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

This study is currently recruiting participants.
Verified February 2013 by Bayside Health
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: February 17, 2013
Last verified: February 2013
History of Changes
  Purpose

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
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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:

U.S. FDA Resources

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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 7000
Study Start Date: April 2007
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
N2O
N2O Group (FiO2 0.3)
 Drug: Nitrous Oxide
70% N2O V's No N2O
Drug: Nitrous Oxide
N2O 70% v's No N2O
2
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00430989

Contacts
Contact: Sophie Wallace +61 39076 2000 sophia.wallace@alfred.org.au
Contact: Stephanie Poustie +61 38517 5367 admin@enigma2.org.au

Locations
Australia, Victoria
Alfred Hosptial Recruiting
Melbourne, Victoria, Australia, 3004
Contact: Paul S Myles     +61 39076 2000 ext 63176     p.myles@alfred.org.au    
Contact: Sophie K Wallace     +61 39076 2000 ext 63176     sophia.wallace@alfred.org.au    
Principal Investigator: Paul S Myles, MBBS MPH            
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  This link exits the ClinicalTrials.gov site

No publications provided by Bayside Health

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

Responsible Party: Bayside Health
ClinicalTrials.gov Identifier: NCT00430989     History of Changes
Other Study ID Numbers: 6/07
Study First Received: January 31, 2007
Last Updated: February 17, 2013
Health Authority: Australia: Human Research Ethics Committee

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
Anesthetics
Nitrous Oxide
Central Nervous System Depressants
 Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anesthetics, Inhalation
Anesthetics, General

ClinicalTrials.gov processed this record on May 19, 2013