By Tom Heaton
Well a Happy New Year to you all! Despite the length of time since the last post I hope that this latest offering represents the start of a busy 2014 from Rapid Sequence. To make up for lost time I thought that a suitably divisive topic would be the best choice to get some lively debate going. After careful consideration of a wide range of options (there seem to be plenty to choose from - more coming soon I hope), I was prompted by the recent British Journal of Anaesthesia (BJA) review article to delve into the fogs of nitrous oxide use. As the leading review in a prominent journal, I thought dissecting it would be a great springboard to a discussion about the evidence that is out there.
If you’ve not caught a glance of it yet then check out the link below (1):
http://bja.oxfordjournals.org/content/111/6.toc
http://bja.oxfordjournals.org/content/111/6.toc
Let’s Set The Scene
Nitrous oxide is one topic that has really fascinated me since starting as an anaesthetics trainee; not just for its interesting history and physical traits, but even more for its ability to completely polarise consultants. A standard week might be as follows:
Monday: ‘Nitrous is the Devils work!’
Tuesday: ‘I love nitrous! I use it with all my patients’
Wednesday: ‘We’re not trying to kill our patients.’
Thursday…
I’m sure you get the idea, and I’m even more sure that this is a common occurrence in most anaesthetics departments. However, it isn’t that frequently that these are followed by a detailed explanation of the evidence base behind said statements. To me that seems to leave only a couple of explanations:
Monday: ‘Nitrous is the Devils work!’
Tuesday: ‘I love nitrous! I use it with all my patients’
Wednesday: ‘We’re not trying to kill our patients.’
Thursday…
I’m sure you get the idea, and I’m even more sure that this is a common occurrence in most anaesthetics departments. However, it isn’t that frequently that these are followed by a detailed explanation of the evidence base behind said statements. To me that seems to leave only a couple of explanations:
- There are several (otherwise very clever) consultants that have got completely the wrong end of the stick.
- The evidence base for nitrous is pretty equivocal.
The review
The article starts with a nice review of the important questions that we would like evidence to answer:
They follow with a bit of analysis of some of the specific areas that are more contentious than others. These include the benefits of acute pain relief, a reduction in chronic pain, and reduced incidence of awareness, as well as a more detailed analysis of the possible adverse effects of a neurological, cardiovascular and wound healing nature. A pretty good breadth for a 6 page review, though some more analysis on some of the attributes that I think are pretty relevant (post-operative nausea and vomiting for example) would have been rather nice too, though it seems that this side effect of nitrous is pretty much beyond doubt.
What’s their verdict? Well it seems to be a resounding ‘maybe’. This also includes ‘possibly’, ‘potentially’, ‘perhaps’ and a decent amount of ‘in some circumstances’. Hmmm…
- Has nitrous oxide got unique benefits to make it worth using?
- Do these benefits justify its side effects?
They follow with a bit of analysis of some of the specific areas that are more contentious than others. These include the benefits of acute pain relief, a reduction in chronic pain, and reduced incidence of awareness, as well as a more detailed analysis of the possible adverse effects of a neurological, cardiovascular and wound healing nature. A pretty good breadth for a 6 page review, though some more analysis on some of the attributes that I think are pretty relevant (post-operative nausea and vomiting for example) would have been rather nice too, though it seems that this side effect of nitrous is pretty much beyond doubt.
What’s their verdict? Well it seems to be a resounding ‘maybe’. This also includes ‘possibly’, ‘potentially’, ‘perhaps’ and a decent amount of ‘in some circumstances’. Hmmm…
so what have we got to go on?
Well this isn’t the right place to perform a detailed literature review but the main aim of this blog post was to have a look at some of the evidence that was being used to argue these points, and in particular I was interested in the evidence of harm from nitrous that might lead to such strong opinions about it. What are we working with?
I have to admit I was expecting worse, but there still isn’t much to go on. Let’s start with the big one; the ENIGMA trial (2). This is the randomised control trial (RCT) with the troubling results about the impact of N2O on post-operative complications, though the majority of the notable information is actually from a follow up study looking at the long term complications in the study’s patients (3). This demonstrated an increased incidence of myocardial infarction in the years after undergoing a nitrous-based general anaesthetic (adjusted odds ratio of 1.59), though there was no evidence of an increased incidence of death or stroke. As far as I can see, that is about it in terms of high quality trials looking at the adverse cardiovascular effects of nitrous and, as I mentioned, the more relevant results came from the follow up study rather than the initial RCT itself. This consisted of a follow up based on a review of patient’s notes and telephone interviews with a ‘lost to follow up’ rate of 17%. Not the most robust evidence but still enough to raise some concerns.
The results from ENIGMA contrast with the opening shot of the pro nitrous authors which is drawn from a large retrospective cohort analysis of 49,016 patients who underwent non-cardiac surgery (4). This used propensity matching to try and compensate for the lack of RCT-ness, getting matched cohorts of 10,746 patients (not bad numbers). This showed that the nitrous group only did worse with regards to some pulmonary complications (the ENIGMA trial also noted this), and actually showed an improved 30-day mortality compared with non-nitrous. This is similar to the post-hoc analysis of the POISE trial (5). This trial was actually looking at the impact of beta-blockers on morbidity and mortality in non cardiac surgery, but the data was examined to see if the use of nitrous affected outcome. Once again propensity matching was used to try and make up for the fact that the trial was initially looking at something completely different, with the results showing no difference in outcome between the groups that received nitrous and those that didn’t.
With the topic of cardiovascular adverse effects as an example, it would seem that the evidence out there in not of the most robust quality and, on top of that, seems to contradict itself from study to study. Going through the review article’s discussion on adverse neurological effects provides a similar outcome, though probably even less convincing. A notably large number of the references are animal studies, with the post-hoc analysis of the IHAST study (comparing mild hypothermia with normothermia in cerebral aneurysm clipping surgery) providing the best evidence available. Yes, certain adverse effects such an increase in the incidence of post-operative nausea and vomiting (PONV) are clear and well evidenced draw-backs of using nitrous oxide, but beyond areas like this, the waters still seem very murky.
I have to admit I was expecting worse, but there still isn’t much to go on. Let’s start with the big one; the ENIGMA trial (2). This is the randomised control trial (RCT) with the troubling results about the impact of N2O on post-operative complications, though the majority of the notable information is actually from a follow up study looking at the long term complications in the study’s patients (3). This demonstrated an increased incidence of myocardial infarction in the years after undergoing a nitrous-based general anaesthetic (adjusted odds ratio of 1.59), though there was no evidence of an increased incidence of death or stroke. As far as I can see, that is about it in terms of high quality trials looking at the adverse cardiovascular effects of nitrous and, as I mentioned, the more relevant results came from the follow up study rather than the initial RCT itself. This consisted of a follow up based on a review of patient’s notes and telephone interviews with a ‘lost to follow up’ rate of 17%. Not the most robust evidence but still enough to raise some concerns.
The results from ENIGMA contrast with the opening shot of the pro nitrous authors which is drawn from a large retrospective cohort analysis of 49,016 patients who underwent non-cardiac surgery (4). This used propensity matching to try and compensate for the lack of RCT-ness, getting matched cohorts of 10,746 patients (not bad numbers). This showed that the nitrous group only did worse with regards to some pulmonary complications (the ENIGMA trial also noted this), and actually showed an improved 30-day mortality compared with non-nitrous. This is similar to the post-hoc analysis of the POISE trial (5). This trial was actually looking at the impact of beta-blockers on morbidity and mortality in non cardiac surgery, but the data was examined to see if the use of nitrous affected outcome. Once again propensity matching was used to try and make up for the fact that the trial was initially looking at something completely different, with the results showing no difference in outcome between the groups that received nitrous and those that didn’t.
With the topic of cardiovascular adverse effects as an example, it would seem that the evidence out there in not of the most robust quality and, on top of that, seems to contradict itself from study to study. Going through the review article’s discussion on adverse neurological effects provides a similar outcome, though probably even less convincing. A notably large number of the references are animal studies, with the post-hoc analysis of the IHAST study (comparing mild hypothermia with normothermia in cerebral aneurysm clipping surgery) providing the best evidence available. Yes, certain adverse effects such an increase in the incidence of post-operative nausea and vomiting (PONV) are clear and well evidenced draw-backs of using nitrous oxide, but beyond areas like this, the waters still seem very murky.
Let's wrap up
When it comes to looking at the review as a whole, though I like the two questions they have asked at the start, I feel that it is the question they pose prior to their conclusion that is the most relevant:
This is perhaps the most important area of how we apply results to clinical practice. I know that this is not entirely the domain of clinical trials and that this comes more under the remit of our own clinical skills and applying the evidence base to the particular patient that is sat in front of us at any time. However, when drawing on evidence to help us make these decisions, part of the analysis must relate to clinical applicability. If we take the ENIGMA trial as an example, this only looks at major surgery lasting over 2 hours. Indeed the ENIGMA authors in their discussion have specifically warned about extrapolating the results to include minor surgery, and paediatric and obstetric practice. I am looking forward to the results of the ENIGMA II trial with 7112 patients randomised to identical anaesthetics other than the nitrous component. However, this is still looking at patients undergoing major surgery and who have moderate or high cardiovascular risk factors. Can we use this evidence to help us make decisions about the young ASA 1 patient undergoing a short general anaesthetic? I think the trials that have included this group of patients the best are the (admittedly less robust) retrospective analyses, and they are the ones who haven’t really shown any difference.
So after all that rambling, where does it leave us? I think there clearly are some drawbacks to using nitrous oxide; increased PONV, diffusion hypoxia, and certainly some evidence of increased cardiovascular risk with extended use. I still think that there isn’t much evidence out there (yet at least) to stop nitrous having at least some role in anaesthetic practice. For the young patients undergoing short procedures, some of the benefits of nitrous may outweigh the side effects, which in this group probably only really relates to increased PONV. An example that comes immediately to my mind are those patients who are undergoing incision and drainage of a very painful abscess. Nitrous allows the greater depth of anaesthesia without as much cardiovascular depression and with a short acting analgesia effect that stops patients jumping off the table (and laryngospasm etc) when the first incision is made. As with any drug we can look at the pros and cons that we know about and apply them to the patient that is in front of us. The days of nitrous for every anaesthetic are definitely gone, but I think that we can still apply our judgement and find situations where we are benefiting our patients. As the authors of the review note, nitrous has been used for over 150 years without leaving a noticeable trail of death and destruction. The evidence may come that shows more subtle adverse effects in all patients, and we can take that into account when it arrives, but I don’t think we are there yet.
Thanks for reading and as always please let me know any comments and thoughts you may have. Links to new articles are especially welcome, as are your personal tales of nitrous.
Tom Heaton
- Which patients are these risks and benefits applicable to?
This is perhaps the most important area of how we apply results to clinical practice. I know that this is not entirely the domain of clinical trials and that this comes more under the remit of our own clinical skills and applying the evidence base to the particular patient that is sat in front of us at any time. However, when drawing on evidence to help us make these decisions, part of the analysis must relate to clinical applicability. If we take the ENIGMA trial as an example, this only looks at major surgery lasting over 2 hours. Indeed the ENIGMA authors in their discussion have specifically warned about extrapolating the results to include minor surgery, and paediatric and obstetric practice. I am looking forward to the results of the ENIGMA II trial with 7112 patients randomised to identical anaesthetics other than the nitrous component. However, this is still looking at patients undergoing major surgery and who have moderate or high cardiovascular risk factors. Can we use this evidence to help us make decisions about the young ASA 1 patient undergoing a short general anaesthetic? I think the trials that have included this group of patients the best are the (admittedly less robust) retrospective analyses, and they are the ones who haven’t really shown any difference.
So after all that rambling, where does it leave us? I think there clearly are some drawbacks to using nitrous oxide; increased PONV, diffusion hypoxia, and certainly some evidence of increased cardiovascular risk with extended use. I still think that there isn’t much evidence out there (yet at least) to stop nitrous having at least some role in anaesthetic practice. For the young patients undergoing short procedures, some of the benefits of nitrous may outweigh the side effects, which in this group probably only really relates to increased PONV. An example that comes immediately to my mind are those patients who are undergoing incision and drainage of a very painful abscess. Nitrous allows the greater depth of anaesthesia without as much cardiovascular depression and with a short acting analgesia effect that stops patients jumping off the table (and laryngospasm etc) when the first incision is made. As with any drug we can look at the pros and cons that we know about and apply them to the patient that is in front of us. The days of nitrous for every anaesthetic are definitely gone, but I think that we can still apply our judgement and find situations where we are benefiting our patients. As the authors of the review note, nitrous has been used for over 150 years without leaving a noticeable trail of death and destruction. The evidence may come that shows more subtle adverse effects in all patients, and we can take that into account when it arrives, but I don’t think we are there yet.
Thanks for reading and as always please let me know any comments and thoughts you may have. Links to new articles are especially welcome, as are your personal tales of nitrous.
Tom Heaton
references
- Nitrous oxide: are we still in equipoise? A qualitative review of current controbversies. De Vasconcellos, K. Sneyd, JR. British Journal of Anaesthesia. 111 (6): p877-885 (2013)
- Avoidance of Nitrous Oxide for Patients Undergoing Major Surgery: A Randomized Controlled Trial. Myles P et al. Anesthesiology. 107(2): p221-231 (2007).
- Nitrous Oxide and Long-Term Morbidity and Mortality in the ENIGMA Trial. Leslie K et al. Anesthesia & Analgesia. 112(2): 387–393 (2011)
- The Association Between Nitrous Oxide and Postoperative Mortality and Morbidity After Noncardiac Surgery. Turan A et al. Anesthesia & Analgesia. 116: p1026-1033 (2013)
- Nitrous Oxide and Serious Morbidity and Mortality in the POISE Trial. Leslie K et al. Anesthesia & Analgesia. 116(5): p1034–1040 (2013)
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