NCT00430989

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]).

• Status: Completed
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 7,112 (actual)
• Sponsor: Bayside Health · Other Government
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Coronary Artery Disease

Interventions

Type	Name	Description
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

Timeline

• Start date: 2007-04-01
• Primary completion: 2013-09-01
• Completion: 2013-09-01
• First posted: 2007-02-02
• Last updated: 2026-01-20
• Results posted: 2019-06-17

Locations

1 site across 1 country: Australia