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

This study has been completed.
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
Bayside Health Identifier:
First received: January 31, 2007
Last updated: September 24, 2013
Last verified: September 2013
To investigate the safety of nitrous oxide (N2O) anaesthesia in patients with risk factors for coronary artery disease undergoing major surgery.

Condition Intervention Phase
Coronary Artery Disease
Drug: Nitrous Oxide
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Prevention
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]).

Resource links provided by NLM:

Further study details as provided by Bayside Health:

Primary Outcome Measures:
  • 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:
  • Myocardial Infarction (MI) [ Time Frame: 30 days post op ]
  • Cardiac failure [ Time Frame: 30 days ]
  • Cardiac arrest [ Time Frame: 30 Days Post op ]
  • Pulmonary embolism [ Time Frame: 30 Days Post op ]
  • Stroke [ Time Frame: 30 Days Post op ]
  • Wound infection [ Time Frame: 30 Days Post op ]
  • Hospital Stay [ Time Frame: 30 Days Post Op ]

Enrollment: 7103
Study Start Date: April 2007
Study Completion Date: September 2013
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
N2O Group (FiO2 0.3)
Drug: Nitrous Oxide
70% N2O V's No N2O
Drug: Nitrous Oxide
N2O 70% v's No N2O
N2O free group (FiO2 0.3)
Drug: Nitrous Oxide
70% N2O V's No N2O
Drug: Nitrous Oxide
N2O 70% v's No N2O

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


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

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.
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Please refer to this study by its identifier: NCT00430989

Australia, Victoria
Alfred Hosptial
Melbourne, Victoria, Australia, 3004
Sponsors and Collaborators
Bayside Health
National Health and Medical Research Council, Australia
Principal Investigator: Paul S Myles, MBBS MPH MD The Alfred
  More Information

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Bayside Health Identifier: NCT00430989     History of Changes
Other Study ID Numbers: 6/07
Study First Received: January 31, 2007
Last Updated: September 24, 2013

Keywords provided by Bayside Health:
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
Arterial Occlusive Diseases
Vascular Diseases
Nitrous Oxide
Central Nervous System Depressants
Physiological Effects of Drugs
Anesthetics, Inhalation
Anesthetics, General
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents processed this record on April 28, 2017