Nitrous oxide toxicity title image showing whippet canisters and a red balloon on a hospital stretcher

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💨 What Is Nitrous Oxide?

Nitrous Oxide (N2O) is a colorless, odorless inhaled anesthetic that has been used for centuries, particularly in the surgical world. Mechanistically, it can induce euphoria, anxiolysis, and intoxication via NMDA receptor antagonism.

During the late twentieth century, nitrous oxide was increasingly used recreationally due its accessibility and perceived benign nature.

The modern day slang term for nitrous oxide is “whippets” – which tends to refer to the canisters that contain this agent and are frequently used as whipped cream foaming agents.

Despite the legal nature and benign perception of nitrous, frequent use can lead to lasting and permanent neurologic effects.

🧠 How Nitrous Oxide Causes Toxicity

Nitrous oxide toxicity results from its ability to oxidize the cobalt moiety in Vitamin-B12, thus leading to a functional B12 deficiency, despite adequate consumption and absorption.1

Functioning B12 is needed as a cofactor for methionine synthase.2 This enzyme has two critical roles:

The conversion of 5-methyl tetrahydrofolate to tetrahydrofolate; tetrahydrofolate is essential for the synthesis of our DNA.

And the conversion of homocysteine to methionine; methionine is needed to maintain the integrity of the myelin sheath of our axons.

As a result, nitrous toxicity leads to: a megaloblastic anemia and demyelination of both the dorsal columns and the lateral corticospinal tracts (also known as subacute combined degeneration).

🚶‍️ Clinical Manifestations of Nitrous Oxide Toxicity

These patients will have a combination of both upper and lower motor neuron symptoms due to demyelination of the dorsal columns, lateral corticospinal tracts, and peripheral nerves. As a result, the following may manifest:

Dorsal Columns: diminished sense of proprioception, vibration, and fine touch.

Lateral Corticospinal Tracts: upgoing plantars, hyperreflexia, weakness of voluntary distal muscle control

Peripheral Nerves: numbness/tingling and weakness in a glove and stocking pattern (symptoms that start initially in the feet and hands that progressively spread proximally to the ankles and wrists)

Taking all of this into account, patients may present with difficulty ambulating, positive Romberg sign, dysmetria (difficulty with finger to nose or heel to shin), upgoing Babinski reflex, and decreased strength and sensation in a glove and stocking pattern.

🔍 How to Diagnose Nitrous Oxide Neurotoxicity

History is key! As with a lot of pathologies in toxicology, identifying the exposure will expedite management.

A thorough neurologic exam will narrow the differential – with a particular focus to fine, peripheral motor and sensory deficits, dysmetria, proprioception, and ability to ambulate.

Magnetic resonance imaging of the spine may identify enhancement and/or edema of the dorsal columns, specifically on T2 weight axial imaging – sometimes referred to as the “inverted V” or “inverted rabbit ears appearance.”3

Serum B12 concentrations may be normal as the issue is with a functional deficiency as opposed to a vitamin absence. However, patients have elevated concentrations of both homocysteine and methylmalonic acid, both of which are metabolized in the presence of functional B12.

💉 Management of Nitrous Oxide Toxicity

First and foremost, cessation of nitrous oxide abuse is crucial to limit/prevent toxicity.

While there is no universally agreed upon treatment regimen, supplementation with intramuscular B12 is recommended.

Approaches vary from daily or every other day injections until symptoms improve at which point injections can be spaced out to weekly and then monthly.

Physical and occupational therapy may be needed depending on the degree of functional debility.

It is important to note, that depending of the severity and chronicity of toxicity, some proportion of patients may not fully return to their baseline.

📌 Take-Home Points

Though legal and seemingly benign, nitrous oxide abuse can lead to permanent neurologic dysfunction.
Nitrous oxide toxicity can affect the dorsal columns, lateral corticospinal tracts, and peripheral nerves.
Thus leading to a constellation of both upper and lower motor neuron deficits, particular in a glove and stocking pattern: deficits in proprioception and fine motor skills, positive Romberg, upgoing Babinski, peripheral numbness, tingling, and weakness.
Magnetic resonance imaging may identify symmetric high signal intensity in the dorsal columns.
Treatment includes B12 supplementation and physical/occupational therapy as needed.

📚 References

Long H. Chapter 81. Inhalants. In: Nelson LS, et al. Goldfrank’s Toxicologic Emergencies. 11^th ed. New York: McGraw-Hill; 2019
Shah K, Murphy C. Nitrous Oxide Toxicity: Case Files of the Carolinas Medical Center Medical Toxicology Fellowship. J Med Toxicol. 2019 Oct;15(4):299-303. doi: 10.1007/s13181-019-00726-x. Epub 2019 Aug 6. PMID: 31388940; PMCID: PMC6825085.
Schmitz ZP, Hoffman RS. Magnetic resonance imaging in a patient with nitrous oxide-induced subacute combined degeneration of the spinal cord. Clin Toxicol (Phila). 2023 Nov;61(11):1006-1008. doi: 10.1080/15563650.2023.2286205. Epub 2023 Dec 19. PMID: 38060330.

Post Peer Reviewed By: Marco Propersi, DO (Twitter/X: @Marco_propersi), and Mark Ramzy, DO (X: @MRamzyDO)

REBEL Core Cast—Nitrous Oxide Toxicity: Whippets and Neurologic Injury

REBEL Cast

REBEL Core Cast—Nitrous Oxide Toxicity: Whippets and Neurologic Injury