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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.
Sponsor:
Collaborator:
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
Bayside Health
ClinicalTrials.gov Identifier:
NCT00430989
First received: January 31, 2007
Last updated: September 24, 2013
Last verified: September 2013

January 31, 2007
September 24, 2013
April 2007
September 2013   (final data collection date for primary outcome measure)
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 ] [ Designated as safety issue: Yes ]
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.
Complete list of historical versions of study NCT00430989 on ClinicalTrials.gov Archive Site
  • Myocardial Infarction (MI) [ Time Frame: 30 days post op ] [ Designated as safety issue: Yes ]
  • Cardiac failure [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
  • Cardiac arrest [ Time Frame: 30 Days Post op ] [ Designated as safety issue: Yes ]
  • Pulmonary embolism [ Time Frame: 30 Days Post op ] [ Designated as safety issue: Yes ]
  • Stroke [ Time Frame: 30 Days Post op ] [ Designated as safety issue: Yes ]
  • Wound infection [ Time Frame: 30 Days Post op ] [ Designated as safety issue: Yes ]
  • Hospital Stay [ Time Frame: 30 Days Post Op ] [ Designated as safety issue: Yes ]
  • Myocardial Infarction (MI)
  • Cardiac failure
  • Cardiac arrest
  • Pulmonary embolism
  • Stroke
  • Wound infection
  • Hospital Stay
Not Provided
Not Provided
 
The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial
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]).

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

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Outcomes Assessor)
Primary Purpose: Prevention
Coronary Artery Disease
  • Drug: Nitrous Oxide
    70% N2O V's No N2O
  • Drug: Nitrous Oxide
    N2O 70% v's No N2O
  • N2O
    N2O Group (FiO2 0.3)
    Interventions:
    • Drug: Nitrous Oxide
    • Drug: Nitrous Oxide
  • 2
    N2O free group (FiO2 0.3)
    Interventions:
    • Drug: Nitrous Oxide
    • Drug: Nitrous Oxide

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
7103
September 2013
September 2013   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Australia
 
NCT00430989
6/07
Yes
Bayside Health
Bayside Health
National Health and Medical Research Council, Australia
Principal Investigator: Paul S Myles, MBBS MPH MD The Alfred
Bayside Health
September 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP