Toxicology, Recreational Drugs

N2O Toxicity: A Rising Concern as Street Use Surges

Nitrous oxide (N2O) toxicity is an uncommonly encountered patient complaint in the emergency department; however, it is a diagnosis the emergency physician should remember, as it could be responsible for unexplained neurological symptoms. N2O was first developed in 1775 by Joseph Priestley after combining nitric acid with iron shavings. Its potential medical use was later noted by Sir Humphrey Davy who, after inhaling the gas, noted the qualities of euphoria and anesthesia and suggested its use for surgery. Similar to today, the potential for abuse was quickly recognized, and soon the British elite were holding “laughing parties” where they inhaled the gas for entertainment.1 Since its discovery N2O has been used in various ways, including general anesthesia, pain control, food preservation, air compressors, additive to fuel to enhance combustion, and for the treatment of withdrawal of nicotine, opioids, and cocaine.2 In the 1980s, N2O became a popular street drug and is commonly known today as laughing gas, hippy crack, and whippets.

Uses/Abuse
One reason N2O is so commonly abused is the ease with which it can be obtained. It is sold as whippets, which are small containers of N2O intended to be used for refillable whipped cream containers or to inflate balloons. Recreational use of N2O varies across the world, with the United Kingdom logging the highest prevalence of use. Within the U.S. the lifetime use prevalence is approximately 29%.

A single bulb is approximately equal to a single hit. After inhalation, symptoms of euphoria and sometimes visual hallucinations ensue within seconds and then dissipate after several minutes.2 Adverse events are related to the number of hits per session and concomitant use of another drug or alcohol. Typical adverse events include fainting, nausea, and accidental injury. At higher doses (about 27 hits/session), accidental injury has been shown to be common, whereas at lower doses (14 hits/ session), nausea was the prevailing symptom.1 The typical individual will do fewer than 5 hits in a single session. Patients presenting with neurologic complications typically do 10-100 hits in a session over a long-term course.1,3

Mechanism of Toxicity
There are several different biochemical pathways that contribute to the toxicity of N2O. B12 is an essential vitamin that is needed for brain and nervous system. Nitrous oxide oxidizes the cobalt moiety on B12 and renders it inactive. The downstream effect of this is that methionine synthase — which requires active B12 to function — is irreversibly blocked. This leads to depletion of methionine and tetrahydrofolate, which are required for DNA synthesis and myelin production. In turn, this depletion results in a clinical picture that resembles the characteristic findings of pernicious anemia (bone marrow depression and polyneuropathy).4-6 This demyelination can be seen on MRI and is diagnosed as Subacute Combined Degeneration (SDG).7

Symptoms: Hematological and Neurological
Side effects of long-term nitrous oxide use vary. The most common side effects that may be encountered in the ED are peripheral neurologic disorders. As discussed earlier, N2O has a large impact on myelin resulting in a sensorimotor polyneuropathy, often with combined signs of lateral and posterior cord involvement. Patients present with numbness, tingling, weakness, and truncal ataxia. These clinical symptoms are indistinguishable from SDG seen with B12 deficiency. Bone marrow suppression with a macrocytic anemia can be seen on lab testing.

Other less common manifestations of toxicity include frostbite of the mouth (secondary to breathing it directly from pressurized tanks), urinary retention, painful erection, decreased libido, delusions, paranoia, anxiety, and even death.2,4 Asphyxiation is seen in patients who inhale in closed spaces such as cars, face masks, or bags over the head resulting in a low partial pressure of oxygen.2 Testing and Diagnostics There are no ideal lab tests to evaluate for nitrous oxide toxicity in the ED because B12 levels may be low, normal, or even high, especially if patients are taking B12 supplements at home. Typically, methylmalonic acid (MMA) and homocysteine levels will be elevated; however, these tests are not routinely performed in the ED.8 In patients with more severe symptoms (incontinence, paresthesias, and motor deficits) an MRI may be obtained. The distribution of the demyelination may not always correspond to the symptoms being demonstrated.7

Treatment
Treatment is aimed primarily at stopping the exposure after other potential etiologies have been ruled out, such as syphilis, HIV, mercury toxicity, copper deficiency, cord compression, and electrolyte deficiency. Afterward, B12 can be administered as IM shots. There is no standardized B12 regimen, but a commonly accepted plan is 1000µg IM for 5 days and then intermittently until symptoms resolve. An alternative plan is 1000µg-2000µg PO daily for 1-2 weeks and then 1000µg daily.7

When the presenting symptoms are minor, such as decreased vibration sense or decreased peripheral sensation, it may be acceptable to discharge these patients with a prescription for PO B12 and close outpatient neurology follow-up. In patients exhibiting more severe symptoms, such as ataxia and motor deficits, admission for imaging and further evaluation may be warranted. Even with B12 replacement and cessation of use, patients may never return to their baseline and may have permanent neurologic symptoms.8

Patients can be given basic information on safe practices of recreational N2O. These basic practices include avoiding use with other drugs or alcohol, using while seated to prevent falls, following up early with a doctor if peripheral neurological symptoms occur, using in ventilated spaces, and avoiding placing bags of N2O over the head do not put bags of N2O over the head.1

Conclusion
As EM providers we must remember to consider N2O toxicity as a potential etiology of vague neurological complaints, especially paresthesias. Cessation of use and administration of B12 are the mainstays of treatment; however, symptoms do not always resolve completely, and some effects can be permanent. All but the mildest of symptomatic patients should be admitted to receive B12 and neurology consultation.

References

1. Kaar SJ, Ferris J, Waldron J, Devaney M, Ramsey J, Winstock AR. Up: The Rise of Nitrous Oxide abuse. An International Survey of Contemporary Nitrous Oxide Use. J Psychopharmacol. 2016;30(4):395-401.
2. van Amsterdam J, Nabben T, van den Brink W. Recreational Nitrous Oxide Use: Prevalence and Risks. Reg Toxicol Pharmacol. 2015;73(3):790-796.
3. Cheng HM, Park JH, Hernstadt D. Subacute Combined Degeneration of the Spinal Cord Following Recreational Nitrous Oxide Use. BMJ Case Rep. 2013;1-3.
4. Garakani A, Jaffe RJ, Savla D, Welch AK, Protin CA, Bryson EO, McDowell DM. Neurologic, Psychiatric and Other Medical Manifestations of Nitrous Oxide Abuse: A Systematic Review of the Case Literature. Am J Addict. 2016;25(5):358-369.
5. Miller MA, Martinez V, McCarthy R, Patel MM. Nitrous Oxide Whippit Abuse Presenting as Clinical B12 Deficiency and Ataxia. Am J Emerg Med. 2004;22(2):124.
6. Sethi NK, Mullin P, Torgovnick J, Capasso G. 2006. Nitrous Oxide Whippit Abuse Presenting with Cobalamin Responsive Psychosis. J Med Toxicol. 2006;2(2):71-74.
7. Pugliese RS, Slagle EJ, Oettinger GR, Neuburger KJ, Ambrose TM. Subacute Combined Degeneration of the Spinal Cord in a Patient Abusing Nitrous Oxide and Self-Medicating with Cyanocobalamin. Am J Health Syst Pharm. 2015;72(11):952-957.
8. Shoults K. 2016. Case Report: Neurological Complications of Nitrous Oxide Abuse. BCMJ. 2016;58(4):192-194. 

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