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

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

Detailed Description
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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.

Official Title
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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]).

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Other: Nitrous Oxide
* Other: No Nitrous Oxide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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) high-risk type of surgery (i.e. intrathoracic or intraperitoneal) Exclusion Criteria 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 70% Nitrous Oxide<br>General anaesthesia using 70% Nitrous Oxide with fraction of inspired oxygen at 30% | Other: Nitrous Oxide<br>* General anaesthesia with the inclusion of Nitrous Oxide at 70%<br>|
| Other: No Nitrous Oxide<br>General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen at 30% | Other: No Nitrous Oxide<br>* General anaesthesia with no use of Nitrous Oxide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Hospital Stay (Days) |  | 30 Days Post Op | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anaesthesia, Major Surgery, Coronary artery disease, Nitrous oxide, Effects of Nitrous Oxide following Anaesthesia, Anaesthesia and coronary artery disease