Nitrous Oxide Exposure Research Articles

Association Between Intrapartum Nitrous Oxide for Labor Analgesia and Short-Term Neonatal Outcomes.

To evaluate the association between intrapartum nitrous oxide use and adverse short-term neonatal outcomes. This was a retrospective cohort study of individuals with singleton gestations at 35 or more weeks who attempted labor and delivered at an academic hospital between June 1, 2015, and February 28, 2020. Data were extracted from the electronic medical record using billing and diagnostic codes. Patients were classified based on whether they received no intrapartum analgesia or received nitrous oxide only. Those who received other analgesia types were excluded. The primary outcome was neonatal intensive care unit (NICU) admission. Secondary outcomes included Apgar score less than 7 at 1 minute and 5 minutes, respiratory composite outcome (including meconium aspiration syndrome, neonatal bronchopulmonary disorders, neonatal transient tachypnea, and other neonatal respiratory distress that required NICU admission), hypoglycemia, and hyperbilirubinemia. Univariable and multivariable analyses were used to estimate the association between nitrous oxide exposure intrapartum and the selected outcomes. Of 6,047 included, 4,153 (68.7%) received no analgesia, and 1,894 (31.3%) received nitrous oxide only. In comparison with individuals who received no analgesia, those who received nitrous oxide were more likely to be nulliparous, be of Black racial identity, have noncommercial insurance, and be less likely to deliver by intrapartum cesarean. The reception of nitrous oxide, compared with the reception of no analgesia, was associated with a lower likelihood of NICU admission (6.4% vs 8.1%; adjusted odds ratio [aOR] 0.77, 95% CI, 0.62-0.96) and an increased likelihood of neonatal hyperbilirubinemia (aOR 1.23, 95% CI, 1.08-1.41). Inhaled nitrous oxide exposure, in comparison with the reception of no analgesia, was not associated with the other secondary outcomes, including Apgar score less than 7 at 1 minute (odds ratio [OR] 0.74, 95% CI, 0.50-1.10) or 5 minutes (OR 0.91, 95% CI, 0.32-2.60), respiratory composite outcome (OR 0.91, 95% CI, 0.70-1.17), and hypoglycemia (OR 0.82, 95% CI, 0.64-1.05). In this single-center retrospective cohort of low-risk patients, intrapartum inhaled nitrous oxide, compared with the reception of no analgesia, was associated with a decreased risk for NICU admission but with an increased risk for hyperbilirubinemia; other outcomes did not differ. These findings may be used to counsel patients when considering nitrous oxide for labor analgesia.

Nitrous Oxide Abuse: Clinical Outcomes, Pharmacology, Pharmacokinetics, Toxicity and Impact on Metabolism.

The recreational use of nitrous oxide (N2O), also called laughing gas, has increased significantly in recent years. In 2022, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) recognized it as one of the most prevalent psychoactive substances used in Europe. Chronic nitrous oxide (N2O) exposure can lead to various clinical manifestations. The most frequent symptoms are neurological (sensitive or motor disorders), but there are also other manifestations like psychiatric manifestations or cardiovascular disorders (thrombosis events). N2O also affects various neurotransmitter systems, leading to its anesthetic, analgesic, anxiolytic and antidepressant properties. N2O is very challenging to measure in biological matrices. Thus, in cases of N2O intoxication, indirect biomarkers such as vitamin B12, plasma homocysteine and plasma MMA should be explored for diagnosis and assessment. Others markers, like oxidative stress markers, could be promising but need to be further investigated.

Nitrous oxide for the treatment of complex regional pain syndrome: a randomized blinded trial

IntroductionComplex Regional Pain Syndrome (CRPS) is a debilitating neuropathic condition often refractory to conventional treatments. N-methyl-D-aspartate (NMDA) receptor antagonists have a well-established role in the development and modulation of chronic...

Impaired Synaptic Plasticity in the mPFC and Anxiety-Like Behaviour in Rats Following Repeated Nitrous Oxide Exposure

Impaired Synaptic Plasticity in the mPFC and Anxiety-Like Behaviour in Rats Following Repeated Nitrous Oxide Exposure

Cortical Acetylcholine Levels Correlate With Neurophysiologic Complexity During Subanesthetic Ketamine and Nitrous Oxide Exposure in Rats.

BACKGROUND:Neurophysiologic complexity has been shown to decrease during states characterized by a depressed level of consciousness, such as sleep or anesthesia. Conversely, neurophysiologic complexity is increased during exposure to serotonergic psychedelics or subanesthetic doses of dissociative anesthetics. However, the neurochemical substrates underlying changes in neurophysiologic complexity are poorly characterized. Cortical acetylcholine appears to relate to cortical activation and changes in states of consciousness, but the relationship between cortical acetylcholine and complexity has not been formally studied. We addressed this gap by analyzing simultaneous changes in cortical acetylcholine (prefrontal and parietal) and neurophysiologic complexity before, during, and after subanesthetic ketamine (10 mg/kg/h) or 50% nitrous oxide.METHODS:Under isoflurane anesthesia, adult Sprague Dawley rats (n = 24, 12 male and 12 female) were implanted with stainless-steel electrodes across the cortex to record monopolar electroencephalogram (0.5–175 Hz; 30 channels) and guide canulae in prefrontal and parietal cortices for local microdialysis quantification of acetylcholine levels. One subgroup of these rats was instrumented with a chronic catheter in jugular vein for ketamine infusion (n = 12, 6 male and 6 female). The electroencephalographic data were analyzed to determine subanesthetic ketamine or nitrous oxide–induced changes in Lempel-Ziv complexity and directed frontoparietal connectivity. Changes in complexity and connectivity were analyzed for correlation with concurrent changes in prefrontal and parietal acetylcholine.RESULTS:Subanesthetic ketamine produced sustained increases in normalized Lempel-Ziv complexity (0.5–175 Hz; P < .001) and high gamma frontoparietal connectivity (125–175 Hz; P < .001). This was accompanied by progressive increases in prefrontal (104%; P < .001) and parietal (159%; P < .001) acetylcholine levels that peaked after 50 minutes of infusion. Nitrous oxide induction produced a transient increase in complexity (P < .05) and high gamma connectivity (P < .001), which was accompanied by increases (P < .001) in prefrontal (56%) and parietal (43%) acetylcholine levels. In contrast, the final 50 minutes of nitrous oxide administration were characterized by a decrease in prefrontal (38%; P < .001) and parietal (45%; P < .001) acetylcholine levels, reduced complexity (P < .001), and comparatively weaker frontoparietal high gamma connectivity (P < .001). Cortical acetylcholine and complexity were correlated with both subanesthetic ketamine (prefrontal: cluster-weighted marginal correlation [CW r] [144] = 0.42, P < .001; parietal: CW r[144] = 0.42, P < .001) and nitrous oxide (prefrontal: CW r[156] = 0.46, P < .001; parietal: CW r[156] = 0.56, P < .001) cohorts.CONCLUSIONS:These data bridge changes in cortical acetylcholine with concurrent changes in neurophysiologic complexity, frontoparietal connectivity, and the level of consciousness.

A retrospective cohort study on red blood cell morphology changes in pre-school age children under nitrous oxide anesthesia

BackgroundMegaloblastic anemia or bone marrow changes could occur after prolonged nitrous oxide inhalation via vitamin B12 inactivation related DNA synthesis impairment. Previous researches have studied hematological changes with nitrous oxide exposure, but only in adults or adolescents. Pre-school age children with active hematopoietic red bone marrow are more vulnerable to potential side effects of nitrous oxide and might experience growth impairment. The purpose of our study was to analyze red blood cell morphology changes under nitrous oxide anesthesia in pre-school age children.MethodsOne hundred thirty-six children under 5 years old scheduled for hemivertebra resection were analyzed. According to fresh gas type in anesthesia records, 71 children who received nitrous oxide in oxygen during anesthesia maintenance were categorized into the nitrous oxide group and the other 65 who received air in oxygen were the air group. Complete blood counts in perioperative period were assessed for anemia, macrocytosis, microcytosis, anisocytosis, hyperchromatosis and hypochromatosis. The peak value and change percentage were calculated for mean corpuscular volume and red cell distribution width.ResultsForty-two children in the air group (64.6%) and 30 in the nitrous oxide group (42.3%) developed anemia (P = 0.009). None developed macrocytosis in both groups. Postoperative mean corpuscular volume peaked (mean [95% confidence interval]) at 83.7(82.9–84.4) fL, and 83.2(82.4–83.9) fL and postoperative red cell distribution width at 13.8% (13.4–14.2%), and 13.9% (13.6–14.2%) for the air group and the nitrous oxide group. Both the relative change of mean corpuscular volume (P = 0.810) and red cell distribution width (P = 0.456) were similar between the two groups.ConclusionsNo megaloblastic red blood cell changes were observed with nitrous oxide exposure for 4 h in pre-school age children undergoing hemivertebra resection.

Subacute Combined Degeneration with Involvement of Concurrent Anterior, Lateral, Posterior Column after Nitrous Oxide Exposure

Subacute Combined Degeneration with Involvement of Concurrent Anterior, Lateral, Posterior Column after Nitrous Oxide Exposure

This Month in Anesthesiology

This Month in Anesthesiology

An Electroencephalogram Metric of Temporal Complexity Tracks Psychometric Impairment Caused by Low-dose Nitrous Oxide.

Nitrous oxide produces non-γ-aminobutyric acid sedation and psychometric impairment and can be used as scientific model for understanding mechanisms of progressive cognitive disturbances. Temporal complexity of the electroencephalogram may be a sensitive indicator of these effects. This study measured psychometric performance and the temporal complexity of the electroencephalogram in participants breathing low-dose nitrous oxide. In random order, 20, 30, and 40% end-tidal nitrous oxide was administered to 12 participants while recording 32-channel electroencephalogram and psychometric function. A novel metric quantifying the spatial distribution of temporal electroencephalogram complexity, comprised of (1) absolute cross-correlation calculated between consecutive 0.25-s time samples; 2) binarizing these cross-correlation matrices using the median of all channels as threshold; (3) using quantitative recurrence analysis, the complexity in temporal changes calculated by the Shannon entropy of the probability distribution of the diagonal line lengths; and (4) overall spatial extent and intensity of brain complexity, was quantified by calculating median temporal complexity of channels whose complexities were above 1 at baseline. This region approximately overlay the brain's default mode network, so this summary statistic was termed "default-mode-network complexity." Nitrous oxide concentration correlated with psychometric impairment (r = 0.50, P < 0.001). Baseline regional electroencephalogram complexity at midline was greater than in lateral temporal channels (1.33 ± 0.14 bits vs. 0.81 ± 0.12 bits, P < 0.001). A dose of 40% N2O decreased midline (mean difference [95% CI], 0.20 bits [0.09 to 0.31], P = 0.002) and prefrontal electroencephalogram complexity (mean difference [95% CI], 0.17 bits [0.08 to 0.27], P = 0.002). The lateral temporal region did not change significantly (mean difference [95% CI], 0.14 bits [-0.03 to 0.30], P = 0.100). Default-mode-network complexity correlated with N2O concentration (r = -0.55, P < 0.001). A default-mode-network complexity mixed-effects model correlated with psychometric impairment (r2 = 0.67; receiver operating characteristic area [95% CI], 0.72 [0.59 to 0.85], P < 0.001). Temporal complexity decreased most markedly in medial cortical regions during low-dose nitrous oxide exposures, and this change tracked psychometric impairment.

Pupillometry is not sensitive to gas narcosis in divers breathing hyperbaric air or normobaric nitrous oxide.

Gas narcosis impairs divers when diving deeper. Pupillometry is sensitive to alcohol intoxication and it has been used in anaesthesia to assess nitrous oxide narcosis. It is a potential novel method to quantify narcosis in diving. The aim of this study was to evaluate pupillometry for objective measurement of narcosis during exposure to hyperbaric air or nitrous oxide. Pupil size in 16 subjects was recorded directly at surface pressure and during air breathing at 608 kPa (equivalent to 50 metres' seawater depth) in a hyperbaric chamber. Another 12 subjects were exposed to nitrous oxide at end-tidal percentages of 20, 30 and 40% in random order at surface pressure. Pupil size and pupil light reflex were recorded at baseline and at each level of nitrous oxide exposure. Pupil size did not significantly change during exposure to hyperbaric air or nitrous oxide. The pupil light reflex, evaluated using percentage constriction and minimum diameter after exposure to a light stimulus, was affected significantly only during the highest nitrous oxide exposure - an end-tidal level of 40%. Pupillometry is insensitive to the narcotic effect of air at 608 kPa in the dry hyperbaric environment and to the effects of low dose nitrous oxide. Pupillometry is not suitable as a monitoring method for gas narcosis in diving.

Astrocyte activation following nitrous oxide exposure is related to oxidative stress and glutamate excitotoxicity

Background and AimsNitrous oxide is commonly used as an anesthetic agent and its exposure produces prolonged inactivation of vitamin B12. Nitrous oxide toxicity is associated with central nervous system changes which are similar to sub-acute combined degeneration (SACD). Astrocytes have important role in neurotoxic injuries, but have not been evaluated in N2O toxicity. In the present study, we have evaluated the changes in astrocytes in N2O exposed rats and correlated with neurobehavioral changes, oxidative stress and glutamate level. Material and MethodsAdult wistar male rats were exposed to N2O oxygen mixture in 1:1 ratio at a rate of 2 L/min for 120 min for 60 days. Control rats underwent similar exposure to oxygen. At the end of exposure, spontaneous locomotor activities (total distance travelled, time resting, time moving, number of rearing, stereotypic count) and grip strength were evaluated. Plasma glutathione (GSH), total antioxidant capacity (TAC), serum malonodialdehyde (MDA) and serum homocysteine (Hcy) were measured by spectrophotometer. Glutamate in the cerebral cortex and cerebellum were measured by colorimetry. Immunohistochemistry for astrocyte (GFAP) phenotypic analysis and its activation in brain and spinal cord were measured using image J software in N2O exposed and control rats. ResultsThe N2O exposed rats had significant reduction in total distance travelled, time moving and number of rearing whereas time resting increased compared to the control rats. Hcy, glutamate and MDA levels were significantly increased, however GSH and TAC level decreased in N2O exposed group compared to the controls. Astrocyte phenotype and its activation was significantly altered more so in spinal cord compared to cerebral cortex and was associated with neurobehavioral changes, oxidative stress and glutamate level. ConclusionsN2O related clinical dysfunction may be related to changes in astrocyte activation which is related to oxidative stress and glutamate neurotoxicity.

Nitrous Oxide Impairs Axon Regeneration after Nervous System Injury in Male Rats.

Nitrous oxide can induce neurotoxicity. The authors hypothesized that exposure to nitrous oxide impairs axonal regeneration and functional recovery after central nervous system injury. The consequences of single and serial in vivo nitrous oxide exposures on axon regeneration in four experimental male rat models of nervous system injury were measured: in vitro axon regeneration in cell culture after in vivo nitrous oxide administration, in vivo axon regeneration after sharp spinal cord injury, in vivo axon regeneration after sharp optic nerve injury, and in vivo functional recovery after blunt contusion spinal cord injury. In vitro axon regeneration 48 h after a single in vivo 70% N2O exposure is less than half that in the absence of nitrous oxide (mean ± SD, 478 ± 275 um; n = 48) versus 210 ± 152 um (n = 48; P < 0.0001). A single exposure to 80% N2O inhibits the beneficial effects of folic acid on in vivo axonal regeneration after sharp spinal cord injury (13.4 ± 7.1% regenerating neurons [n = 12] vs. 0.6 ± 0.7% regenerating neurons [n = 4], P = 0.004). Serial 80% N2O administration reverses the benefit of folic acid on in vivo retinal ganglion cell axon regeneration after sharp optic nerve injury (1277 ± 180 regenerating retinal ganglion cells [n = 7] vs. 895 ± 164 regenerating retinal ganglion cells [n = 7], P = 0.005). Serial 80% N2O exposures reverses the benefit of folic acid on in vivo functional recovery after blunt spinal cord contusion (estimate for fixed effects ± standard error of the estimate: folic acid 5.60 ± 0.54 [n = 9] vs. folic acid + 80% N2O 5.19 ± 0.62 [n = 7], P < 0.0001). These data indicate that nitrous oxide can impair the ability of central nervous system neurons to regenerate axons after sharp and blunt trauma.

163 Nitrous Oxide Exposure in Emergency Medical Services Providers: A Novel Direct Measurement Approach With Concerning Preliminary Findings

The use of inhaled nitrous oxide (N2O) as a pain control agent by emergency medical services (EMS) has notably increased nationwide in recent years. N2O offers numerous benefits as a out-of-hospital analgesic but is also exhaled unmetabolized by patients and accumulates in confined areas, with potential for chronic health implications or acute intoxication at high levels. While there is a wealth of literature addressing occupational N2O exposure in hospital and outpatient settings, the literature on out-of-hospital provider exposure is outdated and inadequate. This ongoing study is the first to measure levels of EMS provider exposure to N2O during actual (non-simulated) patient encounters. The primary study objective is to obtain an average value of ambient N2O concentration during a typical EMS patient encounter in which N2O is used, and to compare this sample mean to national standards for safe exposure limits. Ambient N2O concentrations were directly sampled via externally validated dosimeter badges (Kem Medical Products Corp.) worn in the breathing zone of EMS providers while caring for patients who met clinical criteria for (and were subsequently given) N2O, on-scene and/or during transport, as dictated by existing statewide EMS protocols for pain control. The primary provider of participating EMS crews unsealed and donned a dosimeter badge when N2O was started and wore the badge until care was transferred at the hospital. The delivery system (Nitronox) provided N2O with oxygen in a fixed 50/50 mix; patients self-administered ad libitum via a hand-held mouthpiece, with flow regulated via a demand valve. Per state protocol, crews were always required to open a patient compartment window and utilize the exhaust fan during N2O administration. Used badges were immediately re-sealed and later shipped for lab analysis by the supplier. Additional data including total exposure time were gathered for each call. Enrollment was started on a continuous basis at three 911 agencies within a single EMS district containing both urban and rural service areas in late March 2019. At the time of abstract submission, lab analysis was complete for three dosimeters, with a fourth pending. The average ambient N2O concentration over the three corresponding patient encounters was calculated to be 275 parts per million (ppm) as a time-weighted average (TWA). This preliminary sample mean exceeds the National Institute of Occupational Safety and Health (NIOSH) Recommended Exposure Limit (REL) of 25 ppm as a TWA, as well as the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) of 50 ppm as a TWA. Of note, during the only patient encounter in which N2O was used as the exclusive pain control agent for the duration of transport, ambient concentrations exceeded the validated limit of the dosimeter (N2O >700 ppm as a TWA). Preliminary findings suggest EMS providers in the study area may be unintentionally exposed to ambient N2O concentrations in excess of the NIOSH REL and ACGIH TLV during administration for out-of-hospital analgesia; however, no conclusions may be drawn yet given the current n of 3. Data collection was ongoing at the time of submission; if further data suggests excessive exposure, it may prompt early study termination and reassessment of EMS N2O protocols or delivery systems.

Effect of endotracheal tube lubrication on cuff pressure increase during nitrous oxide exposure: a laboratory and prospective randomized controlled trial

BackgroundWe previously demonstrated that lubrication of an endotracheal tube (ETT) cuff with K-Y™ jelly strongly and significantly inhibited the increase in cuff pressure during nitrous oxide (N2O) exposure in vitro. However, in our previous study, we identified critical differences between some influential factors, such as the amount of lubricant retained on the cuff, and studied temperature differences between laboratory and clinical conditions. Therefore, it remained unclear whether this effect holds true in clinical settings.MethodsWe first sought to study how changes in the amount of K-Y™ jelly and temperature influence the inhibitory effects of the lubricant on the increase in N2O-induced cuff pressure in vitro. Furthermore, we aimed to determine whether the application of K-Y™ jelly inhibits the increase in ETT cuff pressure during general anesthesia using N2O in adult patients.ResultsIn the laboratory studies, we found that K-Y™ jelly inhibited the cuff pressure increase dose-dependently when the dose of K-Y™ jelly was varied (P = 0.02), and that such an inhibitory effect decreased with an increase in the studied temperature (P = 0.019). In the clinical study, lubrication with K-Y™ jelly slightly, but significantly, delayed the increase in ETT cuff pressure during general anesthesia with N2O (P = 0.029). However, the inhibitory effect in the clinical settings was smaller than that in vitro.ConclusionsLubrication of the ETT cuff with K-Y™ jelly may delay the increase in cuff pressure during general anaesthesia with N2O. However, the clinical significance of this effect may be limited.Trial registrationUMIN Clinical Trials Registry: UMIN000031377 on March 1, 2019.

Pro-Con Debate: Nitrous Oxide for Labor Analgesia.

This Pro-Con debate will provide the practitioner with an evidence-based knowledge approach to assist the clinician in determining whether to employ (Pro) or not to employ (Con) this technique in the obstetrical suite for labor analgesia. Nitrous oxide has been used safely in dentistry and medicine for many centuries. However, accumulating preclinical and clinical evidence increasingly suggests previously unrecognized adverse maternal and fetal effects of nitrous oxide, which warrants reconsideration of its use in pregnant women and a more detailed informed consent. Nitrous oxide is associated with metabolic, oxidative, genotoxic, and transgenerational epigenetic effects in animals and humans that may warrant limiting its usefulness in labor. This debate will discuss and review the clinical uses, advantages, and disadvantages of nitrous oxide on occupational effects of nitrous oxide exposure, neuroapoptosis, FDA warning on inhalational anesthetics and the developing brain, research limitations, occupational exposure safety limits, effects on global warming, and potential for diversion.

118 Case series: subacute combined degeneration of the spinal cord in vitamin B12-replete recreational nitrous oxide abusers

IntroductionWithin a few years of its discovery in late 18th century, nitrous oxide was being used recreationally for its pleasurable effects. It remains in widespread use as an inhaled stimulant today, and can be legally acquired in bulk quantities with relative ease. In the body prolonged exposure to nitrous oxide leads to the oxidization of vitamin B12, rendering it unusable in key enzymatic reactions necessary for myelin synthesis. Over time this qualitative deficiency leads to a central demyelination syndrome that characteristically develops despite normal serum vitamin B12 levels and, with continued exposure to nitrous oxide, resists treatment with vitamin B12 supplementation.MethodNitrous oxide abusers presenting with a central demyelination syndrome were enrolled in this case series. Serum levels of vitamin B12, active B12, folate and homocysteine were measured. Nitrous oxide exposure was discontinued, and all patients were treated in accordance with evidence-based guidelines.ResultsEight patients presented with predominantly moderate-to-severe clinical deficits. The majority were vitamin B12 replete. In most cases individuals had actively engaged in prolonged vitamin B12 supplementation in an attempt to circumvent the harmful pathophysiology, of which they were loosely aware. Following treatment and rehabilitation several patients were discharged into full-time care, and most had significant residual disability at follow-up.ConclusionsThis case series not only illustrates the tragic consequences of abuse of this widely available and legally procured stimulant, but also highlights the futility of pursuing a nominally ‘protective’ strategy of vitamin B12 supplementation in the context of continued nitrous oxide exposure.

Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis.

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.

Nitrous Oxide Exposure Among Dental Personnel and Comparison of Active and Passive Sampling Techniques.

This study measured dental personnel's exposure to nitrous oxide during dental procedures to compare exposures to occupational exposure limits, exposures between similar exposure groups, and results between passive and active sampling methods. Forty-one paired samples were collected using the Thermo Scientific™ Miran SapphIRe portable analyzer and the Advanced Chemical Sensor™ N-10 Passive Badge. Results were compared to the American Conference of Governmental Industrial Hygienists nitrous oxide 250 parts per million by volume (p.p.m.v) excursion limit and 50 p.p.m.v 8-h threshold limit values. Similar exposure groups were determined by job title for dentists and dental assistants across six dental clinics. An independent t-test was used to determine if there was a mean difference between exposures for similar exposure groups. A Bland-Altman analysis was used to assess level of agreement between the two methods. Results over the 250 p.p.m.v excursion limit were identified in 21 of 41 (51%) paired procedures. Two passive 8-h threshold limit value-time weighted averages were over the 50 p.p.m.v occupational exposure limit, one for each similar exposure group. There was no significant difference between similar exposure group concentrations using either sampling method (Miran, P = 0.071; passive badge, P = 0.106). However, the sampling results revealed dentists had higher exposures than assistants 81-86% of the time. The Bland-Altman analysis revealed the direct reading instrument and passive sampling methods differed by >25%. However, unexpectedly, the passive sampling method generally produced higher nitrous oxide results compared to the direct reading instrument sampling method. This study suggests nitrous oxide remains a serious exposure concern for both short-term high-intensity exposures and longer term 8-h exposures. Greater nitrous oxide exposures among dentists compared to dental assistants allow for prioritizing control measures between similar exposure groups. Both sampling methods provide valuable worker exposure information, with the direct reading instrument monitoring providing a larger range for short-term exposures and passive sampling providing a less invasive monitoring option.

Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: An Individual Patient Data Meta-Analysis

Background: The risk of adverse effects of nitrous oxide (N2O) exposure is insufficiently recognised despite its widespread use. These effects are mainly reported through case reports. Methods: 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. Findings: 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 generalised 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 paraesthesia (80%; 72·0%-88·0%), unsteady gait (58%; 48·2%-67·8%), and weakness (43%; 33·1%-52·9%). At least one haematological abnormality was retrieved in 71·7% (59·9%-83·4%) of patients. Most patients had vitamin B12 deficiency: vitamin B12 15 µmol/L (90·3%; 79·3%-100%), and methylmalonic acid >0·4 µmol/L (93·8%; 80·4%-100%). Interpretation: N2O can produce severe outcomes, with neurological or haematological 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. Funding Statement: INSERM UMR_S 1256. Declaration of Interest: Authors declare no conflict of interest

Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: A systematic review of cases

ObjectiveVitamin B12 deficiency can lead to subacute combined degeneration (SCD). Nitrous oxide (N2O) is an anesthetic which oxidizes the cobalt ion of vitamin B12, interfering with its function as a coenzyme. In this study, we conduct a systematic review of reported cases of SCD following nitrous oxide anesthesia. Patients and MethodsA comprehensive search of multiple databases was conducted, and information about patient characteristics, symptomatology, clinical work-up, and treatment was extracted from eligible articles. Univariate analyses were performed to identify predictors of poor neurological recovery following SCD. Results32 studies, reporting 39 cases of nitrous oxide-induced SCD, were included through the screening process. These cases included 22 male patients and 17 female patients, with an average age of 51.3 years (SD 17.6). An etiology for subclinical B12 deficiency was determined in 31 reports; of these, 26 were due to vitamin malabsorption secondary to a gastrointestinal disorder. Duration of nitrous oxide exposure was described in 19 reports, and ranged from 30 min to 11 h. Univariate analysis failed to find an association between post-operative recovery and age (p = 0.41), sex (p = 0.48), positive MRI findings (p = 0.42), post-operative serum B12 (p = 0.96), post-operative hemoglobin (p = 0.17), type of surgery (p = 0.58), or post-operative high mean corpuscular volume (p = 0.14). ConclusionIn patients with postsurgical myelopathy, surgeons should evaluate B12 status and consider the possibility that nitrous oxide could cause a subclinical B12 deficiency to become overt, particularly in patients with malabsorptive GI comorbidities. Treatment with B12 in this population can result in significant improvement of neurological function.