The ENIGMA-II trial

by Dr. Matthew Vella

#Anaesthesia #anaesthetics #anesthesiology #anesthesia #anesthetic #abcsofanaesthesia #medicine #anesthesiologist #anaesthetist #anesthetist #anaesthesiology #nurse #medical #meded #FOAMed #medicalstudent #ENIGMAtrial # ENIGMA2trial #safety #generalanaesthesia #GA #Nitrousoxide #N2O #Gas #MajorSurgery #cardiacriskfactors


The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial

Myles, P. S., Leslie, K., Chan, M. T., Forbes, A., Peyton, P. J., Paech, M. J., Beattie, W. S., Sessler, D. I., Devereaux, P. J., Silbert, B., Schricker, T., Wallace, S., & ANZCA Trials Group for the ENIGMA-II investigators (2014). The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet (London, England)384(9952), 1446–1454.

Where is it published?


Who is involved?

It’s an ANZCA (Australian and New Zealand College of Anaesthetists) multi-centre trial with contributions from 45 centres across 10 countries

What did they set out to do?

To gather evidence for the safety of using nitrous oxide (N2O) in general anaesthesia (GA) – particularly in at-risk patients having major surgery, but not cardiac surgery (and as follow-up on the previous ENIGMA-I trial, but more on that later!)

What is significant about the study?

It addresses important safety questions for an anaesthetic drug that is – and has been – used billions of times over 150-years

There is conjecture that – through its tendency to increase post-op homocysteine plasma levels and impairment of endothelial function (keeping in mind the association between chronic hyperhomocysteinaemia and heart disease) N2O may trigger cardiovascular complications

The initial ENIGMA trial wasn’t designed to explore this matter, so they recruited more patients for ENIGMA-II (i.e., 7011 vs 2050), and ensured they had a higher risk profile (note: ENIGMA-II n=579 perioperative cardiovascular events, compared to ENIGMA just n=20)

How was it done?

A big group of at-risk patients over 45-years-old, from multiple centres across the globe, were randomly allocated to receive N2O or nil N2O as part of a GA for major non-cardiac surgery

Only the anaesthetists knew group allocation, and interval post-operative assessments were conducted to measure some key outcomes, including:

Mortality and cardiovascular events, surgical site infection, all-cause mortality, stroke, pulmonary embolism (PE), cardiac arrest, severe post-operative nausea and vomiting (PONV), length of stay in post-acute care unit (PACU), ICU admission, hospital admission, and overall quality of recovery


Why do we care about nitrous oxide use?

It can be used to spare other anaesthetic agents that have more severe side-effects, greater financial and/or environmental costs, and it confers some analgesic benefit

If N2O is associated with greater cardiovascular complications, continuing its use poses an unacceptable risk to patient safety, along with an increased burden on healthcare system through potentially avoidable increases in length-of-stay, and cost of inpatient and outpatient services rendered (i.e., length of admissions in high-dependency / intensive care and outpatient follow-up)

What do they mean by “at-risk”?

Anybody with known or suspected coronary artery disease (CAD), heart failure, cerebrovascular disease, peripheral vascular disease (PVD), or age > 70 with multiple comorbidities

What did they find?

It’s safe!
N2O is safe to use in major non-cardiac surgery. There is no increased risk of death or cardiovascular complications

The PONV is manageable
The emetogenic impact of nitrous oxide can be controlled with provision of anti-emetic medication and sparing use of volatile agents

Don’t worry about homocysteine levels
The post-op increase in plasma homocysteine associated with N2O use is of little clinical consequence

Don’t worry about infection risk

Patients receiving nitrous oxide aren’t at increased risk of developing a surgical site infection

Any limitations?

By the authors’ admission, the results should be interpreted with the following in mind:

1. The patient cohort is elderly, have cardiac risk factors, and the surgery was non-cardiac

2. They didn’t control specifics of anaesthetic or analgesic drugs given

3. They didn’t standardise post-operative management of haemodynamics or cardiac medications


What’s the overall take-home?

N2O can be used safely and effectively in GA for non-cardiac surgery

As for our 66-year-old awaiting a bowel resection, their coronary artery disease is not a contraindication to the use of N2O. As a bonus, we don’t need to worry about increasing the risk of surgical site infection, either.

So, if it’s safe why aren’t we using nitrous oxide as often?

In short, anaesthetists are avoiding using N2O due to recognition of its significant environmental impact through contribution to greenhouse gas accumulation, and related concerns about climate change.

Take a look at the numbers:
– the global warming potential of N2O is 298 times CO2
– running a 50% mix of N2O with O2 at 1L-min for 1-hour equates to driving a car 125km

– over an 8-hour working day, that’s the equivalent of driving 1000km

(Further than Melbourne VIC to Sydney NSW!)

(see Muret et al. 2019; also ANZCA Environmental Sustainability Network)

Further reading:

Postoperative pulmonary complications in the ENIGMA-II Trial: A post hoc analysis (2023)

Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthaesia (ENIGMA)-II trial (2016)

ENIGMA-I (2011)

Nitrous oxide and the environment
ANZCA Environmental Sustainability Network

Muret et al. (2019) Environmental impacts of nitrous oxide: no laughing matter! Comment on Br J Anaesth 2019; 122: 587-604