Nitrous Oxide Exposure Research Articles

Peter Nagele, M.D., Recipient of the 2012 Presidential Scholar Award

Peter Nagele, M.D., Recipient of the 2012 Presidential Scholar Award

Nitrous oxide exposure does not seem to be associated with increased mortality, stroke, and myocardial infarction: a non-randomized subgroup analysis of the General Anaesthesia compared with Local Anaesthesia for carotid surgery (GALA) trial

Nitrous oxide has been associated with increased vascular risk in the perioperative period. Here, we conducted a secondary analysis of the GALA trial to ascertain the impact of nitrous oxide on outcomes after carotid surgery under general anaesthesia (GA). One thousand seven hundred and seventy-three patients underwent GA, but 158 patients were excluded from this analysis as nitrous oxide use was unknown. The decision to use nitrous oxide was at the discretion of the anaesthetist and was not randomized. Six hundred and seventy-one patients received nitrous oxide and 944 patients did not. Logistic regression was used to analyse the same primary outcome as the original trial (risk of death, stroke, or myocardial infarction within 30 days of the operation). Patients who received nitrous oxide were more likely to have had coronary artery disease, peripheral vascular disease, and atrial fibrillation (all P<0.05). Overall, there were 35 (5.2%) primary outcome events in patients receiving nitrous oxide compared with 44 (4.7%) in those who did not [relative risk 1.12, 95% confidence interval (CI: 0.73, 1.73); P=0.63]. The adjustment for the imbalanced baseline variables using logistic regression reduced the point estimate of harm for nitrous oxide [adjusted odds ratio 1.09, 95% CI (0.68, 1.74); P=0.73]. Given the greater prevalence of vascular risk factors in the nitrous oxide group and the lack of any definite effect on the primary outcome measure, these data do not support a clinically meaningful adverse effect of nitrous oxide on our composite outcome in patients undergoing carotid surgery.

Effect of Nitrous Oxide Exposure during Surgery on the Homocysteine Concentrations of Children

Nitrous oxide converts vitamin B12 to its nonmetabolically active form, inhibits methionine synthase, and results in an elevation of plasma total homocysteine (tHcy). The authors investigated the effect of nitrous oxide anesthesia on the plasma tHcy concentrations in children the morning after surgery and whether blood concentrations of folate and vitamins B12 and B6 were associated with any potential increase. The authors measured plasma tHcy concentrations in 32 children before and 24 h after initial exposure to nitrous oxide (≥ 2 h). Genotype for methylenetetrahydrofolate reductase C677T and blood concentrations of folate, vitamins B12 and B6, and methylmalonic acid were measured before surgery. The median age of participants was 11 months (3-126 months). The median (first, third quartile) postoperative plasma tHcy concentration was significantly higher than the preoperative concentration (6.4 [4.7, 8.9] vs. 5.1[4.1, 6.4] μM, P < 0.0001), a 25% (2%, 42%) relative increase. Six of 28 (21%) children with normal, age-appropriate, preexposure plasma tHcy concentrations had postoperative plasma tHcy concentrations greater than the cutoff values. The duration of nitrous oxide exposure was associated positively with the rise in plasma tHcy concentration (R2 = 0.696, P = < 0.001). Exposure to ≥ 2 h nitrous oxide is associated with a small, albeit statistically significant, increase in postoperative plasma tHcy concentrations the morning after surgery in young children. The clinical significance of this increase is unknown.

Notorious Oxide

Notorious Oxide

Intracuff pressure elevation of TaperGuardTM endotracheal tube Is less than that of Hi-LoTM tube during nitrous oxide exposure: a model trachea study

Intracuff pressure elevation of TaperGuardTM endotracheal tube Is less than that of Hi-LoTM tube during nitrous oxide exposure: a model trachea study

Myelopathy and polyneuropathy caused by nitrous oxide toxicity: a case report

A 19-year-old man presented with a 1-month history of progressive 4-limb numbness and gait imbalance. Physical examination revealed mild general muscular weakness, areflexia, and wide-based, ataxic, steppage gait. Sensory tests showed diminished superficial sensation below the level of the cervical-thoracic junction and a glove-and-stocking pattern of sensory loss at the 4 extremities. An initial magnetic resonance imaging examination of the cervical spine revealed an increased bilateral signal from the posterior and anterior columns on T2-weighted images. Nerve conduction velocity and electromyographic tests revealed polyneuropathy. On further inquiry, the patient admitted to chronic recreational use of nitrous oxide. The final diagnosis was nitrous oxide–induced neurotoxicity. The patient was treated for 5 days with injections of 1000 μg/day vitamin B12, followed by an additional 2-month treatment at a dose of 1000 μg/week. The numbness resolved after the first week, but there remained a mild sensory ataxic gait. The patient recovered fully after 2 months of treatment and nitrous oxide abstinence. We recommend an investigation of the patient's history of nitrous oxide exposure in cases where an individual presents to the emergency department or outpatient department with acute numbness characterized by megaloblastic red blood cells and symmetric neurologic deficits.

Journal-related Activities and Other Special Activities at the 2011 American Society of Anesthesiologists Annual Meeting

Journal-related Activities and Other Special Activities at the 2011 American Society of Anesthesiologists Annual Meeting

Is routine blood test of value for evaluating health effects among midwives working with nitrous oxide for pain relief in delivery unit

Chronic workplace exposure to high nitrous oxide concentrations has been suggested to potentially be associated to negative health effects caused by the interference with the vitamin B12, methionine synthase pathway. The objective of the present study was to determine if delivery unit work place ambient air nitrous oxide exposure results in detectable hyperhomocysteinemia or signs of macrocytocis in personnel. Blood samples from thirty healthy female fulltime employees, midwives, aged 43 (range 25-62) years were studied. Routine blood test analysed for plasma homocysteine and blood status; haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, blood status was analysed once before going on vacation and repeated after at least 10 days’ leave, nitrous oxide free period. Median time weighted average was 41 [10 - 547] ppm; 3 out of 11 TWA measurements were above recommended100 ppm limit. Median homocysteine concentrations were 10.7 [5.6 - 16] micromol/L with reference limits of 5.0 – 15 micromol/L. Megaloblastic erythrocytes was not detected in any personnel and no changes in blood status could be detected between before and after a nitrous oxide-free period. Conclusions: One of 3 delivery units’ ambient air quality measures exceed recommended ranges. No signs of routine blood test pathology could be seen in the personnel studied.

Severe Myeloneuropathy from Acute High-Dose Nitrous Oxide (N 2O) Abuse

Background: Myeloneuropathy from chronic exposure to nitrous oxide has been described. Nitrous oxide irreversibly alters B 12 activation, causing signs and symptoms of B 12 deficiency. Objectives: We describe a case of myeloneuropathy secondary to acute use of high-dose nitrous oxide. Case Report: A 24-year-old man presented to the Emergency Department complaining of numbness and tingling of his hands and feet, as well as worsening clumsiness and gait disturbances after escalating use of nitrous oxide in the prior 2 weeks. He was found to have dysmetria, poor proprioception, decreased sensation to vibration and light touch over his extremities, and a mildly positive Romberg sign. Laboratory test values revealed a normal B 12 level but increased methylmalonic acid and homocysteine levels. The patient was admitted to the hospital and started on a course of B 12 injections. He was discharged after 3 days with daily B 12 supplementation. Conclusions: This case demonstrates myeloneuropathic changes secondary to acute high-dose nitrous oxide exposure.

A Single Nitrous Oxide (N2O) Exposure Leads to Persistent Alleviation of Neuropathic Pain in Rats

Using the rat chronic constriction injury (CCI) pain model, we evaluated whether nitrous oxide (N2O), a gas shown to have potent anti-hyperalgesic properties, may alleviate neuropathic pain. Mechanical nociceptive threshold was estimated using the paw pressure vocalization test. Thermal allodynia was challenged by measuring the struggle latency by immersion of the hind paw in a 10 degrees C water bath. A single 50% N2O exposure for 1 hour, 15 minutes not only induced potent anti-nociception during N2O exposure but also provoked a delayed and sustained reduction (37% to 46%) of pain hypersensitivity of the injured hind paw and abolished pain hypersensitivity of the contralateral uninjured hind paw for at least 1 month. Thermal allodynia was completely prevented by a single N2O exposure. A preadministration of naltrexone, which markedly reduced acute N2O-induced anti-nociception, did not affect the persistent reduction of hyperalgesia. The administration of naltrexone in N2O-treated rats, 1 week after the gas exposure, did not induce any effect. This suggests that the long-lasting effect of N2O was not due to its prior acute analgesic effect and was independent of endogenous opioid systems. These data suggest that 50% N2O exposure could be an efficient and safe strategy for alleviating neuropathic pain in a persistent manner. Because a single 50% N2O exposure induced a persistent reduction of hyperalgesia-allodynia in a rat neuropathic pain model, clinical trials must be developed for evaluating the N2O effects in patients with neuropathic pain. The ability of N2O to potentiate analgesic effects of other drugs also must be evaluated.

Does Correcting the Numbers Improve Long-term Outcome?

Does Correcting the Numbers Improve Long-term Outcome?

Subacute Combined Cord Degeneration: A Rare Complication of Nitrous Oxide Misuse

We describe a severe case of subacute combined degeneration of the spinal cord precipitated by overuse of the analgesic Entonox (a 50:50 mixture of nitrous oxide and oxygen) in a 19-year-old female with previously undiagnosed vitamin B12 deficiency. MRI of the spine revealed symmetric abnormal signal in the dorsal and anterolateral columns of the cervical and thoracic cord, correlating with the patient's symptoms. Myeloneuropathy is caused by inactivation of vitamin B12 by nitrous oxide. The patient's condition slowly improved with cessation of nitrous oxide exposure and vitamin B12 replacement therapy.

Oxidant Stress as a Cause of Clinically Significant “Functional” Cobalamin (Cbl) Deficiency

Many patients (pts) with Cbl-responsive disorders identified in the ambulatory care setting have reversible neurologic abnormalities associated with increased levels of the Cbl-dependent metabolites, methylmalonic acid (MMA) and homocysteine (HCys), despite normal serum Cbl values. However, no mechanism to explain these findings has been proposed. Since this picture resembles both the CblC mutation (where reduction of CblCo(III) to CblCo(II) is impaired) and nitrous oxide exposure (which inactivates methionine synthase by oxidation of CblCo(I)), a pathophysiologic role for oxidant stress leading to “Functional” Cbl deficiency was considered. Thus, a retrospective review was performed of 39 pts with Cbl-responsive hematologic or neurologic disorders seen during a 14 yr period for the presence of 6 factors associated with increased oxidant stress: advanced age (>69 yrs); diabetes mellitus; cigarette abuse; alcohol abuse; renal insufficiency; and the presence of active inflammatory disorders. Pts were classified as Cbl-Deficient (Group A: serum Cbl <201 pg/ml; N=9); Possibly Cbl-Deficient (Group B: serum Cbl=201–300 pg/ml with MMA >250 nmol/l; N=12); and “Functional” Cbl Deficiency (Group C: serum Cbl >300 pg/ml with MMA >250 nmol/l; N=18). HCys values were increased (>12.1 μmol/l) in 67%, 75% and 50% of evaluable pts in Groups A, B and C respectively. Reversible neurologic abnormalities occurred in 44% of Group A pts, 67% of Group B pts and 100% of Group C pts. In Group C pts, 83% of cases had at least 2 oxidant risk factors. In contrast, only 22% of Group A pts had 1 risk factor and only 11% had 2 risk factors (p<0.002 vs Group C). Similarly, at least 1 oxidant risk factor was present in 67% of Group B pts (p<0.02 vs Group A) but only 17% had 2 risk factors (p<0.001 vs Group C). Moreover, within Group B, only 1 of 4 pts with serum Cbl values of 201–250 pg/ml had 1 oxidant risk factor (25%), while 7 of 8 pts with serum Cbl values of 251–300 pg/ml had at least 1 risk factor (88%)(p<0.03). Finally, when all 207 pts screened for Cbl deficiency during this period who had serum Cbl values >300 pg/ml were reviewed, MMA values were found to be >250 nmol/l in 81 of them (40%). At least 1 oxidant risk factor was present in 77% of the 81 pts with high MMA values but in only 20% of the 126 pts with normal MMA values (p<0.001). HCys levels were also increased in 42 of the 78 pts with high MMA values studied (54%) and Cbl therapy significantly decreased MMA and HCys values in 83% and 85% respectively of evaluable pts in this population. In contrast, only 11% of the 126 pts with normal MMA values had high HCys levels (p<0.001). It is concluded that “Functional” Cbl-deficiency isassociated with disorders known to induce oxidant stress;more commonly encountered as a cause of elevated metabolite levels and neurologic abnormalities than classic Cbl Deficiency; andoften responds to Cbl therapy.Taken together, these data suggest a cumulative effect of oxidant risk factors at higher serum Cbl values leading first to increases in MMA and then to clinically significant neurologic abnormalities. Thus, Cbl inactivation may play a role in the development of neuropathy when high risk individuals experience inflammatory illnesses or are exposed to prooxidant drugs and a possible prophylactic or therapeutic role for reduced Cbl vitamers should be considered.

Effect of Nitrous Oxide Anesthesia on Plasma Homocysteine and Endothelial Function

Endothelial function is impaired with hyperhomocysteinemia. Plasma homocysteine is increased by nitrous oxide anesthesia. The current study was designed to determine whether endothelial function is impaired after surgery and whether this is made worse by exposure to nitrous oxide. The authors studied 59 patients with cardiovascular disease undergoing noncardiac surgery. Patients were randomly allocated to nitrous oxide-based anesthesia (n = 25) or nitrous oxide-free anesthesia (control, n = 34). Endothelial function was measured by flow-mediated dilation of the brachial artery before and 24 h after surgery. In addition, blood was drawn at both time points for the measurements of plasma homocysteine, folate, L-arginine, L-citrulline, asymmetric dimethylarginine, and nitrate concentrations. The median duration of general anesthesia was 4.5 h. Patients had significantly lower flow-mediated dilation after surgery (5.1 +/- 3.3 to 3.0 +/- 4.1%; P = 0.001). Duration of anesthesia affected endothelial function. In the nitrous oxide group, there was an inverse correlation with flow-mediated dilation (r = -0.60, P = 0.004), but in the control group, there was a positive correlation (r = 0.61, P < 0.001). When compared with control, nitrous oxide exposure was associated with a significant increase in postoperative homocysteine (mean difference, 4.9 microm; 95% confidence interval, 2.8-7.0 microm; P < 0.0005) and decrease in flow-mediated dilation (3.2%; 95% confidence interval, 0.1-5.3%; P = 0.001). Nitrous oxide exposure was not associated with change in nitric oxide substrates. Nitrous oxide-based anesthesia increased plasma homocysteine and significantly impaired endothelial function in patients undergoing noncardiac surgery. Nitrous oxide-based anesthesia could be a risk factor for postoperative cardiovascular morbidity.

Xenon Up-regulates Several Genes That are not Up-regulated by Nitrous Oxide

Xenon and other inhalational agents induce cell and organ effects through different and only partially elucidated molecular mechanisms. In this study, we explored the gene transcription consequences of xenon exposure compared with nitrogen or nitrous oxide exposure in rat brain. Seven-day-old Sprague Dawley rats (n=24, 8 for each group) were exposed for 120 minutes to 75% xenon and 25% oxygen, 75% nitrogen and 25% oxygen (air), or 75% nitrous oxide and 25% oxygen. Using suppression subtractive hybridization, relative real-time polymerase chain reaction, and northern blot analyses of on/off gene expression, we were able to identify a set of genes that are significantly up-regulated by xenon exposure. These genes may help explain some of the molecular mechanisms that account for the neuropreconditioning effects exerted by xenon relative to nitrous oxide and air.

Biologic Effects of Nitrous Oxide

Nitrous oxide is the longest serving member of the anesthesiologist's pharmacologic armamentarium but remains a source of controversy because of fears over its adverse effects. Recently, the Evaluation of Nitrous oxide In a Gas Mixture for Anaesthesia (ENIGMA) trial reported that nitrous oxide use increases postoperative complications; further preclinical reports have suggested that nitrous oxide may contribute to neurocognitive dysfunction in the young and elderly. Therefore, nitrous oxide's longevity in anesthetic practice is under threat. In this article, the authors discuss the evidence for the putative toxicity of nitrous oxide, from either patient or occupational exposure, within the context of the mechanism of nitrous oxide's action. Although it would seem prudent to avoid nitrous oxide in certain vulnerable populations, current evidence in support of a more widespread prescription from clinical practice is unconvincing.

Pharmacogenetics of Nitrous Oxide

Pharmacogenetics of Nitrous Oxide

This Month in Anesthesiology

The change from earth's anoxic to oxic atmosphere in relation to the development of life is discussed. See the accompanying Editorial View on page 1 Total intravenous anesthesia was not associated with improved neurologic outcome in traumatic brain injury.Orally administered cannabis extract did not show analgesic efficacy.The need for large randomized trials to determine whether treatment strategies aimed at glucose control will improve patient outcomes is reviewed. See the accompanying Editorial View on page 1 1 Obesity is a major cause of type 2 diabetes, clinically evidenced as hyperglycemia. The altered glucose homeostasis is caused by faulty signal transduction via the insulin signaling proteins which results in decreased glucose uptake by the muscle, altered lipogenesis, and increased glucose output by the liver. The etiology of this derangement in insulin signaling is related to a chronic inflammatory state, which modifies the insulin signaling proteins' functions. There are substantial differences in the molecular mechanisms of insulin resistance among different organs. Multipronged therapies aimed at rectifying obesity-induced anomalies in the central nervous system and peripheral tissues may be beneficial in obesity-induced insulin resistance.The Laryngeal Tube Suction II (LTSII) is a recent revision of the Laryngeal Tube Suction. This study compared insertion and ventilation profiles of LTSII and ProSeal ™ Laryngeal Mask Airway (PLMA™) in anesthetized patients. The rate of successful insertion, insertion time, airway leak pressure, tidal volume, and postoperative airway morbidity were among many parameters measured. Insertion was successful in 37 and 48 of 50 patients with LTSII and PLMA™, respectively. The PLMA™ was superior to the LTSII in most measures of ventilation performance. Airway management with LTSII is inferior to that with PLMA™.In this editorial, Hogan reviews and comments on the implications of a pharmacogenomics study of nitrous oxide by Nagele et al. In Nagele et al. 's study, patients with a certain genetic mutation develop higher plasma homocysteine levels after nitrous oxide anesthesia than normal patients. The study suggests that deleterious events after nitrous oxide exposure may be enriched in a subset of patients with certain genetic predisposition. Hogan states that trials of nitrous oxide exposure in the clinical setting will be substantially strengthened by inclusion of single-carbon genotyping. Furthermore, knowing in advance who can breathe nitrous oxide without fear of clinically relevant hyperhomocysteinemia may help to sustain its safe use in the future.Recent investigations have focused on increased operating room (OR) throughput without increasing total OR time. The authors examined if a system of parallel processing for lower extremity joint arthroplasties sustainably reduces nonoperative time and increases throughput. The high-throughput parallel processing strategy included neuraxial anesthesia, an induction room, patient selection, an additional circulating nurse, and specific end-of-case transfer to recovery. Throughput increased from 2.6 to 3.4 arthroplasties per day per room. Both nonoperative time and operative time decreased. Because joint arthroplasties generated a positive margin greater than the incremental cost, the high-throughput system improved financial performance. See the accompanying Editorial View on page 3

Ambient levels of nitrous oxide in a modular ambulance

Nitrous oxide has been occasionally used as a prehospital analgesic over the last 3 decades. It has been shown to be an effective analgesic agent [1], but concerns have been raised about exposing prehospital personnel to high ambient levels of nitrous oxide within the confines of the ambulance. Historical concerns about possible detrimental effects of long-term exposure to health care workers prompted the National Institute of Occupational Safety and Health (NIOSH) to issue recommendations regarding acceptable levels of nitrous oxide exposure. NIOSH currently recommends a time-weighted average of 25 ppm for staff exposure during administration of nitrous oxide [2]. El Dorado County Emergency Medical Services (EMS), Placerville, Calif, was granted optional scope permission by the California State EMS Authority to use nitrous oxide in the ambulance for analgesia in 1997. In early 2004, we conducted a study to measure ambient nitrous oxide levels in the ambulance. The study assessed compliance with NIOSH standards for acceptable levels of nitrous oxide. Unlike previous studies, we attempted to replicate actual clinical conditions as closely as possible. This meant setting up the modular ambulance environment in a configuration consistent with how paramedics would normally operate. We also designed the study to examine the effect of patient conversation on ambient nitrous oxide levels.

Nitrous Oxide Decreases Cortical Methionine Synthase Transiently but Produces Lasting Memory Impairment in Aged Rats

Nitrous oxide is a commonly used anesthetic that inhibits the activity of methionine synthase, an enzyme involved in methylation reactions and DNA synthesis and repair. This inhibition triggers vacuole formation and degeneration of neurons in areas of the developing and mature brain that are important for spatial memory, raising the possibility that nitrous oxide might have sustained effects on learning. To test this possibility, we randomized 18-month-old Fischer 344 rats (n = 13 per group) to 4 h of 70% nitrous oxide + 30% oxygen or 70% nitrogen + 30% oxygen (control) and assessed memory using a 12-arm radial maze for 14 days beginning 2 days after nitrous oxide inhalation. In separate, identically treated groups of rats, we measured methionine synthase activity in the cortex and liver at the end of nitrous oxide exposure and 2 days later (n = 3 rats per group per time point) using a standard assay. Liver and cortical methionine synthase was inhibited during nitrous oxide inhalation (6% and 23% of control in liver and cortex, respectively; P < 0.01). Liver enzyme activity remained depressed 2 days later, whereas cortical enzyme activity recovered. There was no difference in error rate between control and nitrous oxide treated rats. However, those exposed to nitrous oxide took more time to complete the maze and made fewer correct choices before first error (P < 0.05). Sedation with 70% nitrous oxide profoundly, but transiently, reduces the activity of cortical methionine synthase but produces lasting impairment in spatial working memory in aged rats.