurz A, Hesler B, Fu AY, Egan C, Fiffick AN, Hutcherson MT, Turan A, Naylor A, Obal D, Cooke E; ANZCA Clinical Trials Network for the ENIGMA-II Investigators. Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial. Anesth Analg. 2018 Nov;127(5):1118-1126. doi: 10.1213/ANE.0000000000003310.

  PMID: 29533264 DERIVED

• Corcoran T, Kasza J, Short TG, O'Loughlin E, Chan MT, Leslie K, Forbes A, Paech M, Myles P; ENIGMA-II investigators. Intraoperative dexamethasone does not increase the risk of postoperative wound infection: a propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX). Br J Anaesth. 2017 Feb;118(2):190-199. doi: 10.1093/bja/aew446.

  PMID: 28100522 DERIVED

• Chan MT, Peyton PJ, Myles PS, Leslie K, Buckley N, Kasza J, Paech MJ, Beattie WS, Sessler DI, Forbes A, Wallace S, Chen Y, Tian Y, Wu WK; and the Australian and New Zealand College of Anaesthetists Clinical Trials Network for the ENIGMA-II investigators. Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial. Br J Anaesth. 2016 Dec;117(6):801-811. doi: 10.1093/bja/aew338.

  PMID: 27956679 DERIVED

• Myles PS, Leslie K, Chan MT, Forbes A, Peyton PJ, Paech MJ, Beattie WS, Sessler DI, Devereaux PJ, Silbert B, Schricker T, Wallace S; ANZCA Trials Group for the ENIGMA-II investigators. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet. 2014 Oct 18;384(9952):1446-54. doi: 10.1016/S0140-6736(14)60893-X.

  PMID: 25142708 DERIVED

• Myles PS, Leslie K, Peyton P, Paech M, Forbes A, Chan MT, Sessler D, Devereaux PJ, Silbert BS, Jamrozik K, Beattie S, Badner N, Tomlinson J, Wallace S; ANZCA Trials Group. Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: rationale and design. Am Heart J. 2009 Mar;157(3):488-494.e1. doi: 10.1016/j.ahj.2008.11.015.

  PMID: 19249419 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease

Interventions

Nitrous Oxide

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Nitrogen Oxides; Gases; Inorganic Chemicals; Nitrogen Compounds; Oxides; Oxygen Compounds

Limitations and Caveats

All 'other' adverse events the events were classed according to system MedDRA reporting and not by individual event.

Results Point of Contact

• Title: Professor Paul Myles
• Organization: Bayside health

p.myles@alfred.org.au

+61390762000

Study Officials

• Paul S Myles, MBBS MPH MD

  The Alfred

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: The treating anaesthetist will be unblinded to the allocation. All other personnel (surgeon, participant and outcome assessor are all blinded to treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: international, randomised, assessor-blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery.

Study Record Dates

• First Submitted: January 31, 2007
• First Posted: February 2, 2007
• Study Start: April 1, 2007
• Primary Completion: September 1, 2013
• Study Completion: September 1, 2013
• Last Updated: January 20, 2026
• Results First Posted: June 17, 2019

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)