Abstract
The risk of adverse effects of nitrous oxide (N2O) exposure is insufficiently recognized despite its widespread use. These effects are mainly reported through case reports. We conducted an individual patient data meta-analysis to assess the prevalence of clinical, laboratory, and magnetic resonance findings in association with N2O exposure in medical and recreational settings. We calculated the pooled estimates for the studied outcomes and assessed the potential bias related to population stratification using principal component analysis. Eighty-five publications met the inclusion criteria and reported on 100 patients with a median age of 27 years and 57% of recreational users. The most frequent outcomes were subacute combined degeneration (28%), myelopathy (26%), and generalized demyelinating polyneuropathy (23%). A T2 signal hyperintensity in the spinal cord was reported in 68% (57.2–78.8%) of patients. The most frequent clinical manifestations included paresthesia (80%; 72.0–88.0%), unsteady gait (58%; 48.2–67.8%), and weakness (43%; 33.1–52.9%). At least one hematological abnormality was retrieved in 71.7% (59.9–83.4%) of patients. Most patients had vitamin B12 deficiency: vitamin B12 <150 pmol/L (70.7%; 60.7–80.8%), homocysteine >15 µmol/L (90.3%; 79.3–100%), and methylmalonic acid >0.4 µmol/L (93.8%; 80.4–100%). Consistently, 85% of patients exhibited a possibly or probably deficient vitamin B12 status according to the cB12 scoring system. N2O can produce severe outcomes, with neurological or hematological disorders in almost all published cases. More than half of them are reported in the setting of recreational use. The N2O-related burden is dominated by vitamin B12 deficiency. This highlights the need to evaluate whether correcting B12 deficiency would prevent N2O-related toxicity, particularly in countries with a high prevalence of B12 deficiency.
Highlights
Nitrous oxide (N2O) is a colorless, sweet-smelling gas that has been widely used in dental, emergency, and anesthetic practices
The present meta-analysis highlights the potential side-effects related to N2O use with a unfavorable risk-benefit ratio for recreational users who represent more than half of the reported subjects
Vitamin B12 is physiologically active in two forms: 1) methylcobalamin which represents a cofactor for the methyltransferase enzyme 5-methyltetrahydrofolate-homocysteine methyltransferase, known as methionine synthase (MTR), and 2) adenosylcobalamin which serves as a cofactor for the enzyme methylmalonyl coenzyme A mutase (MMCoAM) [13,14,15,16,17,18,19,20,21,22,23]
Summary
Nitrous oxide (N2O) is a colorless, sweet-smelling gas that has been widely used in dental, emergency, and anesthetic practices. The first use of N2O as an anesthetic agent was reported on December 1844 by Dr Horace Wells, an American dentist who demonstrated insensitivity to pain from a dental extraction after N2O inhalation [1]. In one patient from this series, the bone-marrow biopsy on the fifth day of N2O anesthesia revealed “strikingly megaloblastic” erythropoiesis and changes in granulocytopoiesis that were typical of “pernicious anemia” [5]. Since this first description of a potential link between N2O exposure and myelosuppression, the hypothesis of a disorder related to vitamin B12 metabolism was suggested [6]. We conducted individual patient data meta-analysis to assess the prevalence of clinical, laboratory, and magnetic resonance findings in association with N2O exposure in medical and recreational settings
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