Has the chemical formula N2O (molecular weight 44) Discovered in 1772 by the chemist Joseph Priestley. Increased recognition of its anaesthetic potential in the 19th century. Also has other applications e.g. car racing.
Production & Storage
Produced by heating ammonium nitrate to 240 degrees celsius. This results in a number of other by products, particularly higher oxides of nitrogen, and ammonia. These are removed by passage through a series of washers and scrubbers and caustic soda.
It is stored in French Blue cylinders (with a white collar) at a pressure of around 4400 kPa. As they are usually stored below the critical temperature (36.5 celsius) it exists as a liquid with the vapour above it. This results in a nearly constant pressure of the vapour, regardless of the remaining volume of nitrous oxide left in the cylinder. They are filled with a filling ratio of 0.75 (and 0.67 in tropical regions because of the higher temperature). This is because if the cylinder were to reach its critical temperature at a filling ratio of 0.75, the liquid would all turn to gas and it would explode.
Boiling point -88.5 oC Critical temperature 36.5 oC Critical pressure 72 bar MAC 105% Blood/gas partition coefficient 0.47 Oil/gas partition coefficient 1.4
N2O has actions on several systems in the body.
Neurological Appears to have action at several neuro receptors. Acts as an inhibitor at the glutamate NMDA receptor, leading to its main effects. Has some stimulatory effects at opioid, alpha adrenergic (1&2) and dopaminergic receptors. These receptors (particularly opioid) are thought to explain the analgesic effect of N2O.
N2O also has a general anaesthetic effect. Although the MAC of 105% means that it is unlikely to be able to provide full anaesthesia by itself, it is commonly used in combination with other anaesthetic agents (although it may produce anaesthesia in some patient groups in large concentrations e.g. the elderly).
Other neurological effects include:
Increased cerebral metabolic rate
Increased cerebral blood flow
It doesn’t appear to potentiate the action of nondepolarizing neuromuscular blockers like some other volatile anaesthetic agents.
Cardiovascular Mild myocardial depressant effect. Often offset by some increased sympathetic ANS activity. As such there is usually little change in BP or cardiac output. Some increase in pulmonary vascular tone.
Respiratory Small drop in tidal volume. Increase in respiratory rate. Overall no real impact on minute ventilation. Depresses mucociliary flow. May also impair neutrophil function.
Metabolic Oxidises the cobalt at the centre of vitamin B12 Prevents it acting as a cofactor for methionine synthase. This impairs synthesis of DNA. Can express as megaloblastic anaemia. For the same reasons can result in neuropathy or subacute combined degeneration of the spinal cord.
Some of the physical properties of N2O mean that it has some specific pharmacokinetic properties.
Concentration effect. This refers to the disproportionately high rise in FA/FI. This come about because of the large amounts of N2O that are usually used (e.g. 60% of the gas mixture). Although it is relatively insoluble, N2O is 20 times more soluble than nitrogen. When combined with the large amounts used, the result is a large amount of N2O being taken up from the lungs by the circulation. This ‘gap’ is subsequently replaced by more inhaled air, resulting in a faster ris in FA/FI.
This phenomenon is the cause of the second gas effect. This refers to the fact that an additional volatile anaesthetic agent is concentrated by this effect, resulting in a faster induction speed.
The reverse of this effect occurs at the end of anaesthesia. Here the alveolar rapidly fill with the large volumes of N2O that have been taken up by the body. This can result in diffusion hypoxia, because of ‘dilution’ of alveolar oxygen. Similarly, the rapid diffusion of N2O can result in a dilution effect of any other anaesthetic vapour used, resulting in a faster offset.
N2O is almost completely excreted unchanged from the lungs. A very small amount diffuses through the skin.
Postoperative Nausea and Vomiting N2O is a significant contributor to PONV. This is likely to be multifactorial in nature, including bowel distension, middle ear distension, and dopaminergic pathway stimulation. Interestingly this is less than previous thought, with a quoted risk ratio of around 1.4. However, an interesting review of the topic (reviewed here: http://www.rapidsequence.org.uk/blog/nitrous-nausea) suggest that this is related to the length of exposure, and may not have much of an effect below 1 hour exposure.
Air filled spaces The discrepancy of solubility between N2O and nitrogen mean that any nitrogen filled spaces in the body will rapidly fill with N2O when it is administered. This can be significant in a number of scenarios:
Bowel - can increase distension in bowel obstruction and may contribute to PONV.
Pneumothorax - can lead to a rapid increase in size
Pneumocephalus - increase in size and risk of cerebral injury
Middle ear gas - disruption of grafts post surgery
Expansion of the cuffs of endotracheal tubes can cause injury if there is prolonged exposure.
Teratogenicity There is good animal evidence that N2O is teratogenic. This is not thought to be purely related to its vitamin B12 effects. Though the human evidence is a little less clear, there is generally guidance to avoid its use early in pregnancy.
Cardiovascular events N2O has been described as raising plasma homocysteine levels, and has been alleged to increase the risk of coronary events because of this. The large ENIGMA II trial went against this though - See: http://www.rapidsequence.org.uk/blog/enigma-ii
General anaesthesia Though not able to provide full general anaesthesia by itself because of its high MAC, it can be used within the gas mixture alongside other volatile agents. This can reduce the amount of volatile anaesthetic needed, reducing the adverse effects associated with them e.g. cardiovascular depression. It can also bring in the positive effects of N2O e.g analgesia, rapid onset/offset.
Analgesia In combination with oxygen (as entonox) it can be used as a acute analgesia agent. This can be within the trauma scenario, or (commonly) within obstetrics as a labour analgesic.
As noted, entonox is the commercially available preparation of N2O and oxygen. It comes as a 50:50 mix. The gases are dissolved in each other, resulting in physical properties that are different from either of the constituent substances - the Poynting Effect. It is stored in french blue cylinders with blue and white checked collars at 137 bar pressure.
At about -7 oC the constituent gases will separate from each other, this is called the pseudocritical temperature, and will vary depending on the pressure it is stored at (being most common at 117 bar. In this situation, if the cylinder is used, the N2O will have condensed into a liquid phase at the bottom of the cylinder, and the gas drawn off the cylinder will be almost entirely O2. As this is used up, the gas mixture will become progressively more N2O, to the point of becoming hypoxic.
Links & References
Banks, A. Hardman, J. Nitrous oxide. CEACCP. 2005. 5(5): 145-148
Peck, T. Hill, S. Williams, M. Pharmacology for anaesthesia and intensive care (3rd ed). 2008. Cambridge University Press.