Biomarkers for the diagnosis and monitoring of nitrous oxide intoxication: objectives and methodology of the SFBC Working Group.

The recreational use of nitrous oxide (N2O) is an emerging public health issue. Chronic N2O abuse may result in various clinical symptoms, encompassing neurological, psychiatric and cardiovascular outcomes. Despite the difficulties for the laboratory investigation of N2O intoxication, there is currently no guidelines in France to help both clinicians and biologists use appropriate biomarkers for the diagnosis and monitoring of patients with clinical symptoms potentially related to N2O intoxication. A multi-disciplinary Working Group, carried out under the auspices of the French Society of Clinical Biology (SFBC) and in collaboration with the French Societies of Emergency Medicine (SFMU), Analytical Toxicology (SFTA), Hemostasis and Thrombosis (SFTH), Vitamins and Biofactors (SFVB), and the French Federation of Neurology (FFN), was recently implemented to elaborate practical guidelines. The methodology of the Working Group is based on the critical analysis of the literature, and raising concerns and objectives are grouped into five working packages. The present manuscript primarily aims to expound upon the methodology and objectives of the ongoing SFBC Working Group on N2O.

Toxic neuropathies.

PURPOSE OF REVIEW: Immunotherapy has had a significant impact on the treatment of an increasing number of cancers as well as in inflammatory, rheumatological and gastroenterological conditions.Recreational nitrous oxide use is now a global epidemic. Linezolid is now recommended for the treatment of drug-resistant tuberculosis (TB); neuropathy is a significant cause of morbidity.Global warming will result in increasing toxin exposure, such as ciguatera, in previously unaffected areas. RECENT FINDINGS: With increasing experience, the pathophysiology underlying the neuropathic complications of these drugs has become clear with guidelines now available, for the complications of immune check-point inhibitors and nitrous oxide toxicity. The optimum dose and duration of treatment for resistant TB with regimens, including linezolid, has been ascertained. SUMMARY: Although neuropathic complications with immunotherapy are relatively rare, it is essential that they are recognized and treated early. Nitrous oxide toxicity should be in the differential diagnosis for all patients, particularly those of younger age, presenting with a neuropathy or myleo-neuropathy. Ciguatera toxicity is under recognized and its geographical spread will increase due to global warming. Further research is necessary on the mechanisms and treatment of both acute and chronic effects, which at present, are only symptomatic.

Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review.

The recreational use of nitrous oxide (N2O) has increased over the years. At the same time, more N2O intoxications are presented to hospitals. The incidental use of N2O is relatively harmless, but heavy, frequent and chronic use comes with considerable health risks. Most importantly, N2O can inactivate the co-factor cobalamin, which, in turn, leads to paresthesia's, partial paralysis and generalized demyelinating polyneuropathy. In some patients, these disorders are irreversible. Several metabolic cascades have been identified by which N2O can cause harmful effects. Because these effects mostly occur after prolonged use, it raises the question of whether N2O has addictive properties, explaining its prolonged and frequent use at high dose. Several lines of evidence for N2O's dependence liability can be found in the literature, but the underlying mechanism of action remains controversial. N2O interacts with the opioid system, but N2O also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, by which it can cause dopamine disinhibition. In this narrative review, we provide a detailed description of animal and human evidence for N2O-induced abuse/dependence and for N2O-induced neurotoxicity.

[Acute and chronic toxicities associated with the use and misuse of nitrous oxide: An update]. / Toxicités aiguës et chroniques associées à l'usage et au mésusage du protoxyde d'azote : mise au point.

Nitrous oxide (N2O) is used since the eighteenth century as an anesthetic and analgesic but also for recreational use. If the labelled uses of N2O and their modalities are nowadays perfectly framed, the misuse of N2O takes very alarming proportions among teenagers and young adults. This misuse is the cause of acute (hypoxia, barotrauma, burns, neuropsychiatric disorders) and chronic complications if repeated (myeloneuropathy, anemia, thrombosis, inhalant use disorder). The main mechanism of the latter is mainly related to a functional deficit in vitamin B12 induced by N2O. The management of acute complications is symptomatic. The management of chronic complications is based on vitamin B12 supplementation. The best biomarker of chronic N2O exposure is the elevation of the plasmatic level of methylmalonic acid. In all cases of recreational misuses, addiction treatment is necessary to prevent complications or their worsening by providing information in order to stop consumption.

Nangs, balloons and crackers: Recreational nitrous oxide neurotoxicity.

BACKGROUND: Nitrous oxide is a colourless, odourless gas that has been used in medicine for more than 150 years for its anaesthetic and analgesic properties. Its first recorded use as a recreational drug was in early 19th century Britain at 'laughing gas parties', where it was used to provide short-lived euphoria to the bored upper class. A recent resurgence of its abuse among Australian youth has led to marked neurological morbidity. OBJECTIVE: The aim of this article is to provide an overview of the clinical presentation, differential diagnosis, investigation and treatment of patients presenting with neurotoxicity due to recreational nitrous oxide abuse. DISCUSSION: Nitrous oxide exerts its neurotoxicity through vitamin B12 inactivation, which disrupts myelin sheath maintenance, leading to peripheral and central nervous system demyelination. Importantly, patients often present with non-specific sensorimotor signs and symptoms with normal serum vitamin B12 levels. Early recognition and treatment are crucial to limit long-term neurological sequelae.

Nitrous Oxide-Induced Neuropathy among Recreational Users in Vietnam.

Nitrous oxide (N2O) commonly referred to as laughing gas, has significant medical uses. This study aims to describe the neurological disorders associated with N2O. We conducted across-sectional study that enrolled patients with nitrous oxide toxicity admitted to Vietnam Poison Control Center, Bach Mai Hospital, Hanoi, Vietnam from June 2018 to July 2019. The questionnaire included demographic characteristics, characteristics of using N2O, signs and clinical symptoms, neuroimaging findings, injury on electromyography (EMG) and the Total Neuropathy Score clinical version (TNSc) criteria. A total of 47 participants were included with mean age: 24.38 ± 6.20 years. The number of balloons used per week was 130.59 ± 117.43. The mean duration of N2O exposure was 8.79 ± 7.1 months. Multivariate linear logistic regression revealed that the number of N2O balloons used per week was significantly associated with TNSc point (Beta: 0.315; 95% CI: 0.001-0.022). We found that myeloneuropathy and peripheral neuropathy were the main neurological disorders related to N2O abuse, which should improve the awareness of the appearance of neurological disorders associated with N2O abuse.

Electrophysiological characteristics of patients with nitrous oxide abuse.

Objective: In the young generations with nitrous oxide abuse (N2O), featured electrophysiological response of the peripheral neuropathy caused by nitrous oxide remains to be defined.Methods: Patients with nitrous oxide abuse (20 cases), two variants of Guillain-Barré syndrome (GBS), that is, acute inflammatory demyelinating polyradiculoneuropathy (GBS-AIDP, 19 cases) and acute motor axonal neuropathy (GBS-AMAN, 18 cases), as well as diabetic peripheral neuropathy (DPN, 20 cases) were enrolled into this study. Electrophysiological parameters including distal motor latency (DML), motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), amplitudes of compound muscle action potential (CMAP), and sensory nerve action potential (SNAP) were measured and analyzed by comparing the parameters between the aforementioned patients groups as well as normal control group (20 subjects).Results: Compared to normal control subjects, patients with nitrous oxide abuse showed prolonged DML, slower MNCV and SNCV in the limbs, lower amplitudes of CMAP in the median, tibial and peroneal nerves, and lower SNAP in median and ulnar nerves. Abnormalities of MNCV and amplitudes of CMAP in the lower limbs were significantly higher than that in the upper limbs . Abnormal electrophysiological features of patients with nitrous oxide abuse were dramatically different from those in GBS-AIDP or DPN patients, but similar to those in GBS-AMAN patients.Conclusions: Nitrous oxide abuse could cause abnormal electrophysiological response in the limbs. Some of the parameters (DML, MNCV, SNCV, CMAP and SNAP) appeared significantly different between the patients with nitrous oxide abuse, GBS with AIDP or AMAN, and DPN patients.Significance: Electrophysiological examination could be considered as an important supporting factor in differential diagnosis for nitrous oxide abuse, GBS with AIDP or AMAN, and DPN.

A health-based recommended occupational exposure limit for nitrous oxide using experimental animal data based on a systematic review and dose-response analysis.

BACKGROUND: Nitrous oxide (N2O) is a common inhalation anaesthetic used in medical, paramedical, and veterinary practice. Since the mid 1950's, concerns have been raised regarding occupational exposure to N2O, leading to many epidemiological and experimental animal studies. Previous evaluations resulted in the classification of N2O as a possible risk factor for adverse reproductive health outcomes based on animal data. Human data were deemed inadequate primarily because of simultaneous co-exposures to other risk factors for adverse reproductive and developmental outcomes, including other anaesthetic gases. Since previous evaluations, controversies regarding N2O use remained and new approaches for dose response modelling have been adopted, calling for an update and re-evaluation of the body of evidence. This review aims to assess available animal evidence on N2O reproductive and developmental outcomes to inform a health-based recommended occupational exposure limit (OEL) for N2O with a benchmark dose-response modelling (BMD) approach. METHODS: Comprehensive searches in PubMed, EMBASE, and Web of Science were performed to retrieve all relevant studies addressing reproductive and developmental outcomes related to inhalation of N2O in animals. The articles retrieved were screened based on title-abstract and full text by two independent reviewers. After data extraction, an overview of all studies was created for the different endpoints, namely foetal outcomes (e.g., resorption), female outcomes (e.g. implantations), and male outcomes (e.g. sperm count). A subset of studies reporting on exposure relevant to workplace settings and with a sufficient number of tested doses were included in dose-response modelling using the BMD approach. RESULTS: In total, 15.816 articles were retrieved, of which 47 articles were finally included while 4 of those were used for the quantitative data synthesis. The overall risk of bias was judged to be probably high (using OHAT risk of bias tool) and unclear (using SYRCLE's risk of bias tool). From eligible rat studies, three studies provided an acceptable result by fitting a Hill model to the dose-response data. The resulting benchmark dose lower bounds (BMDLs) from three studies converged to an average (±sd) exposure level of 925 ± 2 mg/m3 at an additional risk of one standard deviation of implantation losses above those observed in the control group (i.e. reduced number of live foetuses/mother). For extrapolation from rats to humans, an uncertainty factor of 10 was used and an additional factor of 5 was applied to account for interindividual variability within the population of workers. CONCLUSION: With this systematic review, all available evidence for reproductive toxicity and adverse developmental outcomes in animals resulting from inhalation exposure to N2O was used to derive a health-based OEL recommendation of 20 mg/m3 as 8-h time-weighted average.

Recreational Nitrous Oxide Abuse: Prevalence, Neurotoxicity, and Treatment.

Nitrous oxide (N2O), also known as "laughing gas," is a colorless, nonirritating gas. Clinically, it is widely used as an inhaled anesthetic, analgesic, and anxiolytic. In recent years, recreational abuse of N2O has become increasingly common, especially among young adults and adolescents, but many of them lack awareness of the possible side effects associated with this drug. N2O abuse can damage multiple systems, especially the nervous system, but the exact mechanism of N2O toxicity remains controversial. At present, an increasing number of cases of nervous system damage caused by N2O abuse have been reported both at home and abroad. Discontinuation of N2O use and timely supplementation with vitamin B12 are essential for a good prognosis. Long-term abuse without timely treatment will eventually lead to irreversible neurological damage. In this article, we discuss the epidemiology of N2O abuse, neurotoxicity mechanisms, clinical manifestations, relevant auxiliary examinations, treatments, and prognosis to improve social awareness of N2O exposure risk, especially among users and clinicians.

Nitrous oxide-induced neurotoxicity: A case report and literature review.

Nitrous oxide is an increasingly popular recreational drug. However, recurrent or prolonged use can be associated with nitrous oxide toxicity, with numerous reports of harm documented in the literature. Nitrous oxide irreversibly binds and inactivates vitamin B12, which is an important co-factor in metabolic pathways involved in DNA and myelin synthesis. Toxicity is therefore associated with vitamin B12 deficiency-related syndromes, primarily involving haematological and neurological systems. As a "legal high", nitrous oxide use has attracted repeated health warnings from experts. An awareness and understanding of the pathophysiology and management of nitrous oxide toxicity is therefore important for clinicians. We discuss the case of a 29-year-old man presenting with nitrous oxide-induced sensorimotor neuropathy and review the existing literature surrounding toxicity.

Dynamics of soil N2O emissions and functional gene abundance in response to biochar application in the presence of earthworms.

Nitrous oxide (N2O) is a devastating greenhouse gas and acts as an ozone-depleting agent. Earthworms are a potential source of soil N2O emissions. Application of biochar can mitigate earthworm-induced N2O emissions. However, the underlying interactive mechanism between earthworms and biochar in soil N2O emissions is still unclear. A 35-day laboratory experiment was conducted to examine the soil N2O emission dynamics for four different treatments, earthworm presence with biochar application (EC), earthworm presence without biochar application (E), earthworm absence with biochar application (C) and earthworm absence without biochar application, and the control. Results indicated a negative impact of biochar on earthworm activity, displaying a significantly (p ≤ 0.05) lower survival rate and biomass of earthworms in treatment EC than E. Compared with the control, earthworm presence significantly (p ≤ 0.05) increased cumulative N2O emissions, while application of biochar in the presence of earthworms significantly (p ≤ 0.05) decreased cumulative N2O emissions (485 and 690 µg kg-1 for treatments EC and E, respectively). Treatments E and EC significantly (p ≤ 0.05) increased soil microbial biomass carbon (MBC), ammonium (NH4+-N), nitrate (NO3-N), and dissolved organic carbon (DOC) content and soil pH as compared with the control. The gene copy number of 16 S rRNA, AOA, AOB, nirS, and nosZ increased for all treatments when compared with the control; however, a significant (p ≤ 0.05) difference among the studied genes was only observed for the nosZ gene (2.05 and 2.56 × 106 gene copies g-1 soil for treatments E and EC, respectively). Earthworm-induced soil N2O emissions were significantly (p ≤ 0.05) reduced by biochar addition. The possible underlying mechanisms may include: (1) short-term negative impacts on earthworm activity; (2) a change of functional gene abundance in earthworm casts; and (3) an increase in soil pH due to addition of biochar.

Nitrous oxide-induced toxic leukoencephalopathy.

Toxic leukoencephalopathy (TL) is characterised by an insult to the myelin of the cerebral white manner which can be attributed to a number of offending agents, including drugs of abuse. We report a case of a fit and well young man presenting to hospital with an altered mental state. It was subsequently determined that the patient inhaled a significant volume of nitrous oxide recreationally. Nitrous oxide is easily accessible and the second most consumed drug among young adolescents (16-24 years old). Following extensive investigations and brain imaging, the patient was subsequently diagnosed with TL. After a prolonged hospital admission, he went on to make a complete neurological recovery.

Subacute combined degeneration induced by nitrous oxide inhalation: Two case reports.

RATIONALE: Nitrous oxide (N2O), commonly known as "laughing gas," is being increasingly abused by young people as a recreational drug; this can subsequently result in myelopathy and peripheral neuropathy, however, in China, few cases of neurologic deterioration by N2O abuse have been reported. PATIENT CONCERNS: Herein, we present 2 patients who developed progressive limb weakness, numbness, and ataxia. Both of them had recreationally inhaled N2O intermittently for a long time. DIAGNOSIS: Subacute combined degeneration (SCD) based on myelopathy and polyneuropathy after N2O abuse. INTERVENTIONS: The 2 patients were treated with cessation of N2O inhalation, methylcobalamin capsule 500 µg tid (ter in die, which means 3 times a day), and compound vitamin B 1 tablet tid p.o.(per os, which means taken orally) for 1 month. OUTCOMES: The symptoms of altered sensation and the patients' gait improved significantly. LESSONS: The 2 cases raise awareness of the important mechanisms of N2O neurotoxicity, and clinicians should be made fully aware of such substance-related diseases. The incidence of N2O -induced neurotoxicity is insufficiently recognized and should be considered as an important cause of SCD, especially in adolescents with undifferentiated weakness and abnormal sensation; this is essential because serious complications such as irreversible paralysis can result from the absence of early diagnosis and treatment.

Nitrous oxide-induced demyelination: Clinical presentation, diagnosis and treatment recommendations.

BACKGROUND: Recreational use of nitrous oxide (NO) in the general public has led to increasing reports of NO-induced demyelination (NOID). We describe the varying clinical presentations and pathophysiology, and offer a treatment paradigm. METHODS: A literature search of MEDLINE and EMBASE resulted in 42 publications with 37 studies meeting the inclusion criteria, for a total of 51 patients. Our case series included 5 patients seen from 2014 to 2018 followed over 3-60 months. RESULTS: Those with sensory symptoms and subjective weakness were categorized as having "mild" symptoms (25%). Symptoms indicating involvement outside the dorsal columns such as observer-graded weakness were categorized as "moderate" (61%). Patients with the aforementioned plus cognitive effects were categorized as "severe" (12%). There was no dose-dependent relationship between the amount of NO used and clinical impairment. There was a trend between the severity of neurologic impairment and serum levels of B12. Two patients were noncompliant. One initiated only oral therapy and did not improve. One received injections a month apart and worsened. CONCLUSIONS: Patients with NOID tend to have worse symptoms when presenting with lower serum vitamin B12 levels and have good recovery rates when treated with intramuscular B12 and oral supplementation.

Nitrous Oxide Inhalant Use Disorder Preceding Symptoms Concerning for Primary Psychotic Illness.

BACKGROUND AND OBJECTIVE: Nitrous oxide has long been used recreationally for its ability to induce euphoria and other deliriant effects. In modern times, it remains a popular, legal, and widely available option for those seeking altered states. Though substance-induced psychotic symptoms have been mentioned in the literature, the potential long-term negative neuropsychiatric effects related to its use have not been well established. METHODS AND RESULTS: This is a patient case report of a young man (N = 1) who initially presented with acute neurological symptoms requiring hospitalization due to heavy nitrous oxide inhalant use, and went on to present with symptoms concerning for a primary psychotic illness over multiple inpatient admissions. He provided both verbal and written consent to share his story for this case report. DISCUSSION AND CONCLUSIONS: It is important to consider nitrous oxide use as a possible contributing factor to the development of primary psychotic illness. SCIENTIFIC SIGNIFICANCE: Current literature suggests that psychosis associated with nitrous oxide use is transient and resolves upon cessation and treatment of vitamin B12 deficiency. Here, we present a patient with risk factors for psychotic illness developing psychotic illness following extensive nitrous oxide use. This report offers a unique perspective of longitudinal follow-up (often not provided with reports on this topic), and illustrates the importance of healthcare providers inquiring about nitrous oxide abuse in patients presenting with early psychotic symptoms. (Am J Addict 2020;29:525-527).