ENIGMA - Evaluation of Nitrous Oxide In the Gas Mixture for Anaesthesia: a Randomised Controlled Trial

There are some compelling reasons to question the routine use of nitrous oxide (N2O), also known as "laughing gas". Despite being the first anaesthetic drug introduced, and still widely used, there is sufficient doubt as to the risk-benefit profile.

There is strong evidence that N2O is a major risk factor for postoperative nausea and vomiting. It is clear that (even) brief exposure to N2O impairs methionine synthetase, an enzyme required for DNA production, red and white blood cell formation. Tissue hypoxia may be more common. These adverse effects are enhanced in "sick" patients (ie. those at highest risk, increased hospital length of stay and healthcare expenditure), and will be more likely in longer surgery. The extent of wound infection and cardiac morbidity associated with N2O is not known.

Large outcome trial data are lacking. When considering its widespread use in about 90% of all surgery around the world, small differences in outcome would have major implications for healthcare delivery. A large randomised controlled trial is necessary to answer this question.

We have recruited 2000 patients from about 25 centres around the world (mostly Australasia), who are undergoing major surgery.

Inclusion criteria

• Males and females, age 18 years and over
• Planned general anaesthesia for surgery that includes a skin incision and expected to exceed two hours, and the patient is expected to be in hospital for at least three days

Exclusion criteria

• Endoscopic or radiological procedures
• Cardiac surgery
• Marked impairment of gas-exchange (requiring Fi02> 0.3)
• Thoracic surgery requiring one-lung ventilation (requiring Fi02> 0.3)
• Specific circumstances where N2O is contraindicated (eg. volvulus, pulmonary hypertension, raised intracranial pressure)
• Lack of provision of N2O.