Nitrous oxide toxicity
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At the time the article was created Devanshi Dharaiya had no recorded disclosures.View Devanshi Dharaiya's current disclosures
At the time the article was last revised Frank Gaillard had the following disclosures:
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Nitrous oxide (N2O) toxicity has serious medical sequelae affecting both the CNS and the bone marrow. Neurological effects include encephalopathy, myelopathy, and neuropathy. This results from demyelination and gliosis due to selective inhibition of vitamin B12 1. Bone marrow toxicity may lead to myelosuppression, including neutropenia and megaloblastic anemia.
N2O is an established and widely used anesthetic gas though also misused quite commonly for recreational purposes as a legal 'high'. Canisters of nitrous oxide, colloquially known as “whippets”, "nangs", or "bulbs" 5, are used commercially as a propellant for whipped cream, and are commonly abused 6.
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As an end-user, nitrous oxide gas is a close-to-ideal recreational agent, it is legal, inexpensive, easily accessible, and not found on standard illicit substance screens. Physiologically, its effects manifest within seconds of inspiring the gas, and its offset is just as rapid, with no after effects, such that users may continue with their regular activities only minutes post-exposure.
In the 2013/14 Crime Survey for England and Wales, it was reported that almost 8% of 16 to 24-year-olds had used nitrous oxide recreationally in the previous 12 months 8.
Pre-existing vitamin B12 deficiency increases the risk of nitrous oxide-induced toxicity 8.
The classic neurological appearance of vitamin B12 deficiency is the so-called subacute combined degeneration of the cord manifested as damage to the dorsal columns of the spinal cord, responsible for the transmission of vibratory and proprioceptive input. Peripheral neuropathy, optic atrophy, and dementia can also occur.
Neurotoxicity is secondary to the selective inhibition of vitamin B12 (hydroxocobalamin), which serves as a cofactor for methionine synthase, which is an enzyme active in folate metabolism and the formation of myelin sheath phospholipids 2,4.
The end result of overexposure is demyelination and eventual gliosis, both within the central nervous system and to a lesser extent the peripheral nervous system.
Radiographic features are identical to those of subacute combined degeneration of the cord.
- T2: thoracic hyperintense signal involving the dorsal columns (inverted "V" sign), although less commonly lateral tracts of the spinal cord may also be affected; very rarely is there involvement of the anterior spinal cord
Treatment and prognosis
Treatment options include:
- halting exposure to nitrous oxide
- high dose of intramuscular vitamin B12, followed by oral supplementation
- methionine supplementation has also been used 2
Despite optimal treatment, some patients are left with a permanent deficit, including lifelong paraparesis.
Although there is no risk of physical addiction, the risk of a psychological N2O habit is a clear and present danger 8.
History and etymology
Nitrous oxide gas was first synthesized in 1772 by an English theologian and chemist, Joseph Priestly, chiefly remembered historically for his discovery of oxygen. Within only a few years it was already being abused as a recreational 'high', aware of this Humphrey Davy coined the term "laughing gas" 7,8. By 1844, Horace Wells, an American dentist, had reported its usefulness as an anesthetic gas.
On imaging, the differential diagnosis includes:
- other etiologies of subacute combined degeneration of the cord
- copper deficiency myeloneuropathy: can look identical
- vitamin E deficiency: can look identical
- multiple sclerosis: also affects dorsal columns but usually over a shorter length
- transverse myelitis: although longer in length, usually not restricted to dorsal columns
- infectious causes
- HIV vacuolar myelopathy: may appear very similar
- herpes viruses myelitis
- neurosyphilis (tabes dorsalis)
- inflammatory processes
- astrocytoma: not particularly of dorsal columns. usually, more cord expansion; often enhance
- ependymoma: not particularly of dorsal columns. usually, more cord expansion; often enhance
- hereditary syndromes
- leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: characteristically also involves the cerebral white matter and the brainstem
- Friedreich ataxia: also causes cervical cord atrophy ('thinning')
- 1. Shulman R, Geraghty T, Tadros M. A Case of Unusual Substance Abuse Causing Myeloneuropathy. Spinal Cord. 2007;45(4):314-7. doi:10.1038/sj.sc.3101962 - Pubmed
- 2. Stacy C, Di Rocco A, Gould R. Methionine in the Treatment of Nitrous-Oxide-Induced Neuropathy and Myeloneuropathy. J Neurol. 1992;239(7):401-3. doi:10.1007/BF00812159 - Pubmed
- 3. Healton E, Savage D, Brust J, Garrett T, Lindenbaum J. Neurologic Aspects of Cobalamin Deficiency. Medicine (Baltimore). 1991;70(4):229-45. doi:10.1097/00005792-199107000-00001 - Pubmed
- 4. Weimann J. Toxicity of Nitrous Oxide. Best Pract Res Clin Anaesthesiol. 2003;17(1):47-61. doi:10.1053/bean.2002.0264 - Pubmed
- 5. Evans E & Evans M. Nangs, Balloons and Crackers: Recreational Nitrous Oxide Neurotoxicity. Aust J Gen Pract. 2021;50(11):834-8. doi:10.31128/AJGP-10-20-5668 - Pubmed
- 6. Thompson A, Leite M, Lunn M, Bennett D. Whippits, Nitrous Oxide and the Dangers of Legal Highs. Pract Neurol. 2015;15(3):207-9. doi:10.1136/practneurol-2014-001071 - Pubmed
- 7. Oussalah A, Julien M, Levy J et al. Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis. J Clin Med. 2019;8(4):551. doi:10.3390/jcm8040551 - Pubmed
- 8. Randhawa G & Bodenham A. The Increasing Recreational Use of Nitrous Oxide: History Revisited. Br J Anaesth. 2016;116(3):321-4. doi:10.1093/bja/aev297 - Pubmed