Nitrous Oxide in Anaesthetic
Practice
(This talk given in October 2008)
I’m Dr Rod Tayler, a VMO anaesthetist at the Alfred Hospital in Melbourne and I’m talking with Professor Paul Myles. Paul is Professor and Director of the Department of Anaesthesia and Peri-operative Medicine at the Alfred Hospital and Monash University. We are discussing nitrous oxide in anaesthetic practice, particularly in relation to evidence based medicine.
Paul, what triggered your interest in N2O?
I have had a long standing interest in evidence-based anaesthetic practice.
I like to question what is seen as routine anaesthetic practice. N2O is at the top of that list. It has been around for more than 160 years. We do know from a variety of editorials and review papers that it has a longstanding and safe history.
Despite that there have never been definitive randomized control trials to test its overall safety or effectiveness. This issue was raised recently in an editorial in the Acta Anaesthesiologica Scandinavica journal, and that is really what stimulated my interest in this area.
So I went back and reviewed all that is known or had been written about N2O and concluded from that that we really don’t know whether or not it is an effective and safe drug for use in practice today.
What are the known benefits of N20?
The fact that we’ve got a drug that we’ve been using for now for 160 years, underpins the likely safe and simple to use characteristics of this anaesthetic drug. We are all trained to use it. For most anaesthetists it has been part of their routine daily practice. It is easy to use. It appears to be very effective as an adjunctive anaesthetic and helps smoothing out anaesthesia and perhaps speeding up recovery time. Given that it is so simple to use, it forms a basis for what we would normally give for most general anaesthetics. I guess it is a part of our makeup. It is a bit like the potatoes in a roast dinner or the pasta, part of our staple diet.
What are the known or suspected risks of N2O?
Well we’ve known really since the 1950’s that prolonged exposure, particularly in the ICU setting, can lead to symptoms and signs of vitamin B 12 deficiency. That is subacute combined degeneration of the spinal cord and also megaloblastic anaemia. I think most anaesthetic trainees learn that very early on, it is a part of many exams. What probably is not appreciated is that even short term repeat exposure in normal surgical practice has lead to some reports of these serious consequences. It is for that reason that I think we need to question its use in contemporary practice. So that is I guess what the average textbook would talk about and what the average exam candidate would know. But what is probably not appreciated is that the same metabolic pathway that involves methionine synthetase in DNA synthesis actually uses homocysteine as one of the substrates. In cardiovascular medicine particularly over the last 10 years it has become appreciated that elevated homocysteine levels are a risk factor for both coronary artery disease, stroke and probably dementia. In the anaesthetic setting of course we have a lot of patients who are at risk of coronary artery disease and it could be that elevated homocysteine levels after N2O anaesthesia is a new and possibly unappreciated risk factor.
You’ve been involved in a large trial looking at N2O, the ENIGMA trial. What did the ENIGMA trial show?
The ENIGMA trial was a large multi-centred multi-national randomized controlled trial that involved over 2,000 patients in around about 30 hospitals around the world. Particularly in Australia, New Zealand, South East Asia and Europe. The details of the study were published in the journal Anesthesiology in August 2007.
We set up the ENIGMA trial to test the overall safety and effectiveness, or if you like the added benefit of using N2O in routine practice. It involved a wide variety of patients having all types of surgery.
We asked anaesthetists to give their normal anaesthetic with or without N2O according to the randomized design. Our understanding of the effects of methionine synthetase and therefore RNA and DNA synthesis led us to suspect that there could be a number of unexpected side effects of N2O, in particular wound infection or immune suppression as well as the known effects on nerve function, red cell function, nausea and vomiting and possibly cardiovascular effects. So we measured each of these outcomes in the ENIGMA trial.
Firstly and most importantly, we found there was no beneficial effect of N2O. Specifically there was no improvement in the recovery time, there was no improvement in pain scores after surgery and in fact overall patients were less likely to be discharged from the recovery room in a reasonable period of time.
So in other words we could find no net benefit or gain. We also looked for adverse effects. In each area we found marked and clinically significant reductions in these side effects when N2O was avoided in the anaesthetic gas mixture. In particular there was a halving of the rate of severe nausea and vomiting up to and including 24 hours after surgery. We found significant reductions in wound infections, atelectasis and pneumonia when N2O was avoided.
We also found some trends which weren’t statistically significant but were worrying in that there appeared to be a possible increased rate of myocardial infarction and death in the N2O group. Now the simple interpretation of this study is that the removal of nitrous oxide led to better outcomes after surgery, and that could be the case.
Some commentators have argued that the inclusion of additional inspired O2 in the N2O free group of itself could have led to better outcomes and that is a theoretical explanation.
But we could find no evidence to suggest that this was the cause in our study. So we attribute it most likely to adverse effects of nitrous oxide.
However I do acknowledge there are some question marks about the full interpretation of the study and therefore what we need to be considering in our clinical practice now.
What further research is currently being done on these N2O issues?
Well I think the ENIGMA trial raised some very important questions. First of all, could the effects be explained away by supplemental O2. For that reason we are now controlling for that in a large follow up study which we have called ENIGMA 2. This is a 7,000 patient study. Secondly we are focusing on the cardiovascular side effects because of the known effects of.homocysteine on coronary artery disease.
Hence this large trial is looking at post-operative cardiovascular complications and deaths up to 30 days after surgery. And we will take the opportunity to confirm our earlier findings from ENIGMA 1.
So in the light of our current knowledge about N2O, how should we as anaesthetists be currently practicing?
ENIGMA 1 could not identify any positive or
beneficial effects of N2O so there appears to be no real reason for
it to be included. At the same time there are some possible real or
at least suspected serious complications that we can attribute to
N2O. So on balance I think it is clear that N2O should not be a
part of routine anaesthetic practice, and its use
should be questioned. This was the conclusion of our study
As patients are at greater risk of complications I think generally
it should be avoided. That particularly includes elderly patients,
those having more major surgery, those at a greater risk of wound
infection and those with a history of post-operative nausea and
vomiting.
There are other circumstances that we didn’t include in our study such as paediatric practice, or labour ward practice or perhaps young healthy males having more minor surgery where it is probably reasonable to continue to use N2O. Overall I think there is probably still a role for it. However we need to await the results of our larger ENIGMA 2 trial.
Paul, thank you for these perspectives on N2O in anaesthetic practice.
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