Janet Pickles of RA Medical explores the development of nitrous oxide sedation in clinical dental practice

The history of nitrous oxide use for sedation and associated equipment is a fascinating one. Many leading names have played a significant part in the journey and this article will attempt to explore some of the facts associated with nitrous oxide since its discovery.

Statement
Nitrous oxide is manufactured by heating ammonium nitrate to 250 degrees centigrade.

Mechanism of action
Nitrous oxide produces analgesic and anxiolytic effects. The exact mechanism of action through which these effects are perpetuated is unknown. However, t

he most widely accepted theory is that the analgesic effect is mediated through interaction with the opioid receptors. These are the same receptors activated by morphine and heroin.

This stimulation occurs in the midbrain leading to activation of the descending inhibitory pathways, which alters pain processing in the spinal cord. The anxiolytic effect is mediated through interaction with the GABA-A receptors. The mechanism of action closely resembles that of ethanol. GABA is an inhibitory neurotransmitter that inhibits the pre-synaptic cells from transmitting, thus decreasing nervous system activity.

History
The discovery of both oxygen and nitrous oxide is credited to Joseph Priestley somewhere around the period 1771-1777. However, Humphry Davy seems to be the person who initially promoted the inhalation of nitrous oxide.

In order to continue with his experiments, in 1779 James Watt built a portable gas chamber (Fig 1) for the purpose of Davy’s nitrous oxide inhalation experiments, which at one point were combined with wine to judge the efficacy of nitrous oxide as a cure for hangovers (his laboratory notebook indicated success).

Despite the popularity of the gas among Davy’s friends and acquaintances and his copious notes about the ability of the gas to entirely take away the sensation of pain, Davy seems never to have considered the use of nitrous oxide as an anaesthetic, missing a huge opportunity. Anaesthetics would not be regularly used in medicine or dentistry until decades after Davy’s death

On 10 December 1844, American Horace Wells and his wife Elizabeth attended a stage-show laid on by ’Professor’ Gardner Quincy Colton. After watching an acquaintance, store-clerk Sam Cooley, injure his leg without batting an eyelid, Wells recognised that nitrous oxide might prove a godsend to surgical medicine as well as popular entertainment.

Wells decided that the first guinea pig should be himself. An erupting wisdom tooth had been troubling him for some time. This seemed the ideal occasion to remove it. Both Colton and Wells’ partner Dr Riggs were initially reluctant to contemplate using the higher dosages of nitrous oxide needed to induce insensibility rather than intoxication and euphoric excitement. But Wells insisted and the extraction was a success. Wells then enlisted Colton’s help in teaching him how to manufacture and administer nitrous oxide to his patients.

The technique was crude, yet it seemed safe and effective. With the assistance of Riggs, Wells administered nitrous oxide from an animal bladder via a wooden tube into the patient’s mouth while his or her nostrils were compressed. A curious but sceptical John Collins Warren acted as surgeon. After performing more than a dozen extractions under nitrous oxide anaesthesia over the next month, Wells felt ready to share his discovery with a wider audience.

His ex-business partner (1842-3) and former student, William Morton, encouraged Wells to stage a public demonstration with John Warren acting as surgeon. In an article in the Hartford Courant (9 December 1846), Wells explained what happened on the appointed day: “A large number of students, with several physicians, met to see the operation performed, one of their number to be the patient. Unfortunately for the experiment, the gas bag was by mistake withdrawn much too soon, and he was but partially under its influence when the tooth was extracted.

“He testified that he experienced some pain, but not as much as usually attends the operation. As there was no other patient present, that the experiment might be repeated, and as several expressed their opinion that it was a humbug affair (which, in fact, was all the thanks I got for this gratuitous service) I accordingly left the next morning for home.”

Badly emotionally bruised, Wells didn’t give up. He continued his attempts to promote nitrous oxide anaesthesia, even travelling to Europe in the hope of finding a more receptive audience. The Paris Medical Society took a sympathetic interest in his work and recognised his claim to priority. But by the time Wells returned to the USA, the surgical scene had shifted dramatically. Ether anaesthesia was well established and chloroform anaesthesia was vigorously under investigation too; nitrous oxide had been eclipsed. ¹

In the early 1860s a resurgence of nitrous oxide emerged and it was the same Dr Colton who had assisted Wells in 1844 who was responsible. Colton insisted that nitrous oxide was safe and he could prove it. Between 1864 and 1897 he documented 193,000 cases with no fatalities thus establishing the first recorded safety record involving the use of nitrous oxide. In 1968 Paul Bert developed a unit for administration of both oxygen and nitrous oxide, however this proved impractical due to the size and immobility of the equipment.

An interesting note is that the use of nitrous oxide analgesia for cavity preparation dates back to 1889 in Liverpool. At this point, gas machines had improved somewhat and oxygen had been added to the nitrous oxide administered. By our current standards the machines were crude and gases often far from pure – indeed, many dentists used to manufacture their own! ²

Moving forward to the twentieth century and dentistry was the primary health discipline to use nitrous oxide. However, due to unreliable equipment and lack of established technique, nitrous oxide use was almost non-existent, seeing only two periods of interest in nitrous oxide; 1913-1918 and 1932-1938. The loss of interest was occasioned by high failure rate of administration – probably caused by lack of suitable equipment and technique.

The 1940s saw a renewed interest in the use of nitrous oxide sedation and Harry Langa in the US began postgraduate dental education in 1949, training more than 6000 dentists in nitrous oxide sedation. Langa also published a classic textbook Relative Analgesia in dental practice: inhalation analgesia with nitrous oxide published in Philadelphia 1968 by W B Saunders. This became a classic reference book, the second edition being published in 1976.

Dental schools in the States began teaching the concepts of inhalation sedation in the late 1950s, early 1960s and, in 1962, guidelines for teaching pain and anxiety control in dentistry were established by the American Dental Society of Anaesthesiology. Nitrous oxide continues to be very popular in the USA with over 50 per cent of general dentists and 88 per cent of paediatric dentists using it on a regular basis. This is a far higher percentage than currently employed in the UK and Ireland although numbers are continuing to grow. ³

The situation in Europe was somewhat different but encountered more difficulties due to legal restrictions placed on the administration of inhalational anaesthesia by dentists. In the USA there were no such restrictions, therefore reflecting the current usage of nitrous oxide sedation to this day.

Even now, the attitude towards inhalation sedation differs greatly from country to country. While it is well accepted in the UK, Italy, Israel, Switzerland and Scandinavia for example, it is not even licensed in countries such as Greece. Germany is minimal and France only allows the use of 50 per cent/50 per cent premixed oxygen/nitrous oxide (or what we would describe as Entonox) for dental application.

We are fortunate in the UK that Cyprane, based in Keighley, West Yorkshire, did so much to promote the safe and acceptable use of sedation from the late 60s onwards. (Cyprane was also responsible for the design and production of the Tec Vaporizer series which were temperature compensated vaporizers, including the Drawover Vaporizer commonly used with a MDM or AE Gas Machine, for example, to administer dental anaesthesia. It is not for nothing that Keighley was known as the ’Anaesthetic Capital of the World’ at one time!

UK Equipment types
Harry Langa, in his first edition, lists the following unit types: NCG Dental Analgesia unit, McKesson Analor, Ormco, Foregger analgesia machine and the Quantiflex R A (Fig 2) (this is the early Mark I type manufactured by Fraser Sweatman Inc). This latter unit was first manufactured in the UK in the late 1960s, under license from Fraser Sweatman, by Cyprane, West Lane, Keighley. ⁴

By the time that the second edition was published in 1976, the list had added the following units: Sedatron analgesia machine and the Quantiflex R A and MDM flowmeters. The latter were also manufactured at Cyprane in the late 1960s to early 1970s under license. The Quantiflex R A was known in the UK as the Mark II and is still in production at Hatfield, Philadelphia.

The Analogue MDM is currently the most popular model used in the UK to date. The Langa chapter concludes by mentioning that there are analgesia machines manufactured in other countries, but all function on the same principle – being continuous flow types. ⁵

Flowmeters seen since the 1960s on the UK marketplace include Airmed, Ormco, Medrex, McKesson Analor and Simplor, McKesson 882, 883 and Mc1, Walton V, A E Gas Machine (Fig 3) and the Quantiflex range: Mark I, Mark II and MDM. Perhaps the A E gas machine is worthy of note here. The Anaesthetic Equipment (AE) Company was a Cyprane Company, and this dental machine was designed for more accurate supply of known percentages of oxygen and nitrous oxide incorporating a three-stage pressure reduction.

This was an intermittent flow machine, working on a different principle from the Walton V or McKesson and was very popular. They could be used for GA with the addition of an anaesthetic vaporizer and remained in constant use by diverse sites from dental hospitals to high street dental surgeries. Their demise was gradual as plenty of spare parts were available. The Amendment to the National Health Service (General Dental Services) Regulations 1992 issued in 2001 was responsible for the discontinuation of use – but they were missed by their faithful owners. There are examples in several museums, including the Sheffield Museum of Anaesthesia.

Since the 1990s, other types have emerged: Porter C2000 MXR and C3000 MXR, Matrx Digital Centurion, Matrx Digital MDM and Accutron Ultra and Newport. Of all these, only the following are still in common usage in the 21st century – Quantiflex Mark II, MDM (Fig 4), DMDM (Fig 5), Porter C2000 MXR, C3000 MXR, McKesson Mc1 and Accutron Ultra. The three manufacturers involved are: Porter Instruments in Hatfield, Philadelphia, USA, Accutron Inc in Arizona USA and Cestradent/McKesson based in Chesterfield, Derbyshire, UK. All types are dedicated sedation flowmeters with minimum 30 per cent oxygen and maximum 70 per cent nitrous oxide.

Porter Instruments has been a sedation flowmeter manufacturer for many years. It currently makes the Analogue MDM, Digital MDM and the C3000 MXR having purchased the Matrx Nitrous Oxide Sedation Division in November 2008. Accutron no longer have a UK distributor and Cestradent/McKesson is the only remaining UK manufacturer of a dedicated sedation flowmeter at present time. Of all the unit types listed above, the most popular and widely used models are the MDM, DMDM and C3000 MXR with the MDM taking the title as most commonly encountered.

This unit type, first seen in the UK in the late 60s – having undergone very little in the way of design change over the years – is reliable and consistent in performance, clearly a machine design ahead of its time. The proof is the undeniable fact that many MDMs labelled Cyprane are still in daily use requiring little more than an annual OEM service – 40-plus years on from the date of manufacture. Not many pieces of anaesthetic equipment can hold that title!

Sedation equipment has come a long way from the James Watt machine of the 1700s to the digital flowmeters of the 21st century.

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References

1. Extracted from http://www.generalanaesthesia.com

2. H Langa Relative Analgesia in Dental Practice; Inhalation Analgesia with Nitrous Oxide 2nd Ed. W.B. Saunders 1976 p17

3. A Clark, A Brunick Handbook of Nitrous Oxide and Oxygen Sedation 2nd Ed. Mosby 2003 p13-14

4. H Langa Relative Analgesia in Dental Practice; Inhalation Analgesia with Nitrous Oxide. 1st Ed. W.B. Saunders 1968 p92-103

5. H Langa Relative Analgesia in Dental Practice; Inhalation Analgesia with Nitrous Oxide 2nd Ed. W.B. Saunders 1976 p331-347

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