Nitrous oxide (medication)

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Nitrous oxide, as medical gas supply, is an inhaled gas used as pain medication, and is typically administered with 50% oxygen mix. It is often used together with other medications for anesthesia.<ref name="WHO2008" /> Common uses include during childbirth, following trauma, and as part of end-of-life care.<ref name="WHO2008" /> Onset of effect is typically within half a minute, and the effect lasts for about a minute.<ref name="AnUK2009">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Nitrous oxide was discovered between 1772 and 1793 and used for anesthesia in 1844.<ref name=My2007>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO22nd">Template:Cite book</ref> It often comes as a 50/50 mixture with oxygen.<ref name=AnUK2009/> Devices with a demand valve are available for self-administration.<ref name=BNF69>Template:Cite book</ref> The setup and maintenance is relatively inexpensive for developing countries.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

There are few side effects, other than vomiting, with short-term use.<ref name=AnUK2009/><ref name=WHO2008/> With long-term use anemia or numbness may occur.<ref name=WHO2008/> It should always be given with at least 21% oxygen.<ref name=WHO2008/> It is not recommended in people with a bowel obstruction or pneumothorax.<ref name=WHO2008>Template:Cite book</ref> Use in the early part of pregnancy is not recommended.<ref name=AnUK2009/> It is possible to continue breastfeeding following use.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

History

File:Adminsitration of nitrous oxide Wellcome L0013787.jpg

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Pure N₂O was first used as a medical analgesic in December 1844, when Horace Wells made the first 12–15 dental operations with the gas in Hartford.<ref name="Discovery of Wells">Template:Cite journal</ref><ref name=boc>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Its debut as a generally accepted method, however, came in 1863, when Gardner Quincy Colton introduced it more broadly at all the Colton Dental Association clinics, that he founded in New Haven and New York City.<ref name="Drug discovery">Template:Cite book</ref>

The first devices used in dentistry to administer the gas consisted of a simple breathing bag made of rubber cloth.<ref name="use in dentistry">Template:Cite journal</ref>

Breathing the pure gas often caused hypoxia (oxygen insufficiency) and sometimes death by asphyxiation. Eventually practitioners became aware of the need to provide at least 21% oxygen content in the gas (the same percentage as in air).<ref name=boc/> In 1911, the anaesthetist Arthur Ernest Guedel first described the use of self-administration of a nitrous oxide and oxygen mix. It was not until 1961 that the first paper was published by Michael Tunstall and others, describing the administration of a pre-mixed 50:50 nitrous oxide and oxygen mix, which led to the commercialisation of the product.<ref name=boc/>

In 1970, Peter Baskett recognised that pre-mixed nitrous oxide and oxygen mix could have an important part to play in the provision of pre-hospital pain relief management, provided by ambulance personnel. Baskett contacted the Chief Ambulance Officer for the Gloucestershire Ambulance Brigade, Alan Withnell, to suggest this idea. This gained traction when Baskett negotiated with the British Oxygen Company, the availability of pre-mixed nitrous oxide and oxygen mix apparatus for training. Regular training sessions began at Frenchay Hospital (Bristol) and a pilot study was run in Gloucestershire (in which ambulances were crewed by a driver and one of the new highly trained ambulance men), the results of this trial were published in 1970.<ref>Template:Cite journal</ref>

Today the nitrous oxide is administered in hospitals by a relative analgesia machine, which includes several improvements such as flowmeters and constant-flow regulators, an anaesthetic vaporiser, a medical ventilator, and a scavenger system, and delivers a precisely dosed and breath-actuated flow of nitrous oxide mixed with oxygen.Template:Cn

The machine used in dentistry is much simpler, and is meant to be used by the patient in a fully conscious state. The gas is delivered through a demand-valve inhaler over the nose, which will only release gas when the patient inhales through it.Template:Cn

Medical uses

Nitrous oxide (N₂O) is itself active (does not require any changes in the body to become active), and so has an onset in roughly the lung–brain circulation time with peak action 30 seconds after the start of administration.<ref name=AnUK2009/> It is removed from the body unchanged via the lungs, and does not accumulate under normal conditions, explaining the rapid offset of around 60 seconds.<ref name=AnUK2009/> It is effective in managing pain during labor and delivery.<ref name=Coch2012>Template:Cite journal</ref>

Nitrous oxide has been shown to be an effective and safe treatment for alcohol withdrawal.<ref>Gillman M.A, Lichtigfeld, F.J. 2004 Enlarged double-blind randomised trial of benzodiazepines against psychotropic analgesic nitrous oxide for alcohol withdrawal, Addictive Behaviors, Volume 29, Issue 6, Pages 1183–1187</ref>

Nitrous oxide is more soluble than oxygen and nitrogen, so will tend to diffuse into any air spaces within the body. This makes it dangerous to use in patients with pneumothorax or those who have recently been scuba diving, and there are cautions over its use with any bowel obstruction.

Its analgesic effect is strong (equivalent to 15 mg of subcutaneous route morphine<ref name=AnUK2009/>)<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and characterised by rapid onset and offset, i.e. it is very fast-acting and wears off very quickly.Template:Cn

When used in combination with other anesthetics gases, nitrous oxide causes a dose dependent increased respiratory rate and decreased tidal volumes, the net effect is a lower minute ventilation. Like volatile anesthetics, it increases cerebral blood flow and intracranial pressure. However, contrary to volatile anesthetics, it leads to an increase in cerebral metabolic rate of oxygen.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

Contraindications

N₂O should not be used in patients with bowel obstruction, pneumothorax, or middle ear or sinus disease,<ref name=AnUK2009/> or who have had a recent intraocular injection of gas<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and should also not be used on any patient who has been scuba diving within the preceding 24 hours<ref name=SPUMS1998>Template:Cite journal</ref> or in violently disturbed psychiatric patients.<ref name=jrcalc>Template:Cite book</ref> There are also clinical cautions in place for the first two trimesters of pregnancy and in patients with decreased levels of consciousness.<ref name=AnUK2009/>

Composition

The gas is a mixture of half nitrous oxide (N₂O) and half oxygen (O₂).<ref name=AnUK2009/><ref name=jrcalc/> The ability to combine N₂O and oxygen at high pressure while remaining in the gaseous form is caused by the Poynting effect (after John Henry Poynting, an English physicist).<ref name=AnUK2009/> The Poynting effect involves the dissolution of gaseous O₂ when bubbled through liquid N₂O, with vaporisation of the liquid to form a gaseous O₂/N₂O mixture.<ref name=AnUK2009/>

Since the two substances are homogeneously mixed gases, the cylinder delivers a consistent 50/50 mixture all the way down to empty, even if the cylinder adiabatically cools somewhat from the discharge.<ref name=Litwin2010/>

Some N₂O may condense into a liquid if the cylinder is cooled to low temperatures (−7 °C or below), which can be dangerous if unaddressed.<ref name=Litwin2010>Template:Cite journal</ref> This occurs most easily with partially used / lower pressure cylinders. Even after warming the contents back into a gaseous state, they may remain nonhomogenous for days. Thus it is typically instructed to warm cylinders in a horizontal orientation (to maximize heat transfer) for a 48 hour period, then rehomogenize the gas by inverting the cylinder three times.<ref name=Litwin2010/>

• Entonox Shoulder.png

  Distinct blue and white cap of an Entonox cylinder

• Entonox schrader valve.png

  Typical Schrader valve attachment, making the gas usable only with demand based giving sets

Administration

File:An Operation at the Military Hospital, Endell Street - Dr L Garrett, Dr Flora Murray, Dr W Buckley Art.IWMART4084.jpg

Surgeons at Endell Street Military Hospital operating on an anaesthetised soldier during World War I. In the foreground, the anaesthetist is holding a mask in front of the patient's face.

The gas is self-administered through a demand valve, using a mouthpiece, bite block or face mask.<ref name=jrcalc/> Self-administration of Entonox is safe because if enough is inhaled to start to induce anaesthesia, the patient becomes unable to hold the valve, and so will drop it and soon exhale the residual gas. This means that unlike other anaesthetic gases, it does not require the presence of an anaesthetist for administration. The 50% oxygen in Entonox ensures the person will have sufficient oxygen in their alveoli and conducting airways for a short period of apnea to be safe.Template:Cn

Mechanism of action

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} The pharmacological mechanism of action of Template:Chem in medicine is not fully known. However, it has been shown to directly modulate a broad range of ligand-gated ion channels, and this likely plays a major role in many of its effects. It moderately blocks NMDAR and [[CHRNB2|β

1. redirect Template:Smallsub-subunit]]-containing nACh channels, weakly inhibits AMPA, kainate, [[GABAA-rho receptor|GABA
2. redirect Template:Smallsub]] and [[5-HT3 receptor|5-HT
3. redirect Template:Smallsub receptors]], and slightly potentiates [[GABAA receptor|GABA
4. redirect Template:Smallsub]] and glycine receptors.<ref name="pmid11020766">Template:Cite journal</ref><ref name="pmid9822732">Template:Cite journal</ref> It also has been shown to activate [[Two-pore-domain potassium channel|two-pore-domain Template:Chem channels]].<ref name="pmid14742687">Template:Cite journal</ref> While Template:Chem affects quite a few ion channels, its anesthetic, hallucinogenic and euphoriant effects are likely caused predominantly, or fully, via inhibition of NMDA receptor-mediated currents.<ref name="pmid11020766" /><ref name="pmid17352529">Template:Cite journal</ref> In addition to its effects on ion channels, Template:Chem may act to imitate nitric oxide (NO) in the central nervous system, and this may be related to its analgesic and anxiolytic properties.<ref name="pmid17352529" /> Nitrous oxide is 30 to 40 times more soluble than nitrogen.

Society and culture

Nitronox was a registered trademark of the BOC Group between 1966 and 1999,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and was reregistered by Hs Tm Inc since 2005Template:Cn It is also colloquially known as "gas and air" in the United Kingdom.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

Investigational trials show potential for antidepressant applications of N₂O, especially for treatment-resistant forms of depression, and it is rapid-acting.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Nagele_2021">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> In a phase 2 clinical trial, a treatment with 25% nitrous oxide had comparable efficacy to 50% nitrous oxide but was associated with significantly fewer adverse effects.<ref name="Nagele_2021" />

Further reading

• Template:Cite book

External links

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