At the age of 165 nitrous oxide is twice as old as the oldest practising anaesthetist! As an anaesthetic agent it has had better success at weathering critical reviews and standing the test of time than any other agent. It has been suggested that it owes this success to the fact that it is a weak anaesthetic/analgesic agent with mild adverse effects during an average time use. However, recent research suggests that there are serious adverse events that occur postoperatively due to nitrous oxide. These morbidities are either inadvertently attributed to other causes or the link to the real culprit, nitrous oxide, is nebulous and blurred. The most obvious distressing side effect, but which is not directly fatal, is postoperative nausea and vomiting (PONV). Several trials have shown a significant reduction in PONV by omitting nitrous oxide . The other side effects are long-term and are either due to recreational abuse or prolonged exposure . As a result there is no universality in the use of nitrous oxide as a routine anaesthetic agent, with some practitioners calling for an all out ban on its use. This survey was carried out to assess which way the pendulum is swinging regarding the use of nitrous oxide.
An electronic questionnaire was sent to members of the European Society of Anaesthesiology (ESA) through the ESA Secretariat. Responding members sent their completed questionnaires directly to the author by E-mail.
A total of 123 questionnaires were returned from all over the world, with the majority of the responses coming from Europe (Table 1). The majority (86.1%) of respondents were specialist anaesthesiologists or consultants. Out of the total 64.3% admitted to using nitrous oxide in their clinical practice. Approximately 29% of the nitrous oxide users always use it for general anaesthesia without exception. The cases in which nitrous oxide is used included in-patients, day surgery and paediatric patients. The majority (71%) of nitrous oxide users would not use it in some cases. Only 33% (41) of the total respondents never at all use nitrous oxide in their practice. Air is used by the majority (73.2%) of anaesthesiologists as an alternative to nitrous oxide. Xenon is still not widely used (1.6%). Of the respondents from the UK 92% use nitrous oxide compared with 50% in Holland, 50% in Spain and 30% in Germany.
On the prediction of the future use of nitrous oxide, 53% believe nitrous oxide will disappear from routine clinical use. Reasons expressed by proponents for the use and for nonuse of nitrous oxide range from clinical to environmental issues. Proponents for nitrous oxide use emphasized time-tested safety record, low cost anaesthesia and convenience. On the contrary nonusers highlighted PONV, the emerging myocardial adverse effects, and more importantly the fatalities that ensue when human error comes into play, something that would never happen with use of air. Table 2 shows commonly cited reasons for and against use of nitrous oxide.
The survey clearly shows that nitrous oxide is still pretty much in vogue with the current generation of anaesthesiologists notwithstanding the piling evidence against it. The majority of the respondents (64.3%) use nitrous oxide in their anaesthetic practice, with a minority (33.3%) never at all using it. A similar survey 7 years ago showed that 95% of UK anaesthetists used nitrous oxide (frequently or occasionally), with a tiny minority (5%) never using it . These results, albeit from a small sample, show that in the UK there has not been any change in the usage of nitrous oxide since the Henderson et al.  survey in 2002. However, in Europe the drive to remove nitrous oxide from routine practice seems to be moving faster than in the UK. Some of the European respondents reported that nitrous oxide has been banned and is no longer available in their hospitals.
Biochemically nitrous oxide inhibits methionine synthase, an essential ubiquitous cytosolic enzyme, by oxidizing the cobalt ion in cobalamin (vitamin B12) from Co+ to Co3+. This results in failure to generate the intermediary methyl donor, S-adenosylmethionine, key to the synthesis of DNA, RNA, myelin, catecholamines and other substances requiring the methylation process. Folate is an intermediary in the methylation process and is essential in the biosynthesis of purines, pyrimidines, serine and glycine. Homocysteine levels rise due to the blockade of methionine synthase. Homocysteine has been shown to cause endothelial dysfunction and increased tendency to coagulation. The biosynthetic dysfunction caused by nitrous oxide provides the link to the feared teratogenic, subacute combined neurodegeneration of the cord, haematological toxicity, immune dysfunction, and myocardial ischaemic complications of nitrous oxide .
Except in cases of abuse, the nationally set occupational exposure limits (OEL) guarantee minimal safe exposure in clinical practice. However, this does not apply to the patient whose exposure is time-dependent. Methionine synthase activity approaches zero after about 200 min of exposure to nitrous oxide in mice . For the average clinical exposure of about 1.5 h there is a 50% reduction in methionine synthase activity and takes 3–4 days to fully recover. Although the ENIGMA I trial  demonstrated a reduction in major complications with avoidance of nitrous oxide, it has been suggested that it was probable that the use of high oxygen (80%) was the reason rather than omission of nitrous oxide. That fact was confirmed earlier by Fleischmann et al. , who found no statistically significant difference in the rate of infection and other secondary outcomes between use of nitrous oxide and nitrogen. The ENIGMA I group has since embarked on ENIGMA II, which might shed more light on the clinical adverse effects, if any, of nitrous oxide, particularly the endothelial dysfunction related to perioperative high levels of homocysteine [6,7].
The use of anaesthetic machines without antihypoxia devices or some other mishap in which nitrous oxide is delivered without oxygen have resulted in fatalities. Such accidents do not occur when air is substituted for nitrous oxide. It can be argued that, except for these cases of human error, nitrous oxide has been successfully used in clinical practice without major problems for more than one and half centuries. Use of nitrous oxide more than doubles the incidence of postoperative nausea and vomiting . This is the most quoted reason in the survey for abandoning use of nitrous oxide. A real threat to nitrous oxide, however, is posed by its being the third most climatologically significant greenhouse gas after carbon dioxide and methane . With a 120 year long atmospheric lifetime and 300 times the global warming potential of carbon dioxide, nitrous oxide is likely to be banned from use unless ways are found to prevent atmospheric pollution. Most of the atmospheric nitrous oxide (99%), however, originates from agricultural and industrial sources, with probably about 0.05% coming from medical and dental use. The impact of eliminating medical and dental nitrous oxide contributions on the greenhouse effect is not known, but it is thought it would be negligible.
The limitation of the survey is that it was small, and, like any survey, may suffer from response bias. However, this was an international survey and therefore probably provides a global opinion on the use of nitrous oxide.
Nitrous oxide occupies such a unique niche that no other agent has managed to dislodge it for more than one and half centuries. Although there is a trend towards reducing use of nitrous oxide, it is quite probable that this agent will outlive any currently practising anaesthesiologist.
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