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

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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:
Collaborator:
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
Bayside Health

Tracking Information
First Submitted Date  ICMJE January 31, 2007
First Posted Date  ICMJE February 2, 2007
Results First Submitted Date  ICMJE February 16, 2016
Results First Posted Date  ICMJE June 17, 2019
Last Update Posted Date December 4, 2019
Study Start Date  ICMJE April 2007
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2019)
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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: February 1, 2007)
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2019)
  • Myocardial Infarction (MI) [ Time Frame: 30 days post op ]
  • Cardiac Arrest [ Time Frame: 30 days ]
  • 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 (Days) [ Time Frame: 30 Days Post Op ]
Original Secondary Outcome Measures  ICMJE
 (submitted: February 1, 2007)
  • Myocardial Infarction (MI)
  • Cardiac failure
  • Cardiac arrest
  • Pulmonary embolism
  • Stroke
  • Wound infection
  • Hospital Stay
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial
Official Title  ICMJE 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]).
Brief Summary To investigate the safety of nitrous oxide (N2O) anaesthesia in patients with risk factors for coronary artery disease undergoing major surgery.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE 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
Condition  ICMJE Coronary Artery Disease
Intervention  ICMJE
  • Other: Nitrous Oxide
    General anaesthesia with the inclusion of Nitrous Oxide at 70%
  • Other: No Nitrous Oxide
    General anaesthesia with no use of Nitrous Oxide
Study Arms  ICMJE
  • 70% Nitrous Oxide
    General anaesthesia using 70% Nitrous Oxide with fraction of inspired oxygen at 30%
    Intervention: Other: Nitrous Oxide
  • No Nitrous Oxide
    General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen at 30%
    Intervention: Other: No Nitrous Oxide
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 18, 2019)
7112
Original Enrollment  ICMJE
 (submitted: February 1, 2007)
7000
Actual Study Completion Date  ICMJE September 2013
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00430989
Other Study ID Numbers  ICMJE 6/07
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Bayside Health
Study Sponsor  ICMJE Bayside Health
Collaborators  ICMJE National Health and Medical Research Council, Australia
Investigators  ICMJE
Principal Investigator: Paul S Myles, MBBS MPH MD The Alfred
PRS Account Bayside Health
Verification Date March 2019

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