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Good afternoon ladies and gentlemen, my name is ________ and today I’m going to have a look at the anaesthetic agent nitrous oxide, which was first synthesised by Joseph Priestly, an English natural philosopher, over 200 years ago.  It is the only anaesthetic agent from the 19th century that survives into modern usage and has been used clinically in anaesthesia for over 150 years.
I’ll look first at how this agent came to be used as an anaesthetic following the years of its discovery.  I then want to look at its use in the 20th and 21st centuries.  Nitrous oxide has in recent years been called outdated – what are the indications for the continued use of this agent, and what are its prospects in the future of anaesthetic practice?
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In 1800, Humphry Davy, then only 21, published “Researches, chemical and philosophical, chiefly concerning nitrous oxide” while investigating the drug as a member of the Pneumatic Society at Bristol in Dowry Square. 
Towards the end of Davy’s work is the comment “…” almost a throwaway remark.  He does not mention N20 as an anaesthetic elsewhere.
Description of Davy’s investigations into N2O, including laughing gas experiments and shows.  Conclude with his almost throwaway comment that the gas could be used in surgery.
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For Davy and his colleagues, a far more lucrative venture using N2O existed – as a means of entertainment for paying customers.  The so called “Laughing Gas” filled amphitheatres and featured at parties throughout the country.  Some thought that N2O would eventually replace alcohol as the world’s leading “social intoxicant”.
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The point of N2Os dual use as anaesthetic and stage show comes when we cross the Atlantic to America.  In the years following Davy’s book on nitrous oxide, Gardner Quincy Colton was a medical student in New York.  However, he never graduated – famous as a flamboyant lecturer, Colton found that he made so much money from nitrous oxide shows that he ditched medicine in favour of travelling and doing stage shows with the agent. 
At one such event, the dentist Horace Wells was in the audience.  Colton administered N2O to one of Wells’ acquaintances.  The usual reaction of laughter and mayhem was observed, the audience doubled over as the subject ran giggling around the crowd.  As the effects of the N2O wore of, the man noticed a bloody gash in his leg.  Wells’ realised that while he had been under the influence of the gas, the man had not felt the injury, and wondered if the gas could be used as an anaesthetic agent, as Davy had so briefly conjectured years earlier.
Wells used himself as a guinea pig and instructed Colton to remove an erupting wisdom tooth using nitrous oxide as the anaesthetic.  It was a success.
Wells went on to try and demonstrate nitrous oxide in front of medical students but was unsuccessful.  As would be demonstrated in years to come, N2O was not a strong enough anaesthetic agent to be used for major surgery without adjunctive therapies.  After becoming addicted to chloroform, another anaesthetic of the age, Wells was admitted to a mental hospital, and eventually committed suicide.
Since these events, N2O was used for over 100 years without any serious side-effects, regarded as being completely innocuous.
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1956 – Lancet reports that prolonged use of N2O anaesthesia may result in megaloblastic bone-marrow changes. Triggers a host of research that reveals that N2O can inactivate vitamin B12, specifically the conversion of homocysteine to methionine and the associated DNA synthesis.
1.Nitrous oxide rapidly reduces the activity of Methionine synthase which can lead to megaloblastic haemopoiesis and impaired marrow function.  Exposure to N2O over 6 hours or exposure for patients with existing B12/folate deficiency can cause these changes and be dangerous.  May be dangerous in critically ill patients etc as well
[INFO FOR ME: Megaloblastic bone marrow changes: marcocytic anaemia resulting from the suppression of DNA synthesis in red blood cell production.  Immature and dysfunctional RBCs  (megaloblasts) in the bone marrow]
2.  Subsquent increase in plasma homocysteine – correlating with length of nitrous exposure (less conversion to methionine).  Homocysteine implicated.  Moderate increases in homocysteine have been linked to coronary artery disease – hence possibility that nitrous could increase myocardial ischaemic events.  Currently not enough research done to confirm this, theoretical. 
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LEAD FROM PREVIOUS SLIDE INTO THIS ONE, I.E. OTHER CONSIDERATIONS FOR NITROUS OXIDE?  YES… (GIVE EXAMPLES)
Contraindications: expansion into air-filled spaces
Tendency of the gas to increase pressure of an air-filled space in the human body due to tedancy to diffuse into air-filled compartments
Therefore cannot be used in clinical settings involving air accumulation, such as pneumothorax.  Also in procedures involving air-enclosed spaces, such as middle-ear or eye surgery.  Some surgeons hold that nitrous makes closing abdominal surgery more difficult, although more evidence is needed to support this.
Nitrous oxide has also been proven to increase the incidence of post operative nausea and vomiting compared to other agents.  If we can replace nitrous with other agents that leave patients more comfortable in the recovery room, why not?  Modern anaesthesia has developed several alternatives to nitrous.  However, the increase in vomiting is only seen in a small number of patients; treatment with anti-emetics pre-op for these patients can prevent post-op vomiting.
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OTHER CONCERNS:
Nitrous oxide has a marked effect as a greenhouse gas in the troposphere and is considered an environmental pollutant.  In the stratosphere, the gas destroys ozone.
However, the medical use of nitrous oxide constitutes less than 2% of the total pollution (agriculture and fossil fuels).  It is likely that the production of other anaesthetic agents has a similar environmental effect.
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Nitrous oxide has been used for millions of people over a hundred years, for the most part without incident and with fairly tolerable side-effects.  While historical success should not solely justify modern contexts, this in a way is the largest retrospective study of nitrous oxides use.
As a drug it is relatively cheap, and therefore has a role in the third world and developing countries.
There is evidence to suggest that patients are less likely to experience awareness with nitrous oxide than with other more modern agents. 
Using nitrous oxide in combination with other agents reduces the amount of these more toxic agents needed for anaesthesia, which is useful when thinking about the cardiovascular and respiratory depressive effects of some of these drugs.
Nitrous oxide is a versatile agent in its own right.  Age does not mean something should not be used; while alternatives now exist, the drug uniquely useful in its own right.
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SHOULD WE JUST ACCEPT SOMETHING BASED ON THE FACT THAT IT HAS BEEN AROUND FOR A LONG TIME?
Millions of patients treated safely over the years.  Reason the agent has remained for so long is because it is useful and relatively safe.  There are contraindications, but this is true of any drug, and nitrous oxide is certainly a less potent agent than many modern agents. 
Conversely, historical success should not alone justify the use of nitrous oxide, and it is right that we test using the current evidence base.  There is a strong correlation between post operative vomiting and nitrous oxide, and its effect on immunological, haematological etc… systems is gradually coming to light.  Initial use was demonstrated by an entertainer, not a doctor.  HINDSIGHT: we assume that something is safe and then years after its discovery begin to investigate its effects.
I would conclude that like a fine wine, nitrous oxide has aged well.  Yet its status should not just be accepted because of its age; it should be judged against the most modern vintages of anaesthetics and used accordingly and in line with current evidence. By setting nitrous oxide in its historical context, I hope to have demonstrated both sides of the argument.  There are specific situations where the agent should not be used, or be used with caution, but this is the same for any drug. 
NB COULD SAY SOMETHING ABOUT FACT THAT NITROUS IS CHEAP – i.e. 3rd world use.
Sicker patients these days – perhaps as we treat and save sicker and sicker people, the effects of once innocuous drugs become apparent.  Nitrous not realised as being toxic in the past as these sort of patients were not understood, or at least not treated effectively.
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Modern drug use – still used as entertainment in nightclubs etc, not illegal to own.  Remember that N2O as an anaesthetic was discovered following experimentation and entertainment!
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