Caudwell Xtreme EverestAuthor: Kay Mitchell, Project Manager, Caudwell Xtreme Everest
Caudwell Xtreme Everest is a research project coordinated by the UCL Centre for Altitude, Space and Extreme environment medicine (CASE). A group of doctors and allied health professionals placed a research team on the summit of Mount Everest in May 2007 and made the first ever measurement of the level of oxygen in human blood at 8475m, on the ‘Balcony’ of Everest. This was the centrepiece of an extensive and continuing programme of research into hypoxia and human performance at extreme altitude aimed at improving the care of the critically ill and other patients where hypoxia is a fundamental problem.
The group recruited 235 healthy volunteers, aged between 18 and 73. A base line set of tests were carried out in London, at the expedition’s sea level research laboratory. These tests related to four areas of study: oxygen utilization, oxygen delivery, the brain, and breathing systems. Each individual was then tested at laboratories in Kathmandu (1400m), Namche (3440m), Pheriche (4300m), and Everest Base Camp (5300m) in Nepal. 24 of this group underwent additional tests to the main group, as they stayed at Everest Base Camp to run the laboratory, or climbed higher on the mountain to carry out additional research. This research was carried out in three further laboratories in the Western Cwm (6400m), on the South Col (7950m), and on the Balcony (8475m).
One of the core hypotheses of the Caudwell Xtreme Everest project is that exposure to hypoxia increases our efficiency of oxygen use. Therefore, the healthy subjects who volunteered for the study were all exposed to decreasing levels of oxygen at the same rate. Their physiological adaptation to hypoxia was measured at the same points throughout the process.
In order to obtain all of this data the team needed to recruit over 200 volunteers who were prepared to pay over the odds for a three and a half week trek to Everest Base Camp and back. Moreover, they had to be prepared to undergo 30 minutes of testing every day, and then a full day’s testing every three to four days. In addition, the team recruited 31 researchers to staff all of the laboratories. Those that were stationed at Everest Base Camp underwent testing themselves, as did the 15 western members of the climbing team that went higher on the mountain. Recruiting the subjects was just one part of this whole project. The team also developed more than 40, ethically approved, research protocols to guide the research.
The expedition took 26.5 tonnes of kit to Nepal. Much of this was research equipment, which had to be tested in chambers at low temperatures and pressures to ensure it would function in the cold, low pressure environment. Some of the more complicated protocols involved the use of an exercise bike (Lode) and a breath by breath gas analysis machine (Cortex). This enabled the team to carry out metabolic efficiency tests and ramp tests at each laboratory, except the one placed on the Balcony of Everest. Most of the kit for the higher laboratories was taken by helicopter to Namche, and then transported by yak or porter higher up the mountain. This meant that the majority of the kit was designed to break down into units of less than 40kgs each. The team worked closely with a number of the Caudwell Xtreme Everest sponsors to adapt equipment to meet these weight requirements. Each laboratory was equipped with resuscitation equipment, including laryngoscopes, ET tubes, cannulae, and monitoring equipment. There were even a number of portable ventilators.
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Chris Imray
in the lab at Camp 4 on an exercise bike |
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Sundeep Dhillon
in the Lab at camp 2 on an exercise bike |
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The power supply was unreliable in Kathmandu, and almost non-existent in the higher laboratories. Therefore, the expedition logistics team built a power system at each laboratory that incorporated petrol generators (Honda) and inverters (Victron) to ensure that there were no power failures during any of the testing sessions. All of the equipment was adapted where necessary to use 240V. High on the mountain power was provided via a sequence of car batteries (Exide), charged by solar panels, so all machines were powered using 24V, including the exercise bike. Not only did the laboratory staff have to learn all of the research protocols, and how to use the different machines, they also had to learn how to service the generators.
Over 10,000 blood samples were taken during the course of the expedition, along with about 30 muscle biopsies. These were flash frozen in liquid nitrogen. The liquid nitrogen was stored in dewars, which were kept topped up via a constant supply, brought in by porters walking two weeks from the roadhead at Jiri. It had been driven there by road from Kathmandu. The electricity supply was too unreliable at any of the laboratories to risk storing samples in freezers. Once the research team and equipment had returned to Kathmandu, all of the blood samples were repacked for transportation to a storage facility in the UK. This involved three researchers spending two days inside a meat freezer in a hotel in Kathmandu.
Some of the research kit used is normally rarely seen outside an intensive care unit or operating suite. One particularly unpleasant protocol, undertaken by ten subjects from the core team at both sea level and Everest Base Camp, involved the measurement of end tidal C02, gastric pH, cardiac output and arterial blood gases. Thus, each subject had a nasogastric tonometer, arterial line, and a large bore cannula inserted. They were connected to a LiDCO cardiac output monitor, Dash (GE) portable cardiac monitor, and gastric tonometer machine (Datex Ohmeda). After calibration, the subjects were exercised on a bike with a breath by breath gas analysis machine attached for nearly 2 hours, alternating between periods of rest and exercise at different work rates below and above anaerobic threshold. The team had brought a blood gas analyser (Siemens) with them to process arterial blood gases every five minutes throughout the protocol. This machine was then taken further up the mountain to analyse samples obtained from near the summit of Everest.
The arterial blood gas machine contained a barometer to allow it to correct the values for the pressure the machine was working at. However, the barometer had not been designed to cope with pressures as low as those found near the summit of Everest. Therefore, the team worked with Siemens to fix the machine at a predetermined pressure. All the samples were then recalculated using a formula developed by the software team to correct for the pressure measured where the samples were taken from.
The arterial blood samples taken from the Balcony of Everest were not analysed at the Balcony, but further down at Camp Two. Thus, they had to be stored in a steady state until analysis could take place. Repeated test experiments demonstrated that samples remain stable in an ice slurry for up to 8 hours. The Sherpa made it to the testing lab in only 2.
Taking such a large number of doctors, allied health professionals and sophisticated medical equipment to a remote environment meant that the team were approached for medical advice at each laboratory in the Khumbu valley, and on the mountain itself. The team were involved in a number of rescues on Everest, some of which were reported in newspapers and on the television in America and Europe. But, more frequently, medical officers appointed at each laboratory were involved in treating the local population, climbing Sherpas, porters, and trekkers from their own team and others for more minor complaints. This had been anticipated by the Expedition Chief Medical Officer in the UK before departure, and mechanisms had been put in place to facilitate this. At Everest Base Camp and Pheriche this was not so straightforward, as the Himalayan Mountain Rescue Association (HRA) run clinics at both locations for the majority of the season. Therefore, the Caudwell Xtreme Everest team only got involved when the HRA were not available, or in collaboration with the HRA.
The team have arrived back in the UK with over 10,000 blood samples, 2000 bike tests, 1000 neuropsychological tests and 4000 diary day entries to analyse. There is more data related to other protocols also. The group are currently collating all the results and starting some preliminary examination of the data, with a view to starting formal analysis after Christmas. Results are expected to start being produced at the end of 2008.
For more information on the project please visit
www.xtreme-everest.co.uk
Nitrous Oxide: Myth And RealityAuthor: Dr Karen Stuart-Smith, Consultant Anaesthetist, Glan Clwyd Hospital, Denbighshire, Wales
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An historical review may be useful as offering a kind of a map of the science and the roads by which it has been explored’. Humphry Davy 1810
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I recently received a call from a lady called Zoe at the BBC. She wanted to know how much nitrous oxide was used in British hospitals every day. I told her I had no idea, and asked her why she wanted to know. Her question was related to a paper that had just appeared in Anesthesiology
2, which apparently showed that nitrous oxide was harmful to patients. She asked for my comments. At that point, I had not read the paper, so couldn’t offer an opinion, except to say that basing clinical practice on the evidence of one paper was probably ill advised. So, said Zoe, did I advocate the immediate removal of all nitrous oxide from British hospitals immediately? Certainly not, I said, and trotted out the usual defences of nitrous oxide. In any case, as I had not read the paper, and for the sake of professional probity, I would not commit myself to any public comment. Zoe sighed. She’d obviously done a bit of reading on the subject and knew all this already. I wasn’t providing good copy for the BBC website. Eventually I said that although I could not make off-the-cuff comments, I would research the issue myself, and send her the article which I subsequently wrote. So, Zoe from the BBC, I wrote this article for you. At the end, I’ll be asking for your comments, and we’ll publish them right here in Anaesthesia Product News.
History of nitrous oxide
Any discussion of nitrous oxide has to start with its history, for two reasons. First, nitrous oxide was manufactured a very long time ago and antipathy towards its use is based, in part, on the sheer length of time it has been around-a sort of historical bigotry. In fact brand new work on its mechanism of action points toward very good reasons for its continued use, as we shall see. Second, early experience with nitrous oxide led to deaths from severe hypoxia. As I will explain these catastrophic early experiences with nitrous has led to a lingering suspicion that the ‘black gas’ robs our patients of beneficial oxygen. Very high concentrations of nitrous will certainly do this, and by ‘very high’ I also mean 70% nitrous oxide in oxygen, which was the concentration examined by the paper that so interested Zoe. These considerations may have influenced some of the choices made by the study’s authors.
For the historical material presented here, I have unashamedly raided the pages of several excellent books and papers, to which the reader is directed for more information
1,3,4,5. I have not attempted to provide a comprehensive history here, but simply to illustrate the main points.
Nitrous oxide is of course a manufactured rather than a natural gas, but the identity of the first person to synthesise it is open to debate, and no doubt my readers will have their own opinions as usual. Joseph Black, Professor of Chemistry at Glasgow, is said to have produced nitrous oxide by heating ammonium nitrate in 1762. The chemical equation is straightforward:
NH4NO3 (ammonium nitrate) + heat ’ N2O + 2H2O. I have been unable to determine whether Black conducted any further investigation of this novel gas, and perhaps someone out there can enlighten me. In anaesthetic circles, Priestley (figure 1) is generally credited with the discovery of nitrous oxide. Priestley’s first discovery was actually a gas which he called ‘nitrous air’, and which is in fact nitric oxide (NO). He generated nitrous air by adding nitric acid to various metals. In 1772 Priestley added nitrous air to a bell jar containing a mixture of moist iron filings and brimstone. A vigorous reaction took place, resulting in the formation of a new gas which was able to support combustion. This was ‘dephlogisticated nitrous air’, or nitrous oxide. The relevant chemical equation is: 2NO + H
2O + Fe ’ N
2O + Fe(OH)
2. Priestley did inhale nitrous oxide and was aware of its euphoric effects. However it gave him a violent headache and probably dissuaded him from investigating the gas further. Of course the discovery which made him most famous during his lifetime was the isolation of oxygen and the description of its chemical and biological properties. As far as I am aware he did not recognise a medicinal use for nitrous oxide.
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| Joseph Priestley |
Whoever first invented nitrous oxide, the first person to examine its potential for medicinal use in humans was Humphry Davy. Davy was born into an era when the properties of synthesised gases, or factitious airs, as they were known, were a subject of great scientific and public interest. At the age of 20, Davy decided to investigate the then prevalent theory that nitrous oxide carried disease. He manufactured nitrous oxide in his bedroom (from zinc and nitric acid!). He inhaled the gas himself and immersed a few local rats in it, all to no harm, thus concluding that the gas was safe. He wrote to the originator of the disease theory, Thomas Beddoes, with his results. Beddoes was sufficiently impressed to ask him to join his ‘Pneumatic Institution’ in Bristol, and the concept of a gas manufactured for medicinal purposes was born.
As an aside, Thomas Beddoes was himself an interesting man. Physically he was short even by 18th Century standards, as well as extremely portly. According to Davy he was also rather unappealing in his personal habits. Nevertheless Beddoes had a formidable intellect. He graduated in Chemistry from Edinburgh and gained his MD at Oxford. He gave very popular lectures in chemistry while on Faculty at Oxford, but his egalitarian principles and sympathy with the French Revolution, by then in full gory swing, made it impossible for him to continue there. He moved to Bristol, where he set about raising funds for a Pneumatic Institute where the therapeutic properties of manufactured gases, which he termed the ‘pneumatic sciences’ were to be investigated. In true entrepreneurial spirit he succeeded in obtaining backing from major figures of the day including James Watt and Josiah Wedgewood. James Watt provided Beddoes with specially designed apparatus to make various ‘factitious airs’, including nitrous oxide (figure 2). Humphry Davy was appointed the Institute’s superintendent.
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Fig. (1). The apparatus designed by James Watt for Thomas Beddoes and used by Humphry Davy for making “Factitious Airs”. X – “Refrigeratory”. H – “Hydraulic Bellows”. Y – “Air Holder”. (From Beddoes and Watt, 1796, plate III, fig. 1, by courtesy of and photographed at the Royal Society of medicine. prepared for publication by C.H. Redman. The apparatus was described previously in Beddoes and Watt. 1794.)
Figure 2 is taken from reference 1, with kind permission from Oxford University Press |
Davy set about investigating the potential uses of nitrous oxide. These were published in his 1880 treatise
Researches, Chemical and Philosophical; chiefly concerning nitrous oxide, or dephlogisticated nitrous air, and its respiration. Extensive experiments were carried out on various animals, including rabbits, cats, lizards, fish and even insects. Unfortunately the common outcome for all these experiments was that the animals died. His description of the post-mortem state of the mammals’ organs strongly suggests that the animals asphyxiated, probably from being made to breathe a grossly hypoxic mixture which contained a large number of impurities, including cyanide. In spite of these alarming results, the great and the good were invited to the Institute to become guinea pigs for human studies. These rather less than scientific experiments clearly demonstrated the hallucinatory properties of the gas, and presumably the humans were saved from hypoxic harm because the mouthpiece fell from their lips as they became intoxicated. Inevitably such ‘experiments’ tended to degenerate into nitrous oxide parties, and their usefulness is debatable. Davy experimented on himself repeatedly, and has left many detailed descriptions of nitrous oxide intoxication. He may have become addicted to the ‘laughing gas’, at least temporarily. In 1779, he inhaled nitrous oxide at least 3-4 times per day.
Davy is correctly credited with being the first to describe the biological properties of nitrous oxide, and to speculate (very briefly) on its potential use as an analgesic (not an
anaesthetic) in surgery. However, Davy was essentially a research chemist, not a physician, so he may not have fully appreciated the potential benefits of his discovery. The year following the publication of his treatise, Davy was invited to London to direct the chemistry laboratory at the Royal Institute in London. The studies on nitrous oxide were abandoned for more ‘serious’ subjects, and Beddoes’ Pneumatic Institute ultimately went bankrupt, ironically because no medicinal benefit could be demonstrated from his factitious airs. Beddoes died a broken man. For most of the first half of the 19th Century, nitrous oxide was relegated to upper class evening ‘laughing gas’ parties, freak shows and funfairs.
As every junior anaesthetist should know, the first person to use nitrous oxide as an anaesthetic was a dentist from Connecticut called Horace Wells. In 1844 Wells witnessed a demonstration of the euphoric properties of nitrous oxide at a travelling fair, where an ex-professor of chemistry named Gardner Coulton was exhibiting the gas. Wells noted the ability of inhaled nitrous oxide to abolish pain, and indeed had one of his own teeth extracted under nitrous oxide
analgesia (the distinction is important) administered by Coulton. Wells then performed several dental extractions on his patients in this way. In 1845 Wells demonstrated his nitrous oxide technique for dental extraction at Massachusetts General Hospital. The patient was made to breathe pure nitrous oxide from a rubber bag, and when sufficiently calm the operation began. Unfortunately the patient groaned loudly throughout the procedure, and the sceptical audience booed loudly. In fact the patient felt no pain, and the groaning was probably due to the lightness of the anaesthesia. Wells was acutely aware that pure nitrous oxide had the potential to produce asphyxia, and his own analysis of the public relations disaster was that he had removed the nitrous oxide bag before anaesthesia was complete. Nonetheless the demonstration was a failure. Wells never recovered personally or professionally. He gave up his dental practice, became addicted to nitrous oxide, and ultimately committed suicide. In spite of his tragic end, his colleagues in Connecticut continued to use nitrous oxide as an analgesic for dental extractions. Gardner Coulton continued to demonstrate this use for nitrous oxide in Paris and London, and British dentists rapidly embraced the technique. The concept of nitrous oxide as an anaesthetic had been established.
Somewhat frustratingly, the investigation of nitrous oxide then stalled for a further 20 years, owing to the advent of ether anaesthesia. Ether anaesthesia was first used by a New York physician named Crawford Long to undertake minor surgery in 1841. However the first person to demonstrate ether anaesthesia publicly was another dentist, William TG Morton. Morton was a student and in theory a friend of Wells. Morton used ether, which was easily available from pharmacies, to undertake the removal of a large tumour from a patient’s jaw. The operation took place at Massachusetts General in 1846, and as the patient remained docile throughout, was a resounding success. There then followed an extraordinary legal battle between Morton, friends of the now-deceased Wells, and a third party known to them both, Charles Jackson, to determine which of them could be credited with the discovery of surgical anaesthesia. Bizarrely, a Senate Select Committee determined that Jackson should be awarded this accolade. Morton never recovered from the disappointment and died of a stroke at the age of 48.
The pendulum swung back towards nitrous oxide in the 1860s, when the first real clinical research took place. European clinicians recognised that nitrous oxide had to be given under pressure to be effective (because, as we know now, its MAC is greater than one atmosphere). Elaborate barometric chambers in which patient and surgeon could be sealed for the duration of the operation, were designed. These did allow the administration of nitrous oxide/air mixtures, but were expensive and impractical and soon fell out of use. A Chicago surgeon, Edmund Andrews, noted the extensive use of nitrous oxide by dentists, but observed that the asphyxiating potential of pure gas made it suitable only for the rapid extraction of a few teeth. Andrews wished to adapt nitrous oxide anaesthesia for use in more prolonged surgical procedures, so he added oxygen to the mixture. He used a mix or four fifths nitrous:one fifth oxygen, to mimic the concentration of oxygen in atmospheric air. Using this technique Andrews could safely perform minor surgery while the patient remained pink rather than blue, but the length of anaesthesia was still very short. The real difficulty was that in order to be an effective anaesthetic for surgical purposes, extremely high concentrations of nitrous oxide (80% or greater) had to be used. The patients anaesthetised in this way showed a typical clinical pattern, described by the British dental surgeon Sir Frederick William Hewitt: ‘lividity or actual cyanosis, true stertor, jerky and irregular respiration, clonic
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Figure 12. The complete assembly of Hewitt’s gas and oxygen apparatus. (From Hewitt, 1892).
Figure 3 is taken from reference 4, with kind permission from Oxford University press |
movements of the extremities and elsewhere, dilatation of the pupils, and considerable acceleration of the pulse rate’. Of course these are the signs of cerebral hypoxia, which Hewitt recognised. However, unlike many of his colleagues, he did not consider cerebral hypoxia a necessary part of the anaesthetic. He was able to demonstrate that the addition of oxygen to the anaesthetic completely abolished the distressing clinical signs while maintaining anaesthesia. Over the course of several years (1890s), he experimented with several methods of administering a combination of nitrous oxide and oxygen, eventually perfecting a gas and oxygen apparatus which could deliver varying amounts of the two gases depending on the patient and the operation (figure 3). The apparatus consisted of nitrous oxide and oxygen cylinders containing these gases under pressure (made by this time by BOC) which fed independently into reservoir bags attached to a regulator (‘gasometer’) on which a lever could be rotated to determine the relative contributions of the final anaesthetic mixture.
After Hewitt, several workers on both sides of the Atlantic devised anaesthetic apparatus which could deliver varying nitrous oxide/oxygen mixtures, culminating in the UK in the recognisable Boyle’s anaesthetic machine, introduced by H.E.G. Boyle in 1917.
There are some interesting points to be made about this story. In the 19th Century, the principal medical use of nitrous oxide was as an analgesic for dental extraction. The physical impossibility of anaesthetising a patient with nitrous oxide for prolonged surgery without inducing severe hypoxia was well-recognised, hence the move towards chloroform and ether. Over the course of the 20th Century, as the quality of the available inhalational anaesthetics improved, nitrous oxide took on the role of a carrier for the volatile agent (the ‘second gas’ effect), and an analgesic component of the anaesthetic. It was also used to prevent the theoretical disadvantages of a high inspired oxygen level, namely oxygen toxicity and absorption atelectasis. These disadvantages may considered theoretical rather than real. Atelectasis is a feature of all anaesthetics to a greater or lesser degree, and there is no evidence that oxygen level or the presence of nitrous oxide affects it one way or the other
6. Also, oxygen toxicity is extremely unlikely in the time of an average operation6, but this myth still has my juniors anxiously turning the oxygen down to 30%. What is more worrying is that the original Victorian nitrous oxide concentration of 70-80% seems to have persisted in clinical practice in the face of very little evidence that such a high nitrous oxide fraction is necessary. We are therefore faced with a ‘tradition’ (nothing more) that nitrous oxide/oxygen combinations must be delivered in a 70:30 ratio. It could be argued that the level of nitrous is too high and the level of oxygen is too low. This is particularly worrying in view of Nunn’s seminal work in the 1960s. Nunn clearly stated
7:
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with an average minute volume of 5 L/min, an inspired oxygen concentration of 26-31 per cent was sufficient to maintain normal arterial Po2 in the average patient but not for the majority. Interpolation suggests that 30-40 per cent would be required …’ Nunn 1964.
The italics in the quoted text are Nunn’s own, and although the work he is describing refers to spontaneously breathing patients breathing a nitrous oxide/oxygen mixture, further studies also demonstrated this to be true for ventilated patients. It is clear that there has been no justification for 30% oxygen/70% nitrous oxide since at least the 1960s. It is a myth.
Before throwing the nitrous oxide out, however, there is an additional factor to consider. In a carefully considered computer model of ventilation perfusion matching, Peyton et al
8 investigated another observation made by Nunn, which he was unable to explain at the time. Nunn observed that patients breathing an oxygen/nitrous oxide mixture for 30 minutes had a higher PaO
2 than those breathing an equivalent oxygen fraction in nitrogen. Nunn could not explain this observation, which was the opposite of what he had expected (he had been expecting diffusion hypoxia), and the results were only reported in abstract form. Peyton et al were able to show that the reason for this lies in the second gas and concentrating effect of nitrous oxide, which had originally been described for volatile agents by Stoetling and Eger, again in the 1960s (see Peyton et al for references). Oxygen also undergoes a second gas and concentrating effect in the presence of nitrous oxide, with the result that in areas of low ventilation/perfusion matching, PaO
2 rises. Nitrogen has no such effect. Therefore, if the oxygen tension is 30%, a patient breathing 70% nitrous oxide has a higher PaO
2 than if they were to breathe 70% nitrogen. The model described by Peyton’s group mimics the segments of low ventilation/perfusion matching seen in the ‘typical’ patient undergoing anaesthesia, and it is these poorly ventilated segments that benefit most from the second gas effect of nitrous oxide, resulting in a rise in alveolar Po2. The point is, that if one is to blame nitrous oxide specifically for causing clinical problems one has to compare equivalent tensions of nitrous oxide and nitrogen in the two groups, otherwise the patients are not evenly matched. This is a crucial issue with regard to the interpretation of the paper that Zoe (and the rest of the media) was concerned about.
What about other aspects of nitrous oxide that might preclude its use? Prolonged use of nitrous oxide in abdominal surgery is said to be undesirable because of the accumulation of this gas in the gut. However in modern surgery the length of exposure is unlikely to be long enough for this to happen, and in any case I cannot find any evidence for this in the literature. Another potential area where gas expansion may be a problem is in the presence of a pneumothorax. In theory this is more probable but in practice anyone who anaesthetises someone with a pneumothorax and no chest drain deserves to be shot. Problems with the expansion of a pneumothorax under anaesthesia are, in any case, more likely to occur as a result of mechanical ventilation. The most important adverse effect of nitrous oxide in an enclosed air-containing space is increased pressure in the cochlea. I have seen a paper (although I can’t find the reference at present) strongly implicating this mechanism to explain the increased rates of post-operative nausea and vomiting (PONV) associated with nitrous oxide: i.e. gas in the cochlea not gas in the stomach, which is the commonly supposed explanation. This is a good argument for avoiding N
2O in prolonged ENT surgery, and also in those with a previous history of PONV. However it is worth noting that several meta-analyses have not been able to separate the influence of nitrous from other factors, so it is worth considering the use of nitrous on a patient-by-patient basis. Overall, if you think your patient is at high risk of nausea, either don’t give nitrous oxide or use an adequate combination of anti-emetics, possibly including dexamethasone.
Lastly in this section, there is the issue of inactivation of methionine synthase. Nitrous oxide inhibits methionine metabolism by irreversibly oxidising cobalamin, and thus preventing the activation of methionine synthase. Without going into the details, the result is an accumulation of homocysteine, which may cause bone marrow depression, and neurotoxicity. There are several other potential (and mainly theoretical) consequences of methionine inhibition by nitrous oxide. However it is likely that all of these will be of greatest relevance in those with a cobalamin deficiency-pernicious anaemia, malnutrition, and malabsortion syndromes with a proven cobalamin deficiency. It has been suggested that nitrous oxide should be avoided in the elderly, who may be chronically malnourished. My view is that if the patient does not have either a macrocytic anaemia (or a microcytic anaemia, where cobalamin deficiency may be disguised by iron deficiency), the elderly should not be denied nitrous oxide in the form of Entonox or as part of a short (less than one hour) anaesthetic. This is particularly true for orthopaedic trauma, where the potent analgesic effect of nitrous oxide can be beneficial.
Are there any real positives to nitrous oxide? In my opinion, analgesia is the most important clinical application of nitrous oxide, and should not be overlooked. This is as true today as it was in the time of Horace Wells. It is only recently that the mechanism of analgesic action of nitrous oxide has been elucidated
9. Many years ago it was demonstrated that 30% nitrous oxide provided equivalent analgesia to 10-15mg of morphine. It was also recognised early on that the potent analgesic effect of nitrous could be reversed by naloxone. To paraphrase a good deal of experimental investigation9, N
2O stimulates the release of endogenous opioids in the peri-aqueductal grey area, and thus activates post-synaptic k-opioid receptors. These receptors are involved in the suppression of the detection of noxious stimuli. The analgesic effect of nitrous oxide can be abolished in rats by ablation of the peri-aqueductal grey area, or by k-receptor antagonists. A recent study
10, also carried out in rats, has demonstrated that nitrous oxide in a concentration range of 10-50% prevented the postoperative hyperalgesia that is frequently seen after the intra operative administration of fentanyl and remifentanil
11. I might cheekily suggest that TIVA users might like to add a low percentage of nitrous oxide to their gas mixture to reduce morphine loading towards the end of the operation and into recovery
12. At the very least, the potent analgesic effect of nitrous oxide demands fuller investigation, I hope I have been able to place nitrous oxide in context. We can now turn to the paper by Myles et al which prompted this article2. The study is a multi-centre, randomised controlled trial (ENIGMA trial). A total of 2050 patients undergoing major surgery were enrolled and analysed. Individuals were randomly allocated to receive either 30% oxygen/70% nitrous oxide, or 80% oxygen/20% nitrogen. All other choices were left to the individual anaesthetist. The primary outcome was length of hospital stay, but a large number of secondary outcomes were also recorded, including wound infections, pneumonia, myocardial infarction and severe nausea and vomiting (for complete list see reference). To cut a long story short, the two groups were well-matched demographically, and the anaesthetic techniques were broadly similar, as were analgesia and fluid administration. The primary outcome, length of stay, was the same for the nitrous and the non-nitrous group. Thirty day mortality rate was also similar. The devil is in the secondary outcome measures. There was no difference in rates of stroke, myocardial infarction, thromboembolism or blood transfusion, although it is possible that the study was underpowered to detect these differences. Patients who received nitrous oxide were significantly more likely to experience severe post-operative nausea and vomiting, fever, wound infection or pneumonia. The p-values are impressive, but it is worth noting that rates of pneumonia were low anyway (1.5 % incidence in the non-nitrous group as opposed to 3% in the nitrous group).
I have several comments to make about this study. Firstly, the incidence of complications was generally low. I would be more confident that the study’s findings were correct if, say, 10 000 patients had taken part. In other words, I’m not convinced that the study is adequately powered. Is there a statistician in the audience who can help? Please let me know. Secondly, and most importantly, the two groups may have been well-matched demographically, but they received dramatically different anaesthetics. The nitrous group received only 30% oxygen, which as we have seen is probably too low for major surgery. The nitrogen group received 80% oxygen-a very substantial difference! The authors have clearly had comments from the reviewers about this, as the issue of high versus low oxygen is mentioned at several points in the text. Unfortunately, the topic is mentioned only to be dismissed. I would suggest that the authors’ basis for dismissal, a post-hoc analysis of actual oxygen percentage given, is not valid. Further, based on the research described above, there is a strong possibility that that if 70% nitrous oxide/30% oxygen had been compared with 70%
nitrogen/30% oxygen, the results would have been far less clear cut. I will be cheeky again and suggest that as nitrous has a second gas and concentrating effect on oxygen, the nitrous group might even have done better under those circumstances! Another alternative would be test 80% oxygen/20% nitrous oxide against 80% oxygen/20% nitrogen. Again, I suspect the results would be less significant.
The point is that this study demonstrates a positive benefit of high intra-operative oxygen tension, rather than a negative effect of nitrous oxide. This is highlighted in an editorial accompanying the article
6. Increased arterial oxygen tension significantly reduces wound infection and promotes wound healing
13. This is because subcutaneous tissues have a low capillary density, and wound edges depend on diffusion of dissolved oxygen from distant capillaries for respiration, rather than oxygen attached to haemoglobin. A high partial pressure of oxygen in the capillaries is therefore vital to prevent hypoxia at the wound edges
13. 80% oxygen is bound to provide a greater diffusion gradient than 30% oxygen. It simply demonstrates that a high partial pressure of oxygen should be administered throughout the peri-operative period to improve outcome. There is no justification for the study authors’ conclusion that nitrous oxide should be avoided.
Overall, my personal conclusions would be:
- A high concentration of oxygen should be part of one’s anaesthetic technique, whether the balancing gas is air, nitrogen, nitrous oxide or a more exotic gas. I routinely use 50-60% oxygen.
- Nitrous oxide is probably not the evil gas that modern anaesthetists seem to suppose. There are certain groups that should not have it, but others that should not be denied because of remote or unproven risks. Clinical discretion should be employed. I.e. use your head!
- Nitrous oxide is a potent and effective analgesic whose properties are only now being properly investigated. It is far too early to consider banishing it from our hospitals.
- Post-operative nausea and vomiting is a probably increased with the use of nitrous, but this is probably not true of all patients. Use one or more anti-emetics. In the ENIGMA study, anti emetic use was very low in both groups-35%. Thus, if you give a potentially emetic drug without an anti-emetic, the patient will probably be sick. This probably explains the significantly greater level of PONV in the group given nitrous oxide.
- Lastly, and possibly most surprising to myself, I am using nitrous oxide more commonly as a result of researching this article. Like many authors in the literature, I used to piously avoid the ‘dreadful’ nitrous oxide. Like everyone else, I based my practice on erroneous beliefs that have been absorbed into textbooks but have a limited basis in truth. Our textbooks should not be repositories of mythology. Unfortunately for Zoe from the BBC, I cannot advocate the removal of nitrous oxide. It might just be a useful gas after all. I’d be interested in your comments.
References
- Smith WDA. A history of nitrous oxide and oxygen anaesthesia. Part 1: Joseph Priestley to Humphry Day. Br J Anaesth 1965;37:790-8
- Myles PS et al. Avoidance of nitrous oxide for patients undergoing major surgery. A randomised controlled trial. Anesthesiology 2007;107:221-31
- Smith WDA. A history of nitrous oxide and oxygen anaesthesia. Part II: Davy’s researches in relation to inhalation anaesthesia. Br J Anaesth 1965;37:871-82
- Smith WDA. A history of nitrous oxide and oxygen anaesthesia. Part IX: The introduction of nitrous oxide and oxygen anaesthesia. Br J Anaesth 1966;38: 950-62
- Gases in medicine. Anaesthesia. 8th BOC Priestley Conference. Eds. Smith EB and Daniels S. The Royal Society of Chemistry 1998.
- Hopf HW. Is it time to retire high-concentration nitrous oxide? Anesthesiology 2007;107:200-1
- Nunn JF. Factors influencing the arterial oxygen tension during halothane anaesthesia with spontaneous respiration. Br J Anaesth 1964;36:327-41
- Peyton PJ et al. Effect of ventilation-perfusion inhomogeneity and N2O on oxygenation: physiological modelling of gas exchange. J Appl Physiol 2001;91:17-25
- Emmanouil DE et al. Advances in understanding the actions of nitrous oxide. Anesth Prog 2007;54:9-18
- Richebé P. Nitrous oxide revisited: evidence for potent antihyperalgesic properties. Anesthesiology 2005;103:845-54
- Angst MS et al. Short-term infusion of the k-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003;106:49-57
- Gozdemir M. Remifentanil-propofol in vertebral disk operations: hemodynamics and recovery versus desflurane-N2O inhalation anaesthesia. Adv Ther 2007;24:622-31
- Ueno c et al. Using physiology to improve surgical wound outcomes. Plast Reconstr Surg 2006;117(Suppl):59S-71S
Issue: June 2008
Introduction
Currently, there are several different interventional therapies for lumbar discogenic pain. These include intradiscal injections, radiofrequency annuloplasty (RFA), intradiscal electrothermal therapy (IDET™) and disc decompression. Disc biacuplasty (DB) using the TransDiscal™ System (Baylis Medical, Montreal) utilizes bi-polar heating by placing two straight probes in the postero-lateral region of the annulus and delivering radiofrequency energy between them. Active cooling of the probes during RF delivery results in large, homogenous, and reproducible lesions across the annulus. This is achieved by heating the target area to a temperature of 55°C +/- 5°C. By ablating nociceptive pain fibres, modulating collagen, and stimulating the healing process there should be a decrease in axial discogenic pain resulting from the annular tear.
Methods
All patients had predominantly axial low back pain of over 6 months duration, which failed to improve after conservative therapies. Facet joint injections, sacroiliac joint injections and RF rhizotomies had also failed to give prolonged improvement. All had MRI degenerative disc pathology at one or more levels, and low pressure induced positive concordant pain of intensity >6/10 during provocative lumbar discography at 1 or 2 disc levels with negative control discs at one and preferably two adjacent levels. Disc biacuplasty was performed in the standard prone position after identifying the landmarks using fluoroscopy. In the case of multilevel axial discogenic pain disc biacuplasty was performed at those levels.
Scientific Sessions
