CC BY
20
52. Shmookler Reis R. J., Bharill P., Tazearslan C., Ayyadeva-ra S. Extreme-longevity mutations orchestrate silencing of multiple signaling pathways. Biochim Biophys Acta. 2009;1790(10):1075-1083. doi: 10.1016/j. bbagen.2009.05.011
53. Simko G. I., Gyurko D., Veres D. V. [et al.] Network strategies to understand the aging process and help age-related drug design. Genome Med. 2009;1(9):90. doi: 10.1186/gm90
54. Van Bockstaele F., Holz J. B., Revets H. The development of nanobodies for therapeutic applications. Curr Opin Investig Drugs. 2009;10(11):1212-1224. doi: 10.2217/ nnm.13.86
55. Wang X., Chrysovergis K., Kosak J. [et al.] hNAG-1 increases lifespan by regulating energy metabolism
and insulin/IGF-1/mTOR signaling. Aging (Albany NY). 2014;6(8):690-704. doi: 10.18632/aging.100687
56. Wei D., Jiang X., Zhou L. [et al.] Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching. J. Med. Chem. 2008;51(24):7882-7888. doi: 10.1021/jm8010096
57. Wei M., Fabrizio P., Hu J. [et al.] Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 2008;4(1):e13. doi: 10.1371/journal. pgen.0040013
58. Yanai H., Budovsky A., Barzilay T. [et al.] Wide-scale comparative analysis of longevity genes and interventions. Aging Cell. 2017; doi: 10.1111/acel.12659
About authors:
Moskalev Alexey Alexandrovich, DBSc, RAS professor, correspondind member of RAS, Head of Department for Ecology, Head of Laboratory for Molecular Radiobiology and Gerontology; tel.: +78212312894; e-mail: amoskalev@ib.komisc.ru
Shaposhnikov Mikhail Vyacheslavovich, CBSc, Associate Professor of Department for Ecology; tel.: +78212312894; e-mail: shaposhnikov@ib.komisc.ru
Solovev Ilya Andreevich, Post-graduate student; tel.: +78212312894; e-mail: ilyasolovev-ksc@yandex.ru
© Booij L., 2017
UDC 546.17:616-053.3-009.614
DOI - https://doi.org/10.14300/mnnc.2017.12074
ISSN - 2073-8137
NITROUS OXIDE. SHOULD IT STILL
BE USED IN PEDIATRIC MEDICINE? (PART 1)
Booij L. H. D. Hj.
Radboud University Medical Centre, Nijmegen, The Netherlands
ЗАКИСЬ АЗОТА. НУЖНА ЛИ ОНА НАМ
ПРИ ПРОВЕДЕНИИ АНЕСТЕЗИИ У ДЕТЕЙ? (ЧАСТЬ I)
Лео Бой
Медицинский Центр Радбурдского Университета, Ниемеген, Нидерланды
Nitrous oxide (N2O) has been used in medicine for more than 165 years. By incidence was the analgesic effect recognized by Howard Wells. Originally was it thought to be a clean and anesthetic not causing a single adverse effect, and therefore was it considered the safest anesthetic. However, around 1956 was it recognized that some patients, after prolonged exposure developed, mostly transient, megaloblastic anemia and neurological disorders. Gradually became adverse effects more known. This resulted in discussions in the literature on the safety of N2O. Since the 1990's are there indications that N2O administration in children during the period of brain development and in elderly persons has neurotoxic effects. This lead to the conclusion of many that N2O should no longer be used in medicine. However, other physicians have the opinion that there is no reason to stop the use of N2O.
Keywords: pediatric anesthesia, children surgery, anesthesia associated complications in children, drugs adverse reactions
Закись азота (N2O) применяется в медицинских целях более 165 лет. Ее аналгетический эффект был случайно обнаружен Говардом Веллсом. Изначально считалось, что это достаточно безопасный анестетик, не вызывающий побочных реакций. Однако начиная с середины 1950-х годов было замечено, что у ряда пациентов, получавших этот анестетик, развивались преходящие неврологические расстройства и мегалобластическая анемия. Постепенно все большее количество побочных эффектов данного препарата было замечено при его практическом применении. В 1990-х годах было показано, что его использование у детей в период развития головного мозга, а также у пожилых пациентов приводит к развитию нейротоксических эффектов. Это привело к широкой дискуссии относительно использования закиси азота ввиду его небезопасности для пациентов и персонала, а также к заключению о нецелесообразности использования закиси азота. Однако не менее обширная когорта медицинских профессионалов не видит оснований для прекращения применения закиси азота в своей практике.
Ключевые слова: педиатрическая анестезия, детская хирургия, осложнения анестезии у детей, побочные эффекты лекарственных средств
1. Introduction
For more than 170 years has nitrous oxide (N2O) been used in medicine, after in 1772 the British chemist Joseph Priestley (1733-1804) had discovered the gas [1]. There are, however, some indications that Joseph Black (17281799), Scottish physician, was first to prepare N2O.This translates in the chemical reaction:
NH4NO3^N2O + 2H2O.
In 1793 experimented the British chemist Sir Humphrey Davy (1778-1829) with N2O at the Medical Pneumatic Institution of the British physician Thomas Beddoes (1760-1808) in Hotwells near Bristol, England. This institute was a medical research facility whose aim it was to investigate possible therapeutic uses of newly-discovered gases and chemicals to treat diseases of the lung. Many people came to the Medical Pneumatic Institution to enjoy the effect of N2O under the restriction that they had to write down the experienced effect of N2O. Because of this and other experiences indicated Davy already the possible use in anesthesia.
In 1823 was N2O-gas liquified by the British physicist-chemist Michael Faraday (1791-1897). He had in 1818 already demonstrated that inhalation of ether produced anesthetic effects similar to those of nitrous oxide.
After successful trials in Hartford, in Boston it's public demonstration was considered by most observers to be a failure, because the volunteer cried during tooth extraction under nitrous oxide. That failure was probably because too short an administration of N2O, and because of its only weak analgesic effect. At the same time came chloroform and ether in view as anesthetics. They had a stronger effect and this together with the disappointing effect of N2O prevented the further medical use of N2O. However, in dentistry remained N2O widely used. The use of N2O for tooth extraction became so popular that dentists advertised with it in the newspapers and on billboards. In 1864 started Samuel Lee Rymer (1832-1909), dentist in London, using nitrous oxide [1]. The Austrian physician Hermann Theodor Hillischer (1850-1926) can be regarded as the one introducing N2O in 1886 in dentistry in Austria [2]. The Russian physician Stanislav Klikovich (Klikowitsch, 18531910) studied in 1881 mixtures of 80 % N2O and oxygen use for painful medical manipulations. He was the first to use it in labour without loss of conscious- ness or risk of hypoxia. Klikovich recorded detailed observations on 25 women in labour to whom he had given the nitrous oxide-oxygen mixture [3, 4]. In animal studies did he confirm that nitrous oxide did not chemically combine with hemoglobin, but existed in simple solution in the plasma.
In 1886 published Dudley Wilmot Buxton (1855-1931), British physician-anesthetist his lecture 'On the physiological action of nitrous oxide' for the Odontological Society of Great Britain [5]. He found that N2O was neither a true anesthetic nor a true analgesic, and that the effect is on the central nervous system.
During the 1940s began the administration of N2O in combination with a number of other non-volatile anesthetic agents to allow for lower N2O concentrations to be used. Since then was N2O part of the armamentarium of the anesthetists, mainly as a carrier gas for other volatile anesthetics. It also got a place in obstetrics where an equal mixture of N2O and oxygen became used under the name Entonox. Since then millions of people have received N2O as a so called harmless anesthetic, without awareness of its adverse effects. Until 1956 has N2O thus been regarded as a totally safe drug, but then some reports on adverse hematologic and neurologic effects were published. First with repeated recreational exposure, and thereafter with even limited clinical re-exposure as a sedative in the treatment of tetanus. Although originally suspected to apply to only a small number of children with specific
types of metabolic inborn errors, has it become apparent that these metabolic abnormalities can be present in a far larger number of individuals. Then started the discussion whether we should still use N2O in medicine, because other techniques and better and shorter acting other drugs became available.
N2O nowadays is not only used in medicine, but also in other areas. In industry, N2O is used as an oxidizer in atomic absorption spectrometry and in the manufacture of semiconductors. In the dairy industry, N2O is used as a bacteriostatic, tasteless, odorless food processing propellant. N2O is also injected into the air intake of car engines by racing enthusiasts to boost horsepower. N2O is also used to prepare divers for deep dives because it mimics the disorientation and behavioral changes of decompression illness (the «bends») when a diver surfaces from the depths too rapidly.
2. Mechanism of action of nitrous oxide
The mechanism of action of N2O despite its long time use in medicine is still not completely understood. Only after the discovery that a number of receptors and transmitters are involved in consciousness and in reaching the state of anesthesia, was it recognized that N2O possibly acts on a variety of such receptors. Currently is it indeed known that there are various mechanisms involved in the effect of N2O. A direct modulation of a broad range of li-gand-gated ion channels of N2O has been demonstrated. N2O showed to have an inhibitory action at N-meth-yl-D-aspartate (NMDA) glutamate receptors, while it has a stimulatory activity at dopaminergic, ai and a2 adren-ergic and opioid receptors. It further moderately blocks p2-subunit-containing nicotinic acetylcholine channels, it almost insignificantly inhibits AMPA, kainate, GABAC, and 5-HT3 receptors, and slightly potentiates GABAa and glycine receptors [6]. It has also been shown to activate two-pore-domaine K+channels. In addition to its effects on ion channels, N2O may act to imitate nitric oxide (NO) in the central nervous system, and this may be related to its analgetic and anxiolytic properties. However, still is there much unknown on the real mechanism of action of N2O.
The analgesic effect of N2O is much stronger then its anesthetic effect. Nitrous oxide activates supraspinal opioid receptors. It was Raymond Quock and his colleagues whom, at the Children's Hospital of Wisconsin, have demonstrated that it acts on the complex of opioid receptors in the brain and spinal column, and that this action produces analgesic and euphoric effects [7, 8, 9]. The analgesic effect is inhibited by Naloxone and similar compounds [10, 11]. The and K-opioid receptor are likely the places where N2O acts [12]. In a study were |-receptors competitively inhibited by N2O while -receptors were non-competitively bound [13]. A study where it was used as analgesic for insertion of intraute-rine devices in nulliparous women proved its insufficiency as analgesic [14]. Nitrous oxide stimulates release of enkephalins, which bind to opioid receptors that trigger descending noradrenergic pathways [15]. Its anesthetic, hallucinogenic, and euphoriant effects are likely caused predominantly or fully via inhibition of NMDA receptors [16]. NMDA receptors are excitatory receptors in the body which respond to the endogenous agonist glutamate. NMDA antagonists are known to have both protective and toxic effects depending on their activation. The intervention of N2O with the NMDA receptors has powerful consequences, including the interruption of pain signals between body and brain, the mechanism by which these so-called 'dissociative' anesthetics achieve their effects; however, their onset, or use at sub-anesthetic doses, also produces a marked alteration of consciousness: the sensation that, in various ways, the mind is being unplugged from its habitual relations with the body, and entering into a
disembodied state where even fundamental qualities such as time and space drift loose from their moorings.
Current research thus indicates that the analgesic effect of N2O appears is initiated by stimulated neuronal release of endogenous opioid peptides, with subsequent activation of opioid receptors and descending GABA and noradrenergic pathways that modulate nociceptive processing at the spinal level [17]. The anxiolytic effect of N2O involves activation of the GABAa receptor through the benzodiazepine binding site, although whether N2O acts directly or indirectly upon the latter targets remains uncertain. The anxiolytic pathway that is stimulated includes a segment that involves a sequence of 3 key enzymes, NOS, soluble guanylyl cyclase, and PKG. The anesthetic effect of N2O appears to be caused by inhibition of NMDA glutamate receptors and removing its excitatory influence in the nervous system.
3. The adverse effects of nitrous oxide
Beginning in 1956, several reports appeared implicating that nitrous oxide is involved in the development of aplastic anemia or neurologic findings similar to those of megaloblastic anemia and B12 deficiency [18, 19, 20, 21, 22]. It occurred after relatively long administrations for anesthesia. N2O has been also implicated in the adverse effects on health seen in those individuals who are chronically exposed to trace amounts of the drug [23, 24]. Especially in area's where ventilation of the room is less adequate as in operating theaters or where scavenging of exhaled gases is not used (recovery rooms, obstetric rooms, dental practices, patient wards, etc.). Adverse effects were especially described in dentistry [25]. These adversities include infertility, spontaneous abortion, testicular changes, decreased sperm count, blood dyscrasias, and hematologic and neurologic deficits. In 1986 was it concluded that N2O can lead to many adverse effects i.e. hypoxia, increase in volume and pressure in gas filled body spaces, inactivation of vitamin B12, hema-tological disorders, immune disorders, necrologic disorders, spontaneous abortion, fertility problems, and more [26]. Also immunological problems (decreased leukocyte count, decreased leukocyte motility and chemotaxis, megaloblastic anaemia), liver problems, kidney problems, malignancy and miscellaneous cytotoxicity are described [27, 28]. Many of these adverse effects result from the irreversible inhibition of vitamin B12 by N2O inhibition of methionine synthase, folate metabolism, and deoxyribonucleic acid synthesis is the result [29, 30, 31]. N2O also depresses chemotactic migration by neutrophils and monocytes, apparently by interfering with microtubules [32, 33]. Increase in homocysteine concentration is another effect which may lead to increased myocardial infarction [34]. In 2017 was an extensive study published which clearly demonstrated that postoperative adverse effects such as postoperative fever, wound infection, pneumonia, pulmonary atelectasis, and severe nausea or vomiting decreased when nitrous oxide was avoided [35]. Endothelial function was impaired after surgery in patients with cardiovascular disease, but seemingly only in those exposed to nitrous oxide [36]. The duration of nitrous oxide exposure strongly correlated with the extent of endothelial dysfunction. It could be explained by the observed increase in homocysteine and a reduction in L-arginine and L-citrulline postoperatively. Despite all adverse effects is N2O still used in many hospitals for sedation during labor and for sedation of children; frequently is it then administered without the presence of an anesthesiologist and without scavenging the waste gases.
3.1. Hypoxia and asphyxia disorders
It became known early after its introduction that the analgesic and hypnotic affects of N2O is weak and that 100 % is needed to obtain anesthesia [37]. This of course
conflicts with oxygen uptake and can cause hypoxia and even asphyxia. When the necessary 100 % N2O is administered can hypo easily occur. In 1865 demonstrated the American dentist Zacheus Rogers (1842-1911) the use of vitalized air (N2O) in dentistry. He reported that a mixture with 33 % oxygen was far more pleasant then 100 % N2O. Also Edmund Andrews (1822-1904), American surgeon whom was taught the technique by Rogers, suggested in 1868 to add 20 % oxygen to the inhalation of N2O to avoid hypoxia and make anesthesia safer [38]. In anesthesia is 70 % N2O and 30 % oxygen the usual concentration administered, in sedation 50 % N2O and 50 % oxygen.
3.2. Diffusion hypoxia and filling of gas containing compartments
When a patient's inspired gas mixture is switched from air containing approximately 78 % nitrogen to an anesthetic mixture containing 70 % nitrous oxide, will the nitrous oxide enter gas-filled spaces more than 30 times faster than nitrogen can exit the space. As a result, the volume or pressure within such a space will increase. Thus blood passing a nitrogen-filled gas space within the body can deliver a greater volume of nitrous oxide to the space than the volume of nitrogen it removes from the space. But also does it result in increase of either the volume of, or the pressure within gas filled body spaces [39, 40]. A doubling or tripling of volume of gas-filled spaces can occur. Cuff pressures of endotracheal tubes and laryngeal masks airways (LMA) can in this way increase significantly during prolonged administration of N2O [41, 42, 43]. This may lead to local ischemia and mucosal damage. However, even tracheal rupture has been reported in two patients [44]. Damage from cuff expansion of laryngeal mask devices has also been published [45, 46, 47, 48, 49]. The diffusion is larger in silicone based tubes and laryngeal mask airways than in PVC based tubes and LMA's. Pressure increases can also occur in the middle ear or facial sinuses, the eye injected with air or sulfur hexafluoride, the ventricles of the brain when air is injected for example in pneumoencephalography. It can also cause damage to the eye from increase in pressure [50, 51, 52, 53, 54, 55]. This also occurs in cases of air embolism, expanding its size [56, 57]. It may also expand the volume of gas containing bowels [58]. The expansion becomes important when bowel obstruction is already present and the bowel contains large volumes (in excess of a liter) of gas. Closure of the abdomen becomes difficult, and the pressure of the abdominal contents upon the diaphragm may compromise ventilation.
The rapid exit of N2O from the alveoli causes remaining alveolar gases to be concentrated, thus accelerating the uptake of volatile agents into the blood and speeding the onset of anesthesia (second gas effect) [59, 60]. At the end of anesthesia, the more rapid elimination of nitrous oxide decreases the partial pressure of oxygen in the lungs, an effect known as diffusion hypoxia. For this reason, it is conventional practice to provide the patient with 100 % oxygen during the first few minutes following discontinuation of nitrous oxide. Hypoxemia is significant for only a matter of minutes and has been documented only when high concentrations (70 %) have been delivered by full mask or by endotracheal tube. Nitrous oxide predisposes the patient to atelectasis in isolated alveoli.
3.3. Inactivation of vitamin B12
In 1967-1968 was it found by biochemists that N2O inactivates cobalamin (vitamin B12) by oxidation [61, 62]. This result was not appreciated in the medical community where it was only recognized in 1978 [63]. In 1982 was it demonstrated in patients' liver biopsies after exposure to 50-70 % N2O for 1.25-2.75 hours, that there was a decrease in methionine synthase [64].
Cobalamin is a co-enzyme of methionine synthase, which is essential for the production of methionine and the
production of methyl groups. Methionine is an important amino acid that serves as a methyl donor via its activated form S-adenosyl-methionine in hundreds of biologic reactions, in the production of DNA, RNA, myelin and catecholamines amongst others. The end product of methionine demethylation is homocysteine, whose remethylation is catalyzed by the vitamin B12 dependent enzyme methionine synthase. Hyper-homocysteinemia, cumulation of folinic acid and a shortage of methionine are the result of methionine synthase inhibition [65]. Homocysteine has been shown to act as an agonist on the glutamate binding site on NMDA receptors, having an effect opposed to N2O. While this might suggest that N2O may counteract homocysteine excitotoxicity, in reality is N2O cleared from the system very quickly following cessation of anesthesia, while homocysteine is known to stay elevated in humans serum for days. In adolescents, homocysteine levels return to baseline between 12 and 24 h [66], while in adults this post-exposure increase is still high at 24 h [67] and continued elevation has been noted for up to one week [68, 69]. Certain patient groups may be particularly susceptible to reduced methionine synthase activity, including those deficient in cobalamin. This occurs in patients with pernicious anemia or ileal disease, alcoholics, the elderly, and the malnourished [70]. The duration of administration and concentration of N2O are important factors in the inactivation of vitamin B12 [71]. The authors found that in rats 50 % N2O exposure decreased methionine synthase activity within 30 min, and the activity was virtually undetectable after 6 h. Since N2O readily passes the placenta is also the fetus affected. In 1985 was it for the first time demonstrated that an adverse influence of N2O on vitamin B12 metabolism and DNA synthesis exists also in humans [72]. Exposing rats to N2O for 2 hours revealed in a 50 % reduction of methionine synthetase. Mice, pigs, and rats exposed to N2O have delayed recovery of enzyme activity for periods of four days or more [73, 74, 75, 76]. De novo synthesis of the enzyme is required to restore activity and takes several days [77]. Deficiency of vitamin B12 typically results in degeneration of posterior and lateral columns of the spinal cord, because it is essential in the production and maintenance of myeline. Clinical symptoms include sensory neuropathy, myelo-pathy, and encephalopathy; they can occur within days or weeks after exposure to N2O anesthesia in people with subclinical vitamin B12 deficiency. In humans, the mean half-time for hepatic methionine synthase inactivation by 1 atmosphere N2O is approximately 1 hour (or 0.5 atmospheres for 2 hours), with less than 20 % residual activity after 2 atmosphere-hours of exposure [78]. However, others found 50 % reduction after exposure for 40 minutes to 50 % N2O [79]. This last time span is well within the duration of most medical procedures. The authors found complete inactivation 200 minutes after the start of administration. A second exposure during this interval may be especially harmful because it prolongs the period of diminished methionine synthase activity. Repeated use of N2O depletes the body stores of vitamins B12 even in healthy people. Health care workers are frequently exposed to N2O and may develop all adverse effects of it [80, 81]. Also non-health care workers exposed to N2O can experience adverse effects [82]. Preoperative treatment with folinic acid prevented the development of methionine synthase deficiency in them [83].
3.4. Cognitive and behavioral disturbances
It was demonstrated in rats that decrease in cortical methionine synthase concentration due to N2O causes lasting impairment of memory [84]. Others demonstrated that exposure to N2O may result in short-term behavioral effects and may decrease mental performance, audiovisual ability and manual dexterity. It also can cause mood changes,
psychosis, auditory and visual hallucinations, and violent behavior [85, 86, 87, 88, 89, 90]. Presentation as a conversion disorder with myeloneuropathy was published [91]. N2O in sub anesthetic concentrations produces some subjective effects that are characteristic of psychedelic drugs, i.e., changes in body awareness and image, alterations of time perception, and experiences of a dreamy, detached reverie state [92]. Also diminished cognitive-motor proficiency results from inhalation at sub-anesthetic concentrations [93]. In a study in volunteers was it found that the subjects became more confused, sedated, 'high', dysphoric, and stimulated during inhalation of 40 % nitrous oxide than with the inhalation of 20 %; fatigue, depression and anxiety increased after inhalation of 40 % nitrous oxide had ceased [94].
3.5. Neurologic disturbances
The first reports on N2O-induced neuropathy were after recreational use. It was described after recreational use by two dentists and a hospital technician in 1978 [95]. It was soon followed up by a report on 15 patients of which 14 were dentists [96]. Some of them had occupational prolonged exposure to N2O, but also used it recreationally. Treatment with vitamin B12 resolved the problems. Chronic exposure to low concentrations of N2O in health care workers have resulted in neuropathies [97, 98, 99, 100, 101]. Such neuropathies are thus a major problem in the recreational and less frequently also after anesthesia [102]. Numbness, tingling, ataxia and/or muscle weakness, and impotence are frequently described [103, 104]. Animal studies have confirmed these effects [105, 106]. Vitamin B12-deficient patients are more at risk to develop neurologic disorders from N2O toxicity [107]. Consequently is it important to replace vitamin B12 in the malnourished before nitrous oxide anesthesia administration. However it is difficult to diagnose the deficiency unless clinical symptoms are present.
For subjects with good body stores of cobalamin is methionine synthetase inhibition unimportant, but no one using this agent should remain unaware of the potentially devastating complications in the nervous system of using N2O in subjects who are of borderline or deficient vitamin B12 status. Several investigators have reported the development of myelopathy and cord degeneration 2 to 6 weeks after a single nitrous oxide anesthesia induced for a variety of surgical procedures [108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119]. Some of them had an undetected vitamin B12 deficiency. The myelopathy most frequently occurs in the lower cervical and upper thoracic regions. Vitamin B12 or folate deficiency without exposure to N2O can also lead to sub-acute combined degeneration of the cord, presenting as limb weakness, numbness and tingling with imbalance and other neurologic disorders [120, 121].
Also in recreational use of N2O does myelopathy occur [122, 123, 124, 125, 126]. Most of these patients were found to have underlying vitamin B12 deficiency that was unknown at the time of the N2O use. Then one or two exposures are sufficient to result in myelopathy [127]. Awareness of this process is critical since approximately 14 % of the population have a vitamin B12 deficiency. Most symptoms improve, but do not resolve completely upon administration of vitamin B12 and methionine [128]. Peripheral nerve biopsies in patients with deficiencies show morphologic changes, i.e. degenerated nerve fibers, myelin splitting and formation of intra-myelinic vacuoles containing myelin debris [129]. Also neurophysiologi-cal changes such as delayed conduction velocity, can be observed. For example, a 6-month-old girl developed hypotonia and collapsed with metabolic acidosis, reduced serum cobalamin, and diffuse cerebral atrophy after a short nitrous oxide anesthesia [130]. Both mother and
child had vitamin B12 deficiency, the mother being a strict vegetarian.
Onset of subacute combined degeneration affecting the brain and spinal cord is a well documented event when individuals with low body stores of vitamin B12 are exposed to N2O. Nitrous oxide may also prove toxic in certain rare congenital disorders encountered in pediatric practice [131]. The child in this last case died 130 days of age, 46 days postoperatively and showed to have MTHFR deficiency, a rare autosomal recessive disorder.
3.6. Hematological disturbances
In the 1950's received patients with tetanus N2O for prolonged periods to secure sedation and analgesia [132]. They developed bone marrow depression and granulocytopenia. Two patients died from aplastic anemia. N2O is known to impair neutrophil and monocyte chemotaxis. In 1963 was it found that N2O in rats has a depressant effect on hemopoiesis [133]. The production of white blood cells was decreased. In 1981 demonstrated a study that short exposure to N2O did not cause bone marrow changes, but that longer exposure, i.e. more than 12 hours, did [134]. Administration of folic acid prevented these changes. In 1981 was a relationship between hematologic and neurology disturbances with chronic N2O exposure demonstrated in a survey amongst 18000 dentists and 18000 dental assistants [135]. Also others found that megaloblastic changes in bone marrow are present following exposure to anesthetic N2O concentrations for 24 hours, and that agranulocytosis is apparent after 4 days of exposure to it [136, 137]. However, such changes were by others found to exist already after an exposure during 2 hours and less [138]. Especially older patients are prone to megaloblastic anemia, because 20 % of them have already methionine synthase deficiency from malnutrition [139]. Leucopenia results from nitrous oxide administration [140]. Another study found that mild megaloblastic changes (associated with B12 deficiency) are present after 12 hours, and are marked after 24 hours exposure in patients [141]. After several days exposure, complete bone marrow failure is expected. However, patients deficient in vitamin B12 and substrates for methionine synthase, are at potential risk even with short exposure. Occupational exposure to N2O is reported to cause bone marrow depression, reproductive disturbances, etc [142, 143, 144, 145].
3.7. Malformation and DNA disturbances
Exposure to N2O can also cause congenital anomalies.
Tetrahydrofolate is involved in thymidine synthesis and DNA production. After several hours of N2O anesthesia, activity levels of methionine synthetase are very low and thus decrease tetrahydrofolate formation. The inhibition of methionine-synthetase thus can also results in interference
References
1. Rymer, Samuel Lee. Remarks upon the Use of Nitrous Oxide in Dental Operations. Dental Review: A Quarterly Journal of Dental Science 1864 Jan., 1864.
2. Hilllischer Th. Ueber die allgemeine Verwendbarkeit der Lustgas-Sauerstoffnarkose in der Chirurgie. Wien, Frick, 1886.
3. Klikovich S. Nitrous oxide and experiences with its therapeutic administration. A. M. Kotomin, St Petersburg, 1881.
4. Klikowitscsh S. Ueber das Stickostoffoxydul als Anaesthe-ticum bei Geburten. Archiv Fr Ginaekologie. 1881;18:81-108.
5. Dudley Wilmot Buxton. On the physiological action of nitrous oxide. London, Harrison & Sons. 1886.
6. Mennerick S., Jevtovic-Todorovic V., Todorovic S. M. [et al.] Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J. Neurosci. 1998;18:9716-9726.
7. Quock R. M., Best J. A., Chen D. C. [et al.] Mediation of nitrous oxide analgesia in mice by spinal and supraspinal
with DNA synthesis in both leukocytes and erythrocytes [146]. Patients with sub-clinical B12 deficiency, because of illness, pernicious anemia, or nutritional deficiency, and patients with methylene-tetrahydrofolate-reductase deficiency are especially at risk [147]. Preoperative B12 followed by folate supplementation is recommended in such patients or N2O should in them be avoided.
3.8. Cardio-vascular disorders
It has been documented through a series of clinical studies that nitrous oxide administration is associated with post-operative cardiac problems.
In 2015 were two cases of massive hyperhomocys-teinemia after prolonged intermittent inhalation of 50 % N2O in the treatment of refractory pain reported [148]. Homocysteine has been associated with a high rate of cardiac problems [149] and cerebrovascular diseases [150]. Myocardial infarction and ST-elevation in the electrocardiogram has been demonstrated in recreational use of N2O with increase in homocysteine [151]. It leads to increased postoperative mortality [152]. This postoperative increased homocysteine and higher incidence of my-ocardial ischemia was confirmed in patients in a study in 2000 [153].
4. Neurotoxicity of nitrous oxide
The effect of N2O, and other volatile anesthetics, on the developing infant brain has become perhaps the most contentious area of current pediatric anesthesia discussion [154]. N2O is an NMDA antagonist and thus may have an effect on neuroplasticity and synaptogenesis in the developing brain. Evidence is cumulating that N2O has neurotoxic effects when administered during pregnancy or to children at young age [155]. Also in elderly these effects are expected to occur. Proof has been obtained from rat and non-human primate studies. Rats exposed to N2O in combination with other clinical anesthetics during the period of brain development have a consistent, excessive increase in apoptosis in various brain regions, most notably the retrosplenial cortex and thalamus [156]. Long term impairment of cognitive function in rats is described as result of neurotoxicity [157, 158].. N2O exacerbated the nervous system injury caused by isoflurane [159]. In this study in non-human primates was there widespread apoptosis in the temporal gyrus, hippocampus and frontal cortex, with evidence of both necrotic and apoptotic cell death occurring. Human demonstrated in utero or perinatal exposure to N2O a correlation with short term neurological problems such as resistance to smiles and increased muscle tone [160]. However, human studies are sparse and the results not equivocal, thus further exploration is needed. However, the large number of animal studies without any doubt proof the neurotoxic effects of anesthetics including N2O.
kappa-opioid receptors. Eur. J. Pharmacol. 1990;175:97-100.
8. Chen D. C., Quock RM. A study of central opioid reception involvement in nitrous oxide analgesia in mice. Anaesth. Prog. 1990;37:181-185.
9. Branda E. M., Ramza J. T., Cahill F. J. [et al.] Role of brain dynorphin in nitrous oxide antinociception in mice. Pharmacol. Biochem. Behav. 2000;65:217-221.
10. Berkowitz B. A., Finck A. D., Ngai S. H. Nitrous oxide analgesia: Reversal by naloxone and development of tolerance. J. Pharmacol. Exp. Ther. 1977;203:539-547.
11. Hodges B. L., Gagnon M. J., Gillespie T. R. [et al.] Antagonism of nitrous oxide antinociception in the rat hot plate test by site-specific mu and epsilon opioid receptor blockade. J. Pharmacol. Exp. Ther. 1994;269:596-600.
12. Branda E. M., Ramza J. T., Cahill F. J. [et al.] Role of brain dynorphin in nitrous oxide antinociception in mice. Pharmacol. Biochem. Behav. 2000;65:217-221.
13. Ori C., Fordrice F., London E. D. Effects of nitrous-oxide and halothane on mu-opioid and kappa-opioid receptors in guinea-pig brain. Anesthesiology. 1989;70:541-544.
14. Singh R. H., Thaxton L., Carr S. [et al.] A randomized controlled trial of nitrous oxide for intrauterine device insertion in nulliparous women. Int. J. Gynaecol. Obstet. 2016; 42. 135:145-148.
15. Zhang C., Davies M. F., Guo T. Z., Maze M. The analgesic action of nitrous oxide is dependent on the release of norepinephrine in the dorsal horn of the spinal cord. Anesthesiology. 1999;91:1401-1407. 43.
16. Jevtovic-Todorovic V., Todorovic S. M., Mennerick S. [et al.] Nitrous oxide (laughing gas) is an NMDA antagonists, neuroprotectant and neurotoxin. Nature Medicine. 1998; 4:460-463. 44.
17. Emmanouil D. E., Quock R. M. Advances in understanding the actions of nitrous oxide. Anesth. Prog. 2007;54:9-18.
18. Lassen H. C., Henriksen E., Neukirch F., Kristensen H. S. Treatment of tetanus; severe bone-marrow depression 45. after prolonged nitrous-oxide anaesthesia. Lancet. 1956; 270:527-530.
19. Amess J. A., Burman J. F., Rees G. M. [et al.] Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lan- 46. cet. 1978;2:339-342.
20. Sahenk Z., Mendell J. R., Couri D., Nachtman J. Polyneuropathy from inhalation of N2O cartridges through a whipped-cream dispenser. Neurology. 1978; 28:485-487. 47.
21. Layzer R. B. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet. 1978;2:1227-1230.
22. Layzer R. B., Fishman R. A., Schafer J. A. Neuropathy fol- 48. lowing abuse of nitrous oxide. Neurology. 1978;28:504-
506.
23. Linde H. W., Bruce D. L. Occupational exposure of anes- 49. thetists to halothane, nitrous oxide and radiation. Anes-thesiology. 1969;30:363-368.
24. Kugel G., Norris L. H., Zive M. A. Nitrous oxide and occupational exposure: it's time to stop laughing. Anesth. 50. Prog. 1989;36:252-257.
25. Brodsky J. B., Cohen E. N., Brown B. W. Jr. [et al.] Exposure to nitrous oxide and neurologic disease among den- 51. tal professionals. Anesth. Analg. 1981;60:297-301.
26. Brodsky J. B., Cohen E. N. Adverse effects of nitrous oxide. Med. Toxicol. 1986;1:362-374. 52.
27. Donaldson D., Meechan J. G: The hazards of chronic exposure to nitrous oxide: an update. Br. Dent. J. 1995; 178:95-100. 53.
28. Rowland A. J., Baird D. D., Shore D. L. [et al.] Nitrous oxide and spontaneous abortion in female assistants. Am. J. Epidemiol. 1995;141:531-538. 54.
29. Myles P. S., Leslie K., Silbert B. [et al.] A review of the risks and benefits of nitrous oxide in current anaesthetic practice. Anaesth. Intensive Care. 2004;32:165-172. 55.
30. Vishnubhakat S. M., Beresford H. R. Reversible myelo-neuropathy of nitrous oxide abuse: serial electrophysio-logical studies. Muscle Nerve. 1991;14:22-26.
31. Flippo T. S., Holder W. D. Jr. Neurologic degeneration as- 56. sociated with nitrous oxide anesthesia in patients with vitamin B12 deficiency. Arch. Surg. 1993;128:1391-1395. 57.
32. Moudgil G. C., Pandya A. R., Ludlow D. J. Influence of anaesthesia and surgery on neutrophil chemotaxis. Can. Anaesth. Soc. J. 1981;28:232-238.
33. Nunn J. F., O'Morain C. Nitrous oxide decreases motility of 58. human neutrophils in vitro. Anesthesiology. 1982;56:45-48.
34. Leslie K., Myles P. S., Chan M. T. [et al.] Nitrous oxide and long-term morbidity and mortality in the ENIGMA trial. Anesth. Analg. 2011;112:387-393. 59.
35. Myles P. S., Leslie K., Chan M. T. [et al.] ENIGMA Trial Group. Avoidance of nitrous oxide for patients undergoing
major surgery: a randomized controlled trial. Anesthesio- 60. logy. 2007;107:221-231.
36. Myles P. S., Chan M. T., Kaye D. M. [et al.] Effect of nitrous oxide anesthesia on plasma homocysteine and endothelial function. Anesthesiology. 2008;109:657-663. 61.
37. Hornbein T. F., Eger E. I. 2nd, Winter PM. [et al.]The minimum alveolar concentration of nitrous oxide in man. Anesth. Analg. 1982;61:553-556.
38. Andrews E. The oxygen mixture, a new-anaesthetic com- 62. bination. Chicago Med. Exam. 1868;9:656-661.
39. Eger E. I. II, Saidman L. J. Hazards of nitrous oxide anesthesia in bowel obstruction and pneumothorax. Anesthe-siology. 1965;26:61-66. 63.
40. Wolf G. L., Capuano C., Hartung J. Effect of nitrous oxide on gas bubble volume in the anterior chamber. Arch. Ophthalmol. 1985;103:418-419. 64.
41. Nakao K., Komasawa N., Fujiwara S. [et al.][Difference in nitrous oxide-mediated increases in intracuff pressure
between two tracheal tubes in a simulated pediatric lung model]. Masui. 2014;63:578-581. van Zundert T., Brimacombe J.Comparison of cuff-pressure changes in silicone and pVc laryngeal masks during nitrous oxide anaesthesia in spontaneously breathing children. Anaesthesiol. Intensive Ther. 2012;44:63-70.
Miyashiro R. M., Yamamoto L. G.: Endotracheal tube and laryngeal mask airway cuff pressures can exceed critical values during ascent to higher altitude. Pediatr. Emerg. Care. 2011;27:367-370.
Atalay C., Aykan §., Can A. [et al.] Tracheal Rupture due to Diffusion of Nitrous Oxide to Cuff of High-Volume, Low-Pressure Intubation Tube. Eurasian J. Med. 2009;41:136-139.
Zhang J., Zhao Z., Chen Y., Zhang X. New insights into the mechanism of injury to the recurrent laryngeal nerve associated with the laryngeal mask airway. Med. Sci. Monit. 2010;16:HY7-9.
Goldmann K., Dieterich J., Roessler M. Laryngopharyngeal mucosal injury after prolonged use of the ProSeal LMA in a porcine model: a pilot study. Can. J. Anaesth. 2007;54:822-828.
Maino P., Dullenkopf A., Bernet V., Weiss M. Nitrous oxide diffusion into the cuffs of disposable laryngeal mask airways. Anaesthesia. 2005;60:278-282. Schloss B., Rice J., Tobias J. D.The laryngeal mask in infants and children: what is the cuff pressure? Int. J. Pediatr. Otorhinolaryngol. 2012;76:284-286. Sharma B., Gupta R., Sehgal R. [et al.] ProSeal™ laryngeal mask airway cuff pressure changes with and without use of nitrous oxide during laparoscopic surgery. J. Anaesthesiol. Clin. Pharmacol. 2013;29:47-51. Lockwood A. J., Yang Y. F. Nitrous oxide inhalation anaesthesia in the presence of intraocular gas can cause irreversible blindness. Br. Dent. J. 2008; 204:247-248. Lee E. J. Use of nitrous oxide causing severe visual loss 37 days after retinal surgery. Br. J. Anaesth. 2004;93:464-466.
Astrom S., Kjellgren D., Monestam E. [et al.] Nitrous oxide anesthesia and intravitreal gas tamponade. Acta. Anaesthesiol. Scand. 2003;47:361-362. Silvanus M. T., Moldzio P., Bornfeld N. [et al.] Visual loss following intraocular gas injection. Dtsch. Arztebl. Int. 2008;105:108-112.
Kodjikian L., Fleury J., Garweg J. [et al.] Blindness after nitrous oxide anesthesia and internal gas tamponade. J. Fr. Ophtalmol. 2003;26:967-971. Tanchyk A., Tanchyk A. The absolute contraindication for using nitrous oxide with intraocular gases and other dental considerations associated with vitreoretinal surgery. Gen. Dent. 2013;61(6):e6-7.
Munson E. S., Merrick H. C. Effect of nitrous oxide on venous air embolism. Anesthesiology. 1966;27:783-787. Diemunsch P. A., Noll E., Pottecher J. [et al.] Impact of nitrous oxide on the haemodynamic consequences of venous carbon dioxide embolism: An experimental study. Eur. J. Anaesthesiol. 2016;33:356-360. Akca O., Lenhardt R., Fleischmann E. [et al.] Nitrous oxide increases the incidence of bowel distension in patients undergoing elective colon resection. Acta Anaesthesiol. Scand. 2004;48:894-898.
Salanitre E., Rackow H. N2O volumes absorbed and excreted during N2O anesthesia in children. Anesth. Analg. 1976;55:95-99.
Taheri S., Eger E. I. II. A demonstration of the concentration and second gas effects in humans anesthetized with nitrous oxide and desflurane. Anesth. Analg. 1999; 89:774-780.
Banks R. G. S., Henderson R. J., Pratt J. M. Reactions of gases in solution. Part III: some reactions of nitrous oxide with transition-metal complexes. J. Chem. Soc. 1968; 3:2886-2889.
Banks R. G. S., Henderson R. J., Pratt J. M. Reactions of gases in solution. Part III: Some reactions of nitrous oxide with transition metal complexes. Chemical Communications. 1967;8:387-388.
Deacon R., Lumb M., Perry J. [et al.] Selective inactivation of vitamin B12 in rats by nitrous oxide. Lancet. 1978;2(8098):1023-1024.
Koblin D. D., Waskell L., Watson J. E., Stokstaed L. R., Eger E. I. Nitrous oxide inactivates methionine synthetase in human liver. Anesth. Analg. 1982;61:75-78.
65. Perry J., Deacon R., Lumb M. [et al.] The effect of nitrous oxide-induced inactivation of vitamin B12 on the activity of formyl-methenyl-methylenetetrahydrofolate synthetase, methylene-tetrahydrofolate reductase and formaminotet-rahydrofolate transferase. Biochem. Biophys. Res. Commun. 1980; 97:1329-1333.
66. Nagele P., Tallchief D., Blood J. [et al.] Nitrous oxide anesthesia and plasma homocysteine in adolescents. Anesth. Analg. 2011; 113:843-848.
67. Badner N. H., Drader K., Freeman D. [et al.] The use of intraoperative nitrous oxide leads to postoperative increases in plasma homocysteine. Anesth. Analg. 1998;87:711-713.
68. Ermens A. A., Refsum H., Rupreht J. [et al.] Monitoring cobalamin inactivation during nitrous oxide anesthesia by determination of homocysteine and folate in plasma and urine. Clin. Pharmacol. Ther. 1991;49:385-393.
69. Badner N. H., Freeman D., Spence J. D. Preoperative oral B vitamins prevent nitrous oxide-induced postoperative plasma homocysteine increases. Anesth. Analg. 2001;93:1507-1510.
70. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5:949-960.
71. Sharer N. M., Nunn J. F., Royston J. P., Chanarin I. Effects of chronic exposure to nitrous oxide on methionine synthase activity. Br. J. Anaesth. 1983;55:693-701.
72. Sweeney B., Bingham R. M., Amos R. J. [et al.] Toxicity of bone arrow in dentists exposed to nitrous oxide. Br. Med. J. 1985;291:567-569.
73. Kondo H., Osborne M. L., Kolhouse J. F. [et al.] Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats. J. Clin. Invest. 1981;67:1270-1283.
74. Deacon R., Lumb M., Perry J. [et al.] Inactivation of me-thionine synthase by nitrous oxide. Eur. J. Biochem. 1980;104:419-423.
75. Molloy A. M., Orsi B., Kennedy D. G., Kennedy S., Weir D. G., Scott J. M. The relation- ship between the activity of methionine syn- thase and the ratio of S-ad-enosylmethionine to S-adenosyl-homocysteine in the brain and other tissues of the pig. Biochem. Pharmacol. 1992;44:1349-1355.
76. Koblin D. D., Watson J. E., Deady J. E. [et al.] Inactivation of methionine synthetase by nitrous oxide in mice. Anes-thesiology. 1981;54:318-324.
77. Riedel B., Fiskerstrand T., Refsum H., Ueland P. M. Co-ordinate variations in methylmalonyl-CoA mutase and methionine synthase, and the cobalamin cofac-tors in human glioma cells during nitrous oxide exposure and the subsequent recovery phase. Biochem. J. 1999;341:133-138.
78. Koblin D. D., Waskell L., Watson J. E. [et al.] Nitrous oxide inactivates methionine synthetase in human liver. Anesth. Analg. 1982; 61:75-78.
79. Royston B. D., Nunn J. F., Weinbren H. K., Royston D., Cormack R. S. Rate of inactivation of human and rodent hepatic methionine synthase by nitrous oxide. Anesthesiology. 1988;68:213-216.
80. Gutmann L., Johnsen D. Nitrous oxide-induced myeloneuropathy: report of cases. J. Am. Dent. Assoc. 1981;103:239-241.
81. Lunsford J. M., Wynn M. H., Kwan W. H. Nitrous oxide-induced myeloneuropathy. J. Foot Surg. 1983; 22:222-225.
82. Iwata K., O'Keefe G. B., Karanas A. Neurologic problems associated with chronic nitrous oxide abuse in a non-healthcare worker. Am. J. Med. Sci. 2001; 322:173174.
83. Skacel P. O., Hewlett A. M., Lewis J. D. [et al.] Studies on the haemopoietic toxicity of nitrous oxide in man. Br. J. Haematol. 1983;53:189-200.
84. Culley D. J., Raghavan S. V., Waly M., Baxter M. G., Yukhananov R., Deth R. C., Crosby G. Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth. Analg. 2007;105:83-88.
85. El Otamni H., Moutawakil B., Moutawakil F., Gam I., Ra-fai M. A., Slassi I. Post-operative dementia: toxicity of nitrous oxide. Encephale. 2007;33:95-7.
86. Cousaert C., Heylens G., Audenaert K. Laughing gas abuse is no joke. An overview of the implications for psychiatric practice. Clin. Neurol. Neurosurg. 2013;115:859-862.
87. Tym M. K., Alexander J. Nitrous oxide induced manic relapse. Aust. N. Z. J. Psychiatry. 2011;45:1002.
88. Brodsky L., Zuniga J. Nitrous oxide: a psychotogenic agent. Compr. Psychiatry. 1975;16:185-188.
89. Wong S. L., Harrison R., Mattman A. [et al.] Nitrous Oxide (N2O)-Induced Acute Psychosis. Can. J. Neurol. Sci. 2014;41:672-674.
90. Kaufman E., Galili D., Furer R., Steiner J. Sensory experience induced by nitrous oxide analgesia. Anesth. Prog. 1990;37:282-285.
91. Brett A. Myeloneuropathy from whipped cream bulbs presenting as conversion disorder. Aust. N. Z. J. Psychiatry. 1997;31:131-132.
92. Block R. I., Ghoneim M. M., Kumar V., Pathak D. Psychedelic effects of a subanesthetic concentration of nitrous oxide. Anesth. Prog. 1990;37:271-276.
93. Dohrn C. S., Lichtor J. L., Coalson D. W. [et al.] Reinforcing effects of extended inhalation of nitrous oxide in humans. Drug Alcohol. Depend. 1993;31:265-280.
94. Dohrn C. S., Lichtor J. L., Finn R. S. [et al.] Subjective and psychomotor effects of nitrous oxide in healthy volunteers. Behav. Pharmacol. 1992;3:19-30.
95. Layzer R. B., Fishman R. A., Schafer J. A. Neuropathy following abuse of nitrous oxide. Neurology. 1978;28:504-506.
96. Layzer R. B. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet. 1978;2:1227-1230.
97. Cohen E. N., Gift H. C., Brown B. W. [et al.] Occupational disease in dentistry and chronic exposure to trace anesthetic gases. J. Am. Dent. Assoc. 1980;101:21-31.
98. Brodsky J. B., Cohen E. N., Brown B. W. Jr. [et al.] Exposure to nitrous oxide and neurologic disease among dental professionals. Anesth. Analg. 1981;60:297-301.
99. Kripke B. J., Talarico L., Shah N. K. [et al.] Hematologic reaction to prolonged exposure to nitrous oxide. Anesthe-siology. 1977;47:342-348.
100. Blanco G., Peters H. A. Myeloneuropathy and macrocy-tosis associated with nitrous oxide abuse. Arch. Neurol. 1983;40:416-418.
101. Hayden P. J., Hartemink R. J., Nicholson G. A. Myeloneuropathy due to nitrous oxide. Burns Incl. Therm. Inj. 1983;9:267-270.
102. Ogundipe O., Pearson M. W., Slater N. G. [et al.] Sickle cell disease and nitrous oxide-induced neuropathy. Clin. Lab. Haematol. 1999;21:409-412.
103. Felmet K., Robins B., Tilford D. [et al.] Acute neurologic decompensation in an infant with cobalamin deficiency exposed to nitrous oxide. J. Pediatr. 2000;137:427-428.
104. Rosener M., Dichgans J. Severe combined degeneration of the spinal cord after nitrous oxide anaesthesia in a vegetarian. J. Neurol. Neurosurg. Psychiatry. 1996;60:354.
105. Lumb M., Perry J., Deacon R. [et al.] Changes in plasma folate levels in rats inhaling nitrous oxide. Scand. J. Haematol. 1981;26:61-64.
106. Weir D. G., Keating S., Molloy A. [et al.] Methylation deficiency causes vitamin B12-associated neuropathy in the pig. J. Neurochem. 1988;51:1949-1952.
107. McNeely J. K., Buczulinski B., Rosner D. R. Severe neurological impairment in an infant after nitrous oxide anesthesia. Anesthesiology. 2000;93:1549-1550.
108. Timms S. R., Cure J. K., Kurent J. E. Subacute combined degeneration of the spinal cord: MR findings. AJNR Am. J. Neuroradiol. 1993;14:1224-1227.
109. Renard D., Dutray A., Remy A., Castelnovo G., Labauge P. Subacute combined degeneration of the spinal cord caused by nitrous oxide anaesthesia. Neurol. Sci. 2009;30:75-76.
110. Singer M. A., Lazaridis C., Nations S. P., Wolfe G. I. Reversible nitrous oxide-induced myeloneuropathy with pernicious anemia: case report and literature review. Muscle Nerve. 2008;37:125-129.
111. Somyreddy K., Kothari M. Nitrous oxide induced sub- acute combined degeneration of spinal cord: a case report. Electromyogr. Clin. Neurophysiol. 2008;48:225-228.
112. Wijesekera N. T., Davagnanam I., Miszkiel K. Subacute combined cord degeneration: a rare complication of nitrous oxide misuse. A case report. Neuroradiol. J. 2009;22:194-197.
113. Renard D., Dutray A., Remy A., Castelnovo G., Labauge P. Subacute combined degeneration of the spinal cord caused by nitrous oxide anaesthesia. Neurol. Sci. 2009;30:75-76.
114. Hadzic A., Glab K., Sanborn K. V., Thys D. M. Severe neurologic deficit after nitrous oxide anesthesia. Anesthesiology. 1995;83:863-866.
115. Holloway K. L., Alberico A. M. Postoperative myeloneu-ropathy: a preventable complication in patients with B12 deficiency. J. Neurosurg. 1990;72:732-736.
116. Marié R. M., Le Biez E., Busson P. [et al.] Nitrous oxide anesthesia-associated myelopathy. Arch. Neurol. 2000; 57:380-382.
117. Girón J. M., Muñoz A., Caro P. [et al.] Anesthesia paresthetica: contribution of a new case and evolutive study using magnetic resonance. Neurología. 1998;13:307-310.
118. Sesso R. M., lunes Y., Melo A. C. Myeloneuropathy following nitrous oxide anesthaesia in a patient with macrocytic anaemia. Neuroradiology. 1999;41:588-590.
119. Ahn S. C., Brown A. W. Cobalamin deficiency and subacute combined degeneration after nitrous oxide anesthesia: a case report. Arch. Phys. Med. Rehabil. 2005;86:150-153.
120. Marie R. M., Le Biez E., Busson P. [et al.] Nitrous oxide anesthesia-associated myelopathy. Arch. Neurol. 2000;57:380-382.
121. Schilling R. F. Is nitrous oxide a dangerous anesthetic for vitamin B12-deficient subjects. JAMA. 1986;255:1605-1606.
122. Massey T. H., Pickersgill T. T., J Peall K. Nitrous oxide misuse and vitamin B12 deficiency. BMJ Case Rep. 2016 May 31;2016.
123. Buizert A., Sharma R., Koppen H. When the Laughing Stops: Subacute Combined Spinal Cord Degeneration Caused by Laughing Gas Use. J Addict Med. 2017 Feb 3.
124. Sleeman I., Wiblin L., Burn D. An unusual cause of falls in a young woman. J. R. Coll. Physicians Edinb. 2016;46:160-162.
125. Morris N., Lynch K., Greenberg S. A. Severe motor neuropathy or neuronopathy due to nitrous oxide toxicity after correction of vitamin B12 deficiency. Muscle Nerve. 2015;51:614-616.
126. Ghobrial G. M., Dalyai R., Flanders A. E. [et al.] Nitrous oxide myelopathy posing as spinal cord injury. J. Neurosurg. Spine. 2012;16:489-491.
127. Kinsella L. J., Green R. 'Anesthesia paresthetica': nitrous oxide-induced cobalamin deficiency. Neurology. 1995;45:1608-1610.
128. Stacy C. B., Di Rocco A., Gould R. J. Methionine in the treatment of nitrous-oxide-induced neuropathy and my-eloneuropathy. J. Neurol. 1992;239:401-403.
129. Shimizu T., Nishimura Y., Fujishima Y. [et al.] Subacute myeloneuropathy after abuse of nitrous oxide: an electron microscopic study on the peripheral nerve. Rinsho Shinkeigaku. 1989;29:1129-1135.
130. Scott J. M., Dinn J. J., Wilson P. [et al.] Pathogenesis of subacute combined degeneration: A result of methyl group deficiency. Lancet. 1981;2:334-337.
131. Selzer R. R., Rosenblatt D. S., Laxova R. [et al.] Adverse effect of nitrous oxide in a child with 5,10-methylenetet-rahydrofolate reductase deficiency. N. Engl. J. Med. 2003;349:45-50.
132. Lassen H. C. A., Henricksen E., Neukirch F. [et al.] Treatment of tetanus. Severe bone-marrow depression after prolonged nitrous-oxide anesthesia. Lancet. 1956;1:527-530.
133. Green C. D., Eastwood D. W. Effects of nitrous oxide inhalation on hemopoiesis in rats. Anesthesiology. 1963;24:341-345.
134. O'Sullivan H., Jennings F., Ward K. [et al.] Human bone marrow biochemical function and megaloblastic hema-topoiesis after nitrous oxide anesthesia. Anesthesiology. 1981;55:645-649.
135. Brodsky J. B., Cohen E. N., Brown B. W. [et al.] Exposure to nitrous oxide and neurologic disease among dental professionals. Anesth. Analg. 1981;60:297-301.
136. Nunn J. F. Clinical aspects of the interaction between nitrous oxide and vitamin B12. Br. J. Anaesth. 1987;59:3-13.
137. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5:949-960.
138. Trivette E. T., Hoedebecke K., Berry-Caban C. S. [et al.] Megaloblastic hematopoiesis in a 20 year old pregnant female. Am. J. Case Rep. 2013;14:10-12.
139. Andres E., Loukili N. H., Noel E. [et al.] Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171:251-259.
140. Parbrook G. D. Leucopenic effects of prolonged nitrous oxide treatment. Br. J. Anaesth. 1967;39:119-127.
141. Amess J. A. L., Burman J. F., Rees G. M. [et al.] Mega-loblastic haemopoiesis in patients receiving nitrous oxide. Lancet. 1978;2:339-342.
142. Sanders R. D. B., Weimann J., Maze M. Biologic effects of nitrous oxide: A mechanistic and toxicologic review. Anesthesiology. 2008;109:707-722.
143. Luhmann J. D., Kennedy R. M. Nitrous oxide in the pediatric emergency department. Clin. Pediatr. Emerg. Med. 2000;1:285-289.
144. Yagiela J. A. Health hazards and nitrous oxide: a time for reappraisal. Anesth. Prog. 1991; 38:1-11.
145. Alhborg J. R., Axelsson G., Bodin L. Nitrous oxide exposure and subfertility among Swedish midwives. Int. J. Epidemiol. 1996;25:783-90.
146. Maze M. J., Fujinaga M. Recent advances in understanding the actions and toxicity of nitrous oxide. Anaesthesia. 2000;55:311-314.
147. Doran M., Rassam S. S., Jones L. M. [et al.] Toxicity after intermittent inhalation of nitrous oxide for analgesia. BMJ. 2004;328:1364-1365.
148. Faguer S., Ruiz J., Mari A. Massive hyperhomocystei-naemia as a complication of nitrous oxide inhalation. Br. J. Clin. Pharmacol. 2016;81:391-392.
149. Mayer E. L., Jacobsen D. W., Robinson K. Homocyste-ine and coronary atherosclerosis. J. Am. Coll. Cardiol. 1996;27:517-527.
150. Graham I. M., Daly L. E., Refsum H. M. [et al.] Plasma homocysteine as a risk factor for vascular disease. JAMA. 1997; 277:1775-1781.
151. Indraratna P., Alexopoulos C., Celermajer D., Alford K. Acute ST-Elevation Myocardial Infarction, a Unique Complication of Recreational Nitrous Oxide Use. Heart Lung Circ. 2017 Mar 6 pit: S1443-9506(17)30084-7
152. Nygard O., Nordrehaug J. E., Refsum H. [et al.] Plasma homocysteine levels and mortality in patients with coronary artery disease. N. Engl. J. Med. 1997;337:230-236.
153. Badner N. H., Beattie W. S., Freeman D. [et al.] Nitrous oxide-induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy. Anesth. Analg. 2000;91:1073-1079.
154. Booij L. H. Dj. Neurotoxicity caused by anesthetics in pediatric anesthesia. Medical News of North Caucasus. 2016;11(2):231-235. doi: 10.14300/mnnc.2016.11048
155. Jevtovic-Todorovic V., Hartman R. E., Izumi Y. [et al.] Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J. Neurosci. 2003;23:876-882.
156. Lu L. X., Yon J. H., Carter L. B. [et al.] General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis. 2006;11:1603-1615.
157. Jevtovic-Todorovic V., Hartman R. E., Izumi Y. [et al.] Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J. Neurosci. 2003;23:876-882.
158. Shu Y., Patel S. M., Pac-Soo C. [et al.] Xenon pretreat-ment attenuates anesthetic-induced apoptosis in the developing brain in comparison with nitrous oxide and hy-poxia. Anesthesiology. 2010;113:360-368.
159. Zou X., Liu F., Zhang X., Patterson T. A. [et al.] Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey. Neurotoxicol. Teratol. 2011;33:592-597.
160. Hollmen A. I., Jouppila R., Koivisto M. [et al.] Neurologic activity of infants following anesthesia for cesarean section. Anesthesiology. 1978;48:350-356.
About author
Booij Leo H. D. Hj., MD, PhD, FRCA; Professor emeritus Department of Anesthesia, Pain Treatment and Palliative Care; e-mail: lhdj.booij@upcmail.nl
