Download The increasing recreational use of nitrous oxide: history revisited

Editorials
23. Chen DL, Liess C, Poljak A, et al. Phenotypic characterization
of insulin-resistant and insulin-sensitive obesity. J Clin
Endocrinol Metab 2015; 100: 4082–91
24. Coutinho T, Goel K, Correa de Sa D, et al. Central obesity and
survival in subjects with coronary artery disease: a systematic review of the literature and collaborative analysis with individual subject data. J Am Coll Cardiol 2011; 57: 1877–86
25. Dutton DJ, McLaren L. The usefulness of ‘corrected’ body
mass index vs. self-reported body mass index: comparing
the population distributions, sensitivity, specificity, and predictive utility of three correction equations using Canadian
population-based data. BMC Public Health 2014; 14: 430
26. Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of
myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005; 366: 1640–9
27. Coutinho T, Goel K, Correa de Sa D, et al. Combining body mass
index with measures of central obesity in the assessment of
mortality in subjects with coronary disease: role of ‘normal
weight central obesity’. J Am Coll Cardiol 2013; 61: 553–60
28. Peixoto Mdo R, Benicio MH, Latorre Mdo R, Jardim PC. Waist
circumference and body mass index as predictors of hypertension. Arq Bras Cardiol 2006; 87: 462–70
29. Tanamas SK, Lean ME, Combet E, Vlassopoulos A, Zimmet PZ,
Peeters A. Changing guards: time to move beyond body mass
index for population monitoring of excess adiposity. QJM Advance Access published on November 1, 2015, doi: 10.1093/
qjmed/hcv201
| 321
30. Tsukada K, Miyazaki T, Kato H, et al. Body fat accumulation
and postoperative complications after abdominal surgery.
Am Surg 2004; 70: 347–51
31. Kartheuser AH, Leonard DF, Penninckx F, et al. Waist circumference and waist/hip ratio are better predictive risk factors
for mortality and morbidity after colorectal surgery than
body mass index and body surface area. Ann Surg 2013; 258:
722–30
32. Ozhan H, Alemdar R, Caglar O, et al. Performance of bioelectrical impedance analysis in the diagnosis of metabolic syndrome. J Investig Med 2012; 60: 587–91
33. Wang H, Chen YE, Eitzman DT. Imaging body fat: techniques
and cardiometabolic implications. Arterioscler Thromb Vasc
Biol 2014; 34: 2217–23
34. Bays H. Central obesity as a clinical marker of adiposopathy;
increased visceral adiposity as a surrogate marker for global
fat dysfunction. Curr Opin Endocrinol Diabetes Obes 2014; 21:
345–51
35. Pouliot MC, Despres JP, Lemieux S, et al. Waist circumference
and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am
J Cardiol 1994; 73: 460–8
36. Seidell JC, Perusse L, Despres JP, Bouchard C. Waist and hip
circumferences have independent and opposite effects on
cardiovascular disease risk factors: the Quebec Family
Study. Am J Clin Nutr 2001; 74: 315–21
British Journal of Anaesthesia 116 (3): 321–4 (2016)
Advance Access publication 30 August 2015 . doi:10.1093/bja/aev297
The increasing recreational use of nitrous
oxide: history revisited
G. Randhawa* and A. Bodenham
Leeds General Infirmary, Anaesthesia and Critical Care, Great George Street, Leeds LS1 3EX, UK
*Corresponding author: 7 Bideford Avenue, Leeds LS8 2AE, UK. E-mail: [email protected]
Nitrous oxide (N2O) is used in the food industry as a mixing and
foaming agent (E942) in the production of whipped cream,1 2 and
as a fuel booster in the motor industry.3 It is also a familiar agent
in obstetric, dental, emergency, and anaesthetic practice, where
use is made of its analgesic and anaesthetic properties. However,
nitrous oxide was used recreationally long before its medical
potential was realized. Joseph Priestly is accredited with first synthesizing the gas in 1772,3 and by the late 18th century inhalation
of nitrous oxide became a popular public entertainment.4 The
gas became a fashionable addition to British high-society parties
in the early 1800s thanks to its euphoric and relaxant properties,
which led chemist Humphrey Davy to coin the term ‘laughing
gas’.3
Although the routine use of nitrous oxide in anaesthesia is declining in both the UK5 and internationally,6 there has been a recent resurgence of recreational use of the gas. Its presence is now
commonplace at festivals and university parties,4 with a surprisingly high 7.6% of 16- to 24-yr-olds responding to the 2013/14
Crime Survey for England and Wales reporting nitrous oxide
use in the preceding year.2 This is a greater proportion than
had used cocaine, ecstasy, or ketamine.4 Despite this, it is our impression that many anaesthetists and emergency department
doctors are unaware of the scale of nitrous oxide use in the
community.
The product is freely available from catering outlets, street
vendors, and even via home-delivery service through the Internet or mobile vans advertising nitrous oxide for sale in UK cities.
For recreational use, nitrous oxide is commonly sold in prefilled
balloons (at point of use) or small pressurized metal canisters
(Fig. 1) designed for the food industry. A standard catering canister containing 8 g of nitrous oxide in a volume of 10 cm3 can be
bought for as little as £2,7 and produces the equivalent of ∼8 litres
of nitrous oxide gas at standard temperature and pressure.8 The
pressurized gas is released into balloons using either a puncturing device, called a charger, or equipment designed to produce
whipped cream.2 8 Once a user inhales from a balloon, the partial
322
| Editorials
pressure of nitrous oxide increases in the lungs and subsequently
in the bloodstream, producing the desired neurological effects.
anaesthesia by non-anaesthetists outside the hospital setting.13
The likelihood and severity of resultant hypoxaemia will depend
on the effectiveness of nitrous oxide delivery, air entrainment,
depth of respiration, and breath-holding to alter washout of nitrogen, oxygen, and carbon dioxide from the lungs. Such hypoxaemia should be well tolerated by a fit person but could give rise
to seizures, arrhythmias, or even respiratory or cardiac arrest in
patients with epilepsy, cardiac disease, or other co-morbidities,
especially if combined with other centrally acting or arrhythmogenic drugs.
Vomiting in patients who are obtunded by co-ingestion of
other drugs carries an aspiration risk, and the disorientation
and loss of motor control caused by nitrous oxide can result in
trauma, particularly if used while driving or operating machinery. Although there is said to be no physiological addiction, like
any drug, nitrous oxide can be habit forming, with the associated
financial and social implications.1 A handbill from 1845 advertising a public demonstration of the effects of laughing gas proclaimed ‘those who inhale the Gas once are always anxious to
inhale it a second time.’1
An ideal agent for recreational use?
Problems from chronic use
Fig 1 Nitrous oxide canisters (Image source: pakete©123RF.com).
The first time I inspired the nitrous oxide, I felt a highly pleasurable
sensation of warmth over my whole frame . . . . The only motion
which I felt inclined to make, was that of laughing at those who
were looking at me. My eyes felt distended, and towards the last,
my heart beat as if it were leaping up and down. On removing the
mouth-piece, the whole sensation went off almost immediately.
Samuel Taylor Coleridge, poet, letter to Sir Humphrey Davy, 17999
Nitrous oxide fulfils many of the desirable properties of an ideal
agent for the food industry in that it is non-flammable, bacteriostatic, colourless, tasteless, and odourless.1 It also has properties
that attract recreational drug users. It is legal, cheap, readily
available, and undetectable on routine drug screens. It has a
very rapid onset of action, such that the physiological effects
(behavioural disinhibition, analgesia, and euphoria) begin within
seconds of inhaling the gas. Its rapid offset of action and lack of
hangover effect mean that the user may safely resume normal
activities within a short time of exposure. As one university
student described the experience: ‘it came on fast and totally
wipes you out . . . and in five minutes you are ready to do your
homework.’8
The gas produces minimal cardiorespiratory disturbance in fit
patients and is rapidly and completely eliminated from the body
after exposure, so is generally considered to be safe.10 However, it
may pose significant risks in certain population groups, and with
particular methods of administration. There were 17 deaths related to nitrous oxide misuse reported between 2006 and 2012.4
The true figure could be much higher, with intoxication falsely
attributed to other drugs.
Dangers of recreational nitrous oxide use
Nitrous oxide has a number of specific adverse effects of relevance to patient selection for general anaesthesia involving the
agent,11 12 but also poses risks to fit subjects engaged in recreational use.
High concentrations of inhaled nitrous oxide constitute a
hypoxic inspired mixture. The dangers of such mixtures in the
dental chair will be familiar to older generations of anaesthetists,
and contributed to the Department of Health banning general
Chronic or intensive nitrous oxide abuse carries serious risks. Nitrous oxide interferes with DNA synthesis during even relatively
short exposures,11 by directly inhibiting the enzyme methionine
synthetase and inactivating its cofactor, vitamin B12, resulting in
reduced synthesis of methionine and tetrahydrofolate. A few
hours of exposure can cause megaloblastic changes in the bone
marrow, and days of exposure can cause agranulocytosis.11 12
The likelihood of vitamin B12 inactivation is increased in individuals abusing the gas in poorly ventilated environments and in
those with pre-existing low vitamin concentrations, such as vegans or those with pernicious anaemia. Habitual abuse inhibits
the synthesis of new methionine synthetase.
Chronic vitamin B12 inactivation can present with symptoms
ranging from mild paraesthesiae12 to a neurological condition resembling subacute degeneration of the cord.11 14 15 Impairment of
methylation of myelin sheath proteins results in axonal loss,
causing myelopathy and peripheral neuropathy. Instances linked
to chronic or intensive nitrous oxide abuse have presented with
ascending or intermittent distal numbness, ataxia, impaired proprioception, and reduced grip strength.15 16 Investigations in
these patients have revealed increased mean cell volume despite
normal haemoglobin concentrations, low or low-normal vitamin
B12 concentrations, high homocysteine (methionine precursor)
concentrations, and long segmental hyperintensity changes in
the posterior columns on magnetic resonance imaging.15 Some
of these patients have been treated successfully with vitamin
B12 and folate supplementation alongside cessation of nitrous
oxide use, but others have suffered permanent neuronal damage.15 16
In addition to neurological symptoms, functional vitamin B12
deficiency causes megaloblastic anaemia, skin hyperpigmentation, and vascular disease from hyperhomocysteinaemia, and
is teratogenic.1 12 17
Problems from unregulated methods of administration
In medical practice, nitrous oxide is available as a piped supply of
pure gas, which is delivered to the patient via a breathing circuit
with a controlled supply of oxygen to avoid hypoxic mixtures, or
as Entonox, a 50:50 mixture of N2O and oxygen, which is delivered to the patient via tubing containing a demand valve.11 The
Editorials
demand valve forms a crucial inherent safety feature in that the
patient must be capable of exerting sufficient inspiratory effort to
release any Entonox from the supply, such that no further Entonox can be released to a patient obtunded by hypoxia. In this
scenario, the rapid offset of action of the gas means that consciousness is rapidly restored, and breathing room air reverses
the hypoxia.
In recreational use of nitrous oxide, inhaling the gas from a
balloon has similar safety features. Air, and therefore oxygen,
may be entrained alongside the gas on inhalation, and if the
user is rendered hypoxic and loses consciousness, manual grip
on the balloon will fail, propelling the balloon away. Assuming
the airway remains patent, hypoxic drive will cause the user to
start to breathe room air again, reversing the hypoxia. Permanent
harm could occur if the user is obtunded with other drugs, or aspirates vomit, or is prone to seizures or cardiac dysrhythmias in
the presence of hypoxia.
More dangerous effects have been recorded when alternative
methods of nitrous oxide administration have been used. Some
users dispense the nitrous oxide canisters into whipped cream
dispensers (‘whippets’) and inhale the gas directly from the nozzle. The lack of a reducing valve means that this inhaled gas is
under considerable pressure, and instances of pneumomediastinum and subcutaneous emphysema have been attributed to
intra-alveolar rupture from this practice.18
Through lack of available equipment, or through seeking to
achieve higher concentrations of inspired gas, users may breathe
nitrous oxide directly from canisters. When a compressed gas expands rapidly, it undergoes significant cooling as a result of adiabatic change of state (this is the physical principle underlying the
mechanism of the cryoprobe used in therapeutic rapid freezing of
tissues).19 There is further cooling as a result of loss of latent heat
of vaporization.12 The anaesthetic effects of the gas may make
users initially unaware of the tissue damage being caused by inhalation of such cold gas or freezing of metal components of the
delivery system, and frostbite of the mouth, nose and vocal cords
is a recognized complication.1 8 12 20
The rapid offset of effects may cause abusers of the gas to explore methods of continuous inhalation of higher concentrations
to enhance and prolong the effects, such as rebreathing in an enclosed container, such as a bag over the head, or opening cylinders in a small enclosed space, such as a car. This increases the
ratio of N2O to oxygen. Once there is significantly less than 20%
oxygen in the inhaled gas, there is potential for irreversible hypoxic brain damage or death by asphyxiation.1 8 Simulations have
confirmed the dangerous hypoxic environment that can be created inadvertently. When a standard 8 g nitrous oxide canister
is punctured in an enclosed bag, such as that which has been
found tied over the head of a fatality from nitrous oxide abuse,
the percentage of nitrous oxide rapidly increases to 59%, while
the oxygen concentrations decrease to 13% in 10 s, and only
10% within a minute.8 Adding the effects of respiration within
this enclosed environment would reduce the available oxygen
even further as oxygen is used. At 50% inspired nitrous oxide,
the normal response to hypoxia is blunted, making death from
asphyxia even more likely.8
Problems from unregulated manufacture and storage
Industrial manufacture of nitrous oxide involves heating ammonium nitrate to 250°C and then removing impurities, such as NH3,
N2, NO, NO2, and HNO3, by passage through a series of washers
and scrubbers.11 12 Unregulated manufacturing of the gas for recreational abuse is likely to have less stringent quality-control
| 323
processes, and resultant inhaled impurities can cause harm.21
Deaths have been reported after contamination of nitrous oxide
balloons with butane,7 and older anaesthetists will have learnt
about patient fatalities in the UK in 1966 reported in a special
BJA editorial.22
Improper storage of the gas also creates the potential for
harm. Nitrous oxide for medical use is stored in cylinders below
its critical temperature, so it exists as a vapour above a volume of
nitrous oxide in its liquid phase.12 These cylinders are intentionally under-filled to accommodate increases in pressure as the vapour phase expands. Overfilling of the cylinders and storage
above the critical temperature carries an explosion risk.11
Regulation of nitrous oxide
Nitrous oxide is not a controlled drug and therefore not subject to
the Misuse of Drugs Act 1971.2 The large cylinders of nitrous
oxide seen in hospitals are classed as medicinal products, and
supplying or administering these without MHRA (Medicines
and Healthcare products Regulatory Agency) authorization is a
criminal offence under the Human Medicines Regulations 2012.
However, the small canisters designed for the catering industry
are not classed as medicinal products and therefore not subject
to this Act.2
Until very recently, it was not illegal to sell or possess nitrous
oxide, given its legitimate uses. Possession of nitrous oxide with
the intent to inhale is a misdemeanour in most states in the
USA,1 and in the UK the Intoxicating Substances (Supply) Act
1985 prohibits the sale, to those under the age of 18 yr, of substances which the seller has reason to believe may be inhaled
for the purposes of intoxication.23 Similar to glue, petrol, knives,
and other legal substances that may cause harm through misuse,
regulation of sale of this gas to adults is fraught with difficulty. In
recognition of the resurgence of the recreational use of nitrous
oxide and the difficulties in restricting its availability, the Advisory Council on the Misuse of Drugs recently issued public health
safety advice and recommendations to the Government, local
councils, and the Department of Health to increase awareness
of this issue.24 In response to this, in May this year, the Home Office released new legislation, the Psychoactive Substances Bill
2015,25 which makes it an offence to ‘produce or supply any substance intended for human consumption that is capable of producing a psychoactive effect.’ Although medicinal nitrous oxide
is exempt from this legislation, it does give the police and local
authorities new powers to enforce civil sanctions against the
supply of nitrous oxide for recreational use. It remains to be
seen how effective such legislation will be, with the danger that
resulting covert manufacture may lead to unforeseen consequences, such as increased concentrations of dangerous impurities in supplied nitrous oxide gas, while restrictions on supply of
canisters and balloons may shift recreational abuse toward the
more hazardous larger cylinders and airtight bags.10
Relevance to anaesthetists and other medical
professionals
Perceptions of relative safety of usage coupled with cheapness
and ease of procurement of this gas make it an increasing public
health issue.
Patients who suffer complications of acute nitrous oxide
abuse (e.g. hypoxia, aspiration, cardiac arrthythmias, seizures,
trauma, pneumomediastinum) may present to the emergency
department, and recreational abuse should be considered as a
differential diagnosis in these patients.
324
| Editorials
Chronic nitrous oxide abuse should be considered in the differential diagnosis of patients presenting with atypical neurological symptoms and signs, particularly where these resemble
subacute degeneration of the cord.15
With increasing popularity of this recreational drug, particularly among young adults, consideration should be given to counselling pregnant women against the teratogenic risks of chronic
nitrous oxide use, alongside advice about other drugs, tobacco,
and alcohol.
Increasing usage and documented complications of this gas
may give insight into further potential hazards of medical use
and exposure in health-care workers.
In conclusion, in most people, inhalation of nitrous oxide gas
from balloons produces little or no adverse effect. However, intense or chronic abuse can cause permanent neurological damage, while rebreathing in an enclosed space can cause hypoxia
and asphyxial death. Fatalities can also occur through contaminated supplies, or through trauma or aspiration, particularly
when co-ingested with other drugs or alcohol. There should be
increasing awareness among the clinical staff of the various presentations and dangers of this increasingly popular drug of
abuse.
8.
9.
10.
11.
12.
13.
14.
Authors’ contributions
15.
Co-wrote the manuscript: G.R., A.B.
Declaration of interest
A.B. is on the editorial board of British Journal of Anaesthesia and
Journal of the Intensive Care Society.
16.
17.
References
1. Nitrous oxide frequently asked questions. Available from
http://www.justsayn2o.com (accessed 16 May 2015)
2. Home Office. Guidance on restricting the supply of nitrous
oxide for recreational use. Available from https://www.gov.
uk/government/uploads/system/uploads/attachment_data/
file/368576/RestrictingSupplyNitrousOxide.pdf (accessed 16
May 2015)
3. Zuck D, Ellis P, Dronsfield A. Nitrous oxide: are you having a
laugh? Education in Chemistry. March 2012, 26–9. Available
from www.rsc.org/eic (accessed 16 May 2015)
4. Wolfson S. The Guardian 13 August 2015. Is the growth in
nitrous oxide misuse a laughing matter? Available from
http://www.theguardian.com/society/2014/aug/13/brick-laneis-the-uks-laughing-gas-megastore-but-for-how-long (accessed
16 May 2015)
5. Henderson KA, Raj N, Hall JE. The use of nitrous oxide in anaesthetic practice: a questionnaire survey. Anaesthesia 2002;
57: 1155–8
6. Mitra JK, Jain V, Sharma D, Prabhakar H, Dash HH. A survey on
use of nitrous oxide in current anaesthetic practice in India.
Indian J Anaesth 2007; 51: 405–8
7. Barrett D. The Telegraph 25 July 2013. Laughing gas is party
drug of choice for young people. Available from http://www.
18.
19.
20.
21.
22.
23.
24.
25.
telegraph.co.uk/news/uknews/crime/10202484/Laughing-gasis-party-drug-of-choice-for-young-people.html (accessed 16
May 2015)
Wagner SA, Clark MA, Wesche DL, Doedens DJ, Lloyd AW.
Asphyxial deaths from the recreational use of nitrous oxide.
J Forensic Sci 1992; 37: 1008–15
Davy H. The Collected Works of Sir Humphry Davy: Researches,
Chemical and Philosophical, Chiefly Concerning Nitrous Oxide, or
Dephlogisticated Nitrous air, and its Respiration. London: Smith,
Elder and Company, 1839; 516–7
Jay M. Nitrous oxide: recreational use, regulation and harm
reduction. Drugs and Alcohol Today 2008; 8: 22–5
Peck TE, Hill SA, Williams M. General Anaesthetic Agents. In:
Peck TE, Hill SA, eds. Pharmacology for Anaesthesia and Intensive
Care, 3rd Edn. New York: Cambridge University Press, 2008;
117–21
Banks A, Hardman J. Nitrous oxide. Cont Educ Anaesth Crit Care
Pain 2005; 5: 145–8
Poswillo D. General anaesthesia, sedation and resuscitation
in dentistry. Report of an Expert Working Party prepared for
the Standing Dental Advisory Committee. (The Poswillo Report), Department of Health, 1990
Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 1978; 2: 1227–30
Lin RJ, Chan HF, Chang YC, Su JJ. Subacute combined degeneration caused by nitrous oxide intoxication: case reports.
Acta Neurologica Taiwan 2011; 20: 129–37
Alt RS, Morrissey RP, Gang MA, Hoffman RS, Schaumburg HH.
Severe myeloneuropathy from acute high-dose nitrous oxide
(N2O) abuse. J Emerg Med 2011; 41: 378–80
Chiang TT, Hung CT, Wang WM, Lee JT, Yang FC. Recreational
nitrous oxide abuse-induced vitamin B12 deficiency in a patient presenting with hyperpigmentation of the skin. Case Rep
Dermatol 2013; 5: 186–91
Lipuma JP, Wellman J, Stern HP. Nitrous oxide abuse: a new
cause of pneumomediastinum. Radiology 1982; 145: 602
Davis PD, Kenny GNC. Basic Physics and Measurement in
Anaesthesia, 5th Edn. Edinburgh: Butterworth Heinemann,
2003; 41–2
Hwang JC, Himel HN, Edlich RF. Frostbite of the face after
recreational misuse of nitrous oxide. Burns 1996; 22: 152–3
Clutton-Brock J. Two cases of poisoning by contamination of
nitrous oxide with a higher oxide of nitrogen. Br J Anaesth
1967; 39: 338–92
Editorial: Higher oxides of nitrogen as an impurity in nitrous
oxide. Br J Anaesth 1967; 39: 343–4
The National Archives. Intoxicating substances (supply) Act
1985. Available from http://www.legislation.gov.uk/ukpga/
1985/26/contents (accessed 16 May 2015)
Advisory Council on the Misuse of Drugs. Letter to Home
Secretary and Secretary of State for Health. Available from
https://www.gov.uk/government/uploads/system/uploads/
attachment_data/file/409403/acmd-advice-on-nitrous-oxide.
doc (accessed 16 May 2015)
Home Office. Psychoactive Substances Bill 2015. Available
from https://www.gov.uk/government/collections/psychoactivesubstances-bill-2015 (accessed 23 June 2015)