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

November 24, 2019 updated by: Bayside Health

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

7112

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • Victoria
      • Melbourne, Victoria, Australia, 3004
        • Alfred Hosptial

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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.
Time Frame: 30 days post op
30 days post op

Secondary Outcome Measures

Outcome Measure
Time Frame
Myocardial Infarction (MI)
Time Frame: 30 days post op
30 days post op
Cardiac Arrest
Time Frame: 30 days
30 days
Pulmonary Embolism
Time Frame: 30 Days Post op
30 Days Post op
Stroke
Time Frame: 30 Days Post op
30 Days Post op
Wound Infection
Time Frame: 30 Days Post op
30 Days Post op
Hospital Stay (Days)
Time Frame: 30 Days Post Op
30 Days Post Op

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Bayside Health

Collaborators

National Health and Medical Research Council, Australia

Investigators

  • Principal Investigator: Paul S Myles, MBBS MPH MD, The Alfred

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2007

Primary Completion (ACTUAL)

September 1, 2013

Study Completion (ACTUAL)

September 1, 2013

Study Registration Dates

First Submitted

January 31, 2007

First Submitted That Met QC Criteria

February 1, 2007

First Posted (ESTIMATE)

February 2, 2007

Study Record Updates

Last Update Posted (ACTUAL)

December 4, 2019

Last Update Submitted That Met QC Criteria

November 24, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 6/07

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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