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

• ClinicalTrials.gov Identifier: NCT00430989
• Recruitment Status: Completed
• First Posted: February 2, 2007
• Results First Posted: June 17, 2019
• Last Update Posted: December 4, 2019
• Sponsor: Bayside Health
• Collaborator: National Health and Medical Research Council, Australia
• Information provided by (Responsible Party): Bayside Health

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease	Other: Nitrous Oxide; Other: No Nitrous Oxide	Phase 4

Detailed Description:

Approximately 25% of patients undergoing major surgery have known coronary artery disease (CAD) or risk factors for CAD.

N2O interferes with vitamin B12 and folate metabolism. This impairs production of methionine (from homocysteine), used to form tetrahydrofolate and thymidine during DNA synthesis. It has been repeatedly demonstrated that N2O anaesthesia increases postoperative homocysteine levels. Chronic hyperhomocysteinaemia is associated with cardiovascular disease, and acute hyperhomocysteinaemia is known to cause endothelial dysfunction. One small trial has demonstrated an increased incidence of postoperative myocardial ischaemia in patients receiving N2O anaesthesia. Reducing postoperative myocardial infarction and death are important aims for those with CAD undergoing major surgery.

Our previous trial (ENIGMA) studied 2050 patients and identified some serious adverse effects, but most patients were not at risk of CAD and so we could not reliably assess serious cardiac complications. We propose a large simple randomized clinical trial of 7,000 patients to provide a definitive evaluation of the safety of N2O anaesthesia.

Updated statistical analysis plan can be found at www.enigma2.org.au.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7112 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: international, randomised, assessor-blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery.
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Masking Description: The treating anaesthetist will be unblinded to the allocation. All other personnel (surgeon, participant and outcome assessor are all blinded to treatment.
• Primary Purpose: Treatment
• Official 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]).
• Study Start Date: April 2007
• Actual Primary Completion Date: September 2013
• Actual Study Completion Date: September 2013

Arms and Interventions

Arm	Intervention/treatment
70% Nitrous Oxide; General anaesthesia using 70% Nitrous Oxide with fraction of inspired oxygen at 30%	Other: Nitrous Oxide; General anaesthesia with the inclusion of Nitrous Oxide at 70%
No Nitrous Oxide; General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen at 30%	Other: No Nitrous Oxide; General anaesthesia with no use of Nitrous Oxide

Outcome Measures

Primary Outcome Measures :

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. [ Time Frame: 30 days post op ]

Secondary Outcome Measures :

1. Myocardial Infarction (MI) [ Time Frame: 30 days post op ]
2. Cardiac Arrest [ Time Frame: 30 days ]
3. Pulmonary Embolism [ Time Frame: 30 Days Post op ]
4. Stroke [ Time Frame: 30 Days Post op ]
5. Wound Infection [ Time Frame: 30 Days Post op ]
6. Hospital Stay (Days) [ Time Frame: 30 Days Post Op ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

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.

Contacts and Locations

Locations

Australia, Victoria

Alfred Hosptial

Melbourne, Victoria, Australia, 3004

Sponsors and Collaborators

Bayside Health

National Health and Medical Research Council, Australia

Investigators

• Principal Investigator: Paul S Myles, MBBS MPH MD; The Alfred

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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. Erratum In: Br J Anaesth. 2017 Oct 1;119(4):851.

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.

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.

• Responsible Party: Bayside Health
• ClinicalTrials.gov Identifier: NCT00430989
• Other Study ID Numbers: 6/07
• First Posted: February 2, 2007
• Results First Posted: June 17, 2019
• Last Update Posted: December 4, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Bayside Health:

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

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Nitrous Oxide; Anesthetics, Inhalation; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents