Dose--Response Relationships Between Nitrous Oxide Exposure, Biomarkers, and Neurological Injury
Laxna Bhujel, Angela L. Chiew, Bhashita Jagarlamudi, Pramod Chandru, Naren Gunja, Nancy Briggs, Betty S. Chan
Study at a glance
AI-extracted from the abstract| Characteristics | Retrospective cohort study |
|---|---|
| Sample size | 81 |
| Population | Hospitalised individuals with nitrous oxide toxicity across six Sydney hospitals |
| Key findings | Higher cumulative nitrous oxide exposure was associated with worse neurological impairment, including subacute combined degeneration of the spinal cord (p=0.006) and peripheral neuropathy (p=0.036), with moderate correlation to neuropathy severity (Spearman's rho=0.43). Homocysteine and methylmalonic acid were more sensitive but less specific for diagnosing SCD, while B12 and holotranscobalamin were highly specific but poorly sensitive. |
Abstract
Aims: Recreational nitrous oxide (N 2 O) misuse is a growing problem. It can cause functional hydroxycobalamin (B 12 ) deficiency and severe neurological complications. Despite increasing harms, the dose-response relationship and clinical value of biomarkers remain unclear. This study aimed to characterise the demographics, patterns of use, outcomes, and biomarker utility in patients hospitalised with N 2 O toxicity, and to examine whether a dose-response relationship exists between exposure and toxicity.
Methods: This was a retrospective cohort study of hospitalised individuals with N 2 O toxicity between 1 January 2020 and 31 July 2025 across six Sydney hospitals. Weekly and cumulative N 2 O exposure volumes were estimated. Exposure volumes were compared with clinical outcomes and biomarker results to assess correlations and biomarker utility.
Results: Eighty-one individuals across 100 presentations were included. Higher cumulative volumes of N 2 O exposure were associated with worse neurological impairment, including subacute combined degeneration of the spinal cord (SCD)( p =0.006) and peripheral neuropathy (PN)( p =0.036), and showed moderate correlation with greater neuropathy severity (Spearman’s ⍴=0.43, p =0.001). Median homocysteine was 50 μmol/L(IQR: 32-114; normal 5-15) with a median half-life of 14.59 hours. Median methylmalonic acid was 0.68 μmol/L (IQR: 0.18-3.16; normal <0.27). Regarding diagnosis of SCD, B 12 and holotranscobalamin had high specificity (87% and 98%) but low sensitivity (22% and 5%); while homocysteine and methylmalonic acid were more sensitive (95% and 93%) but less specific (13% and 45%).
Conclusions: Cumulative N 2 O exposure is the strongest predictor of severe neurological outcomes in a dose-dependent manner. Homocysteine and methylmalonic acid are good screening tests for neurotoxicity but poor confirmatory tests.