今日の臨床サポート

シアン・硫化水素中毒

著者: 加藤之紀 医療法人EMS 植田救急クリニック

監修: 林寛之 福井大学医学部附属病院

著者校正/監修レビュー済:2017/01/26
患者向け説明資料

概要・推奨   

疾患のポイント:
  1. シアン中毒、硫化水素中毒は原因不明の意識障害、代謝性アシドーシスを来した際に想起すべき中毒疾患である。
  1. シアン中毒は、アーモンド臭の無色の気体で、シアン化合物の内服、皮膚への接触のほか、物質の燃焼による吸入でも発生する。
  1. 硫化水素中毒は、無色で腐った卵のような匂いがすることが特徴の硫化水素の吸入で起こり、“ノックダウン”ともいわれる突然の意識消失などの神経症状を来すことが多い。汚水処理などの産業現場での報告もあるが、近年は自殺企図の手段として使用されるようになった。
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  1. シアン中毒の診断は、曝露を疑う病歴を伴うことに加え、血清乳酸の上昇とアニオンギャップ上昇性代謝性アシドーシス、静脈血酸素飽和度の上昇から推定することができる。血清乳酸>72mg/dl(8mmol/l)は、血中シアン濃度>1.0mg/lに対して感度94%、特異度70%で診断できる。静脈血が鮮やかな赤色を呈する、またはSvO2>90%は診断を示唆する所見である。口腔からのアーモンド臭が有名だが、全体の60%程度でしか確認できない。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
加藤之紀 : 特に申告事項無し[2021年]
監修:林寛之 : 講演料(メディカ出版),原稿料(羊土社)[2021年]

病態・疫学・診察

疾患情報(疫学・病態)  
  1. シアン化合物は、気体、液体、固体のさまざまな形態で存在し得る物質であり、金属加工や羊毛、ウレタンの製造において発生するほか、ウメやアンズの種やビターアーモンド(食用のアーモンドとは別種)、タピオカの原料のキャッサバの皮などの食料にも、わずかではあるが含まれている[1][2][3][4]<図表> <図表>
  1. ごく少量で人を死に至らしめるシアン化合物の毒性は1700年代後半から知られていた。第一次、二次世界大戦では兵器として使用され、またテロの毒ガス兵器として使用されたこともある[2]
  1. シアン中毒の機序としては、多くをその酵素阻害作用に起因するが、主に細胞内ミトコンドリアのチトクローム酸化酵素の働きの阻害により好気的解糖を不能にすることが、その毒性の原因である。<図表>その結果、組織が酸素を使用できなくなり、組織は低酸素に陥る。代償的な嫌気性解糖によって乳酸が蓄積、水素イオンの過剰も伴って 代謝性アシドーシス が増大し、中枢神経系、心血管系をはじめとする種々の組織に障害を与える。中枢神経については、フリーラジカル産生やGABAの抑制によっても障害を与え、けいれんなどの原因となる[1][2][3][4]
  1. 臨床的には火災における衣料や家具などの燃焼に伴うシアン中毒も問題であり、火災現場からの患者を診察する際には、一酸化炭素(CO)中毒と併せ、特にショック、乳酸アシドーシスを伴う場合想起する必要がある。
  1. 硫化水素は無色で、腐った卵のような匂いが特徴の気体である。石油製造や、自然細菌による硫黄の還元などで起こることが多く、農業従事者や産業従事者の 意識障害 、死亡原因の1つである。高濃度の硫化水素に触れると“ノックダウン”したように意識を失い、助けに入った救助者も意識を失う二次災害も頻繁に報告されている[2]
  1. 日本では2008年から2009年に自殺目的の硫化水素中毒が急増し、労働災害としての硫化水素中毒による死亡者が毎年1~3人程度なのに対し、2008年の硫化水素中毒自殺による死亡者は1,000人を超えた[13][14]
  1. 硫化水素中毒の病態は、シアン中毒と同じく、チトクローム酸化酵素の阻害によるものであるが、近年フリーラジカルの産生による細胞毒性も指摘されている[15][16]
問診・診察のポイント  
  1. シアン中毒の症状はさまざまで非特異的だが、特に中枢神経症状は軽い頭痛、嘔気からけいれん、意識不明まで多様であり、ほかに心血管系への影響として、頻脈、徐脈を含めた不整脈や血圧異常、呼吸障害としては、心原性肺水腫や急性呼吸窮迫症候群(ARDS)など多彩な形態をとる[1][2][3][4]

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文献 

著者: Anthony P Morocco
雑誌名: Crit Care Clin. 2005 Oct;21(4):691-705, vi. doi: 10.1016/j.ccc.2005.06.002.
Abstract/Text Cyanide is a likely weapon for terrorists due to its notoriety, lethality, and availability. Poisoning results in central nervous system and cardiovascular dysfunction due to inhibition of oxidative phosphorylation. Laboratory findings of anion gap metabolic acidosis and hyperlactemia aid in confirming the diagnosis. Treatment for significant poisonings includes aggressive supportive care and administration of antidotes such as sodium nitrite, sodium thiosulfate, and hydroxocobalamin. Survivors of significant poisonings can have long-term neurologic dysfunction.

PMID 16168309  Crit Care Clin. 2005 Oct;21(4):691-705, vi. doi: 10.101・・・
著者: D Yen, J Tsai, L M Wang, W F Kao, S C Hu, C H Lee, J F Deng
雑誌名: Am J Emerg Med. 1995 Sep;13(5):524-8. doi: 10.1016/0735-6757(95)90162-0.
Abstract/Text The authors reviewed the clinical manifestations, complications, and the prognosis affected by Lilly Cyanide Antidote in 21 victims of acute cyanide poisoning over a 10-year period. The clinical signs and symptoms in cyanide poisoning are variable. Among 21 cases, loss of consciousness (15), metabolic acidosis (14), and cardiopulmonary failure (9) were the three leading manifestations of cyanide intoxication. Anoxic encephalopathy (6) was not uncommon in the severely intoxicated victims. Diabetes insipidus (1) or clinical signs and symptoms mimicking diabetes insipidus (3) may be an ominous sign to encephalopathy victims. The major cause of fatal cyanide poisoning is the intentional ingestion of cyanide compounds as part of a suicide attempt. Decrease of arteriovenous difference of O2 partial pressure may be a clue for the suspicion of cyanide intoxication. Although the authors cannot show a statistically significant difference (P = .47) for the Lilly cyanide antidote kit in terms of improving the survival rate for victims of cyanide poisoning, the antidote kit was always mandatory in our study in the cases of severely intoxicated victims who survived. Early diagnosis, prompt, intensive therapy with antidote, and supportive care are still the golden rules for the treatment of acute cyanide poisoning, whether in the ED or on the scene.

PMID 7662055  Am J Emerg Med. 1995 Sep;13(5):524-8. doi: 10.1016/0735・・・
著者: R P Johnson, J W Mellors
雑誌名: J Emerg Med. 1988 Sep-Oct;6(5):401-4.
Abstract/Text Prompt diagnosis and treatment of cyanide poisoning is essential for a successful therapeutic outcome. We present a patient with acute cyanide poisoning in whom venous blood gases disclosed an abnormally high pO2. Prompt treatment of the patient with the cyanide antidote, sodium nitrite plus sodium thiosulfate, rapidly reversed the cardiovascular and central nervous system manifestations of cyanide toxicity. The pathogenesis of cyanide-induced blood gas abnormalities and their potential value in the recognition of cyanide intoxication are discussed. Current treatment recommendations for cyanide poisoning are also reviewed.

PMID 3147294  J Emerg Med. 1988 Sep-Oct;6(5):401-4.
著者: R Martín-Bermúdez, A Maestre-Romero, M V Goñi-Belzunegui, A Bautista-Lorite, C Arenas-Cabrera
雑誌名: Intensive Care Med. 1997 Dec;23(12):1286.
Abstract/Text
PMID 9470088  Intensive Care Med. 1997 Dec;23(12):1286.
著者: F J Baud, P Barriot, V Toffis, B Riou, E Vicaut, Y Lecarpentier, R Bourdon, A Astier, C Bismuth
雑誌名: N Engl J Med. 1991 Dec 19;325(25):1761-6. doi: 10.1056/NEJM199112193252502.
Abstract/Text BACKGROUND: The nature of the toxic gases that cause death from smoke inhalation is not known. In addition to carbon monoxide, hydrogen cyanide may be responsible, but its role is uncertain, because blood cyanide concentrations are often measured only long after exposure.
METHODS: We measured cyanide concentrations in blood samples obtained at the scene of residential fires from 109 fire victims before they received any treatment. We compared the results with those in 114 persons with drug intoxication (40 subjects), carbon monoxide intoxication (29 subjects), or trauma (45 subjects). The metabolic effect of smoke inhalation was assessed by measuring plasma lactate at the time of admission to the hospital in 39 patients who did not have severe burns.
RESULTS: The mean (+/-SD) blood cyanide concentrations in the 66 surviving fire victims (21.6 +/- 36.4 mumol per liter, P less than 0.001) and the 43 victims who died (116.4 +/- 89.6 mumol per liter, P less than 0.001) were significantly higher than those in the 114 control subjects (5.0 +/- 5.5 mumol per liter). Among the 43 victims who died, the blood cyanide concentrations were above 40 mumol per liter in 32 (74 percent), and above 100 mumol per liter in 20 of these (46 percent). There was a significant correlation between blood cyanide and carbon monoxide concentrations in the fire victims (P less than 0.001). Plasma lactate concentrations at the time of hospital admission correlated more closely with blood cyanide concentrations than with blood carbon monoxide concentrations. Plasma lactate concentrations above 10 mmol per liter were a sensitive indicator of cyanide intoxication, as defined by the presence of a blood cyanide concentration above 40 mumol per liter.
CONCLUSIONS: Residential fires may cause cyanide poisoning. At the time of a patient's hospital admission, an elevated plasma lactate concentration is a useful indicator of cyanide toxicity in fire victims who do not have severe burns.

PMID 1944484  N Engl J Med. 1991 Dec 19;325(25):1761-6. doi: 10.1056/・・・
著者: Frédéric J Baud, Stephen W Borron, Bruno Mégarbane, Hervé Trout, Frédéric Lapostolle, Eric Vicaut, Marcel Debray, Chantal Bismuth
雑誌名: Crit Care Med. 2002 Sep;30(9):2044-50. doi: 10.1097/01.CCM.0000026325.65944.7D.
Abstract/Text OBJECTIVE: To test the hypothesis that plasma lactate concentrations could be of confirmatory value in patients with histories consistent with acute pure cyanide poisoning because immediate laboratory confirmation of suspected cyanide poisoning is rarely possible and because clinicians must rapidly decide whether to administer specific antidotes, which may have severe side effects.
DESIGN: Retrospective clinical study.
SETTING: An intensive care unit in a university-affiliated teaching hospital.
PATIENTS: All acute cyanide-poisoned patients admitted to our intensive care unit, excluding fire victims, from 1988 to 1999.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Eleven patients were studied. Before antidotal treatment, the median plasma lactate concentration was 168 mg/dL, the median blood cyanide concentration was 4.2 mg/L. Using Spearman's test, there was a significant correlation between plasma lactate and blood cyanide concentrations ( =.74, =.017). Before antidotal treatment, plasma lactate concentration correlated positively with anion gap and inversely with systolic blood pressure, spontaneous respiratory rate, and arterial pH. During the course of cyanide poisonings, a plasma lactate concentration of >or=72 mg/d/L (8 mmol/L) was sensitive (94%) and moderately specific (70%) for a toxic blood cyanide concentration (>or=1.0 mg/L). The specificity was substantially improved in patients not receiving catecholamines (85%).
CONCLUSIONS: The immediate and serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning.

PMID 12352039  Crit Care Med. 2002 Sep;30(9):2044-50. doi: 10.1097/01.・・・
著者: M Lamine Benaissa, Bruno Mégarbane, Stephen W Borron, Frédéric J Baud
雑誌名: Intensive Care Med. 2003 Aug;29(8):1372-5. doi: 10.1007/s00134-003-1866-0. Epub 2003 Jul 10.
Abstract/Text OBJECTIVE: To examine whether CO poisoning induces a significant increase in plasma lactate concentration.
DESIGN AND SETTING: Prospective observational clinical study in the emergency department and intensive care unit in a university-affiliated teaching hospital.
PATIENTS: 146 pure CO poisonings resulting from dysfunction of gas cookers or water heaters.
MEASUREMENTS AND RESULTS: Patients were classified into four neurological impairment groups: 37% were severely, 8% moderately, and 45% mildly intoxicated, while 1% were asymptomatic. We found only very mild increases in plasma lactate concentration (median 2.30 mmol/l) which, however, was significantly correlated with the severity of neurological impairment and blood CO concentration (1.41 mmol/l, Spearman's test r=0.3).
CONCLUSIONS: Plasma lactate is mildly elevated in pure CO-exposed patients. This mild increase and the extensive overlap between the groups of neurological impairment severity do not suggest the usefulness of systematic plasma lactate measurement in pure CO poisoning.

PMID 12856122  Intensive Care Med. 2003 Aug;29(8):1372-5. doi: 10.1007・・・
著者: Don H Truong, Mohammad A Eghbal, Wayne Hindmarsh, Sheldon H Roth, Peter J O'Brien
雑誌名: Drug Metab Rev. 2006;38(4):733-44. doi: 10.1080/03602530600959607.
Abstract/Text RATIONALE: The toxicity of H2S has been attributed to its ability to inhibit cytochrome c oxidase in a similar manner to HCN. However, the successful use of methemoglobin for the treatment of HCN poisoning was not successful for H2S poisonings even though the ferric heme group of methemoglobin scavenges H2S. Thus, we speculated that other mechanisms contribute to H2S induced cytotoxicity. Experimental procedure. Hepatocyte isolation and viability and enzyme activities were measured as described by Moldeus et al. (1978), and Steen et al. (2001).
RESULTS: Incubation of isolated hepatocytes with NaHS solutions (a H2S source) resulted in glutathione (GSH) depletion. Moreover, GSH depletion was also observed in TRIS-HCl buffer (pH 6.0) treated with NaHS. Several ferric chelators (desferoxamime and DETAPAC) and antioxidant enzymes (superoxide dismutase [SOD] and catalase) prevented cell-free and hepatocyte GSH depletion. GSH-depleted hepatocytes were very susceptible to NaHS cytotoxicity, indicating that GSH detoxified NaHS or H2S in cells. Cytotoxicity was also partly prevented by desferoxamine and DETAPC, but it was increased by ferric EDTA or EDTA. Cell-free oxygen consumption experiments in TRIS-HCl buffer showed that NaHS autoxidation formed hydrogen peroxide and was prevented by DETAPC but increased by EDTA. We hypothesize that H2S can reduce intracellular bound ferric iron to form unbound ferrous iron, which activates iron. Additionally, H2S can increase the hepatocyte formation of reactive oxygen species (ROS) (known to occur with electron transport chain). H2S cytotoxicity therefore also involves a reactive sulfur species, which depletes GSH and activates oxygen to form ROS.

PMID 17145698  Drug Metab Rev. 2006;38(4):733-44. doi: 10.1080/0360253・・・
著者: Mohammad A Eghbal, Peter S Pennefather, Peter J O'Brien
雑誌名: Toxicology. 2004 Oct 15;203(1-3):69-76. doi: 10.1016/j.tox.2004.05.020.
Abstract/Text A number of scavengers of reactive oxygen species (ROS) were found to be protective against cell death induced by hydrogen sulfide (H2S) in isolated hepatocytes. The H2O2 scavengers alpha-ketoglutarate and pyruvate, which also act as energy substrate metabolites, were more protective against H2S toxicity than lactate which is only an energy substrate metabolite. All of these results suggest that H2S toxicity is dependent on ROS production. We measured ROS formation directly in hepatocytes using the fluorogenic dichlorofluorescin method. H2S-induced ROS formation was dose dependent and pyruvate inhibited this ROS production. Non-toxic concentrations of H2S enhanced the cytotoxicity of H2O2 generated by glucose/glucose oxidase, which was inhibited by CYP450 inibitors. Furthermore, hepatocyte ROS formation induced by H2S was decreased by CYP450 inhibitors cimetidine and benzylimidazole. These results suggest that CYP450-dependant metabolism of H2S is responsible for inducing ROS production. H2S-induced cytotoxicity was preceded by mitochondrial depolarization as measured by rhodamine 123 fluorescence. Mitochondrial depolarization induced by H2S was prevented by zinc, methionine and pyruvate all of which decreased H2S-induced cell death. Treatment of H2S poisoning may benefit from interventions aimed at minimizing ROS-induced damage and reducing mitochondrial damage.

PMID 15363583  Toxicology. 2004 Oct 15;203(1-3):69-76. doi: 10.1016/j.・・・
著者: J F Beck, C M Bradbury, A J Connors, J C Donini
雑誌名: Am Ind Hyg Assoc J. 1981 Nov;42(11):805-9. doi: 10.1080/15298668191420738.
Abstract/Text The detoxification of hydrogen sulfide (H2S) by a heme catalyzed oxidation was examined as part of an on-going study of H2S toxicity. Interlocking O2 absorption and sulfide depletion data indicate that both oxyhemoglobin and methemoglobin are effective catalytic agents. Although the latter is more efficacious, the life time of excess sulfide in the presence of oxygen and either of the above is of the order of minutes. It has also been established that the formation of methemoglobin following nitrite administration occurs preferentially under oxygen poor conditions. Under an atmospheric or oxygen enriched environment, which favors sulfide depletion, the nitrite retards sulfide oxidation. Thus nitrite as an antidote for acute H2S intoxication can only be effective within the first few minutes after the exposure, at which time resuscitation and/or ventilation of the victim is likely to produce conditions in which the nitrite actually slows sulfide removal.

PMID 7315740  Am Ind Hyg Assoc J. 1981 Nov;42(11):805-9. doi: 10.1080・・・
著者: Yuji Fujita, Yasuhisa Fujino, Makoto Onodera, Satoshi Kikuchi, Tomohiro Kikkawa, Yoshihiro Inoue, Hisae Niitsu, Katsuo Takahashi, Shigeatsu Endo
雑誌名: J Anal Toxicol. 2011 Mar;35(2):119-23.
Abstract/Text A patient committed suicide with hydrogen sulfide (H(2)S) by combining two commercial products. The patient was given hydroxocobalamin as an antidote in addition to treatment with cardiopulmonary resuscitation, but died approximately 42 min after his arrival at the hospital. The patient's cause of death was attributed to acute hydrogen sulfide poisoning. Serum concentrations of sulfide before and after administration of hydroxocobalamin were 0.22 and 0.11 μg/mL, respectively; serum concentrations of thiosulfate before and after hydroxocobalamin administration were 0.34 and 0.04 μmol/mL, respectively. Hydroxocobalamin is believed to form a complex with H(2)S in detoxification pathways of H(2)S. Although H(2)S is rapidly metabolized and excreted, the decreased sulfide concentration may be also associated with this complex formation. The decreased sulfide concentration suggests that hydroxocobalamin therapy may be effective for acute H(2)S poisoning. The decreased thiosulfate concentration seems to be associated with formation of a thiosulfate/hydroxocobalamin complex, because hydroxocobalamin can form a complex with thiosulfate. The thiosulfate concentration decreased to a greater extent than did sulfide, suggesting that hydroxocobalamin has a higher affinity for thiosulfate than for H(2)S. Therefore, prompt administration of hydroxocobalamin after H(2)S exposure may be effective for H(2)S poisoning.

PMID 21396232  J Anal Toxicol. 2011 Mar;35(2):119-23.
著者: Don H Truong, Aleksandra Mihajlovic, Patrina Gunness, Wayne Hindmarsh, Peter J O'Brien
雑誌名: Toxicology. 2007 Dec 5;242(1-3):16-22. doi: 10.1016/j.tox.2007.09.009. Epub 2007 Sep 15.
Abstract/Text Recently, H(2)S (an environmental toxin) was proposed to induce cytotoxicity not only by inhibiting cytochrome oxidase but also by generating reactive oxygen species [Truong, D., Eghbal, M., Hindmarsh, W., Roth, Sh., O'Brien, P., 2006. Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab. Rev. 38, 733-744]. In the following, evidence is presented supporting the use of hydroxocobalamin (vitamin B(12a)) as an antidote against H(2)S poisoning. More than 60% of the mice administered 35 mg/kg (0.63 mmol/kg) of NaSH (LD(90)) survived (at 24 h) when hydroxocobalamin (0.25 mmol/kg) was given after NaSH administration whereas less than 15% of the mice survived without hydroxocobalamin. Hydroxocobalamin (50-100 microM) or cobalt (50-100 microM) also prevented hepatocyte cytotoxicity induced by NaSH (500 microM). Furthermore, adding hydroxocobalamin 60 min later than NaSH still showed some protective activity. Catalytic amounts of hydroxocobalamin or cobalt added to a solution containing NaSH caused the disappearance of NaSH and induced oxygen uptake, indicative of NaSH oxidation and Co reduction, respectively.

PMID 17976885  Toxicology. 2007 Dec 5;242(1-3):16-22. doi: 10.1016/j.t・・・

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