Hydroxocobalamin Therapy for Acute Hydrogen Sulfide Poisoning
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Fujita.qxd:JATLynneTemplate 1/24/11 1:01 PM Page 1 Journal of Analytical Toxicology, Vol. 35, March 2011 Case Report A Fatal Case of Acute Hydrogen Sul fide Poisoning Caused by Hydrogen Sulfide: Hydroxocobalamin Therapy for Acute Hydrogen Sul fide Poisoning Yuji Fujita 1,2, *, Yasuhisa Fujino 3, Makoto Onodera 3, Satoshi Kikuchi 3, Tomohiro Kikkawa 3, Yoshihiro Inoue 3, Downloaded from https://academic.oup.com/jat/article/35/2/119/773132 by guest on 01 October 2021 Hisae Niitsu 4, Katsuo Takahashi 2, and Shigeatsu Endo 3 1Poisoning and Drug Laboratory Division, Critical Care and Emergency Center, Iwate Medical University Hospital, 3-16-1 Honchoudori, Morioka, Iwate 020-0015, Japan; 2Department of Pharmacy, Iwate Medical University Hospital, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan; 3Department of Emergency Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan; and 4Department of Legal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan Abstract Introduction A patient committed suicide with hydrogen sulfide (H S) by 2 Hydrogen sulfide (H 2S) gas is highly toxic, colorless, and combining two commercial products. The patient was given flammable, with a characteristic “rotten egg” scent. It exists in hydroxocobalamin as an antidote in addition to treatment with raw petroleum and natural and volcanic gases, and is produced cardiopulmonary resuscitation, but died approximately 42 min through leather tanning, processes for kraft and paper pulp, and after his arrival at the hospital. The patient’s cause of death was attributed to acute hydrogen sulfide poisoning. Serum decay of human and animal waste. Accidental H 2S poisoning in concentrations of sulfide before and after administration of industrial plants, dairy farms, and other locations has been re - hydroxocobalamin were 0.22 and 0.11 μg/mL, respectively; ported (1−4). H 2S is quickly absorbed through the lungs and the 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 2S in detoxification pathways of H 2S. Although H 2S 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 2S 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 2S. Therefore, prompt administration of hydroxocobalamin after H 2S exposure may be effective for H 2S poisoning. * Author to whom correspondence should be addressed: Yuji Fujita, Poisoning and Drug Laboratory Division, Critical Care and Emergency Center, Iwate Medical University Hospital, Figure 1. Main metabolic pathway of hydrogen sulfide. 3-16-1 Honchoudori, Morioka, Iwate 020-0015, Japan. Email: [email protected]. Reproduction (photocopying) of editorial content of this journal is prohibited without publisher’s permission. 119 Fujita.qxd:JATLynneTemplate 1/24/11 1:01 PM Page 2 Journal of Analytical Toxicology, Vol. 35, March 2011 gastrointestinal tract; it is eliminated through the lungs or in therapy for acute intoxication, and an accumulation of case re - feces, and its metabolites are passed in urine. H 2S has three ports would be useful for the treatment of acute intoxications in metabolic pathways: oxidation, alkylation, and reactions with the future. metallo- or disulfide-containing proteins (5). Its main metabolic pathway is the oxidation pathway; H 2S metabolizes to sulfate via thiosulfate (Figure 1) through non-enzymatic and enzymatic mechanisms. The oxidation and alkylation pathways are detox - Case History ification pathways, in which H 2S’s toxic mechanisms are reac - tions with essential proteins. In acute human H 2S poisoning In April 2008, a male in his early 20s committed suicide in cases, thiosulfate usually cannot be detected in blood of sur - a car by combining two commercial products to make H 2S vivors, but can be detected in their urine (6). In fatal cases, how - gas. He was unconscious and not breathing when his family ever, thiosulfate usually can be detected in blood, but not in found him in the car (6:40 a.m.). His family confirmed him to urine (7−9). Therefore, detection of thiosulfate in urine for have been alive at midnight (12:00 a.m.). He smelled noticeably survivors and in blood for fatal cases is useful for diagnosing of rotten eggs and had neither pulse nor spontaneous respira - H2S poisoning (6). tions when emergency workers arrived at the site (6:52 a.m.). Downloaded from https://academic.oup.com/jat/article/35/2/119/773132 by guest on 01 October 2021 H2S binds cytochrome oxidase and inhibits its function, On arrival at the hospital (7:19 a.m.), his eyes showed mydri - which is the conversion of molecular oxygen to water. It thus in - asis, and an electrocardiogram showed asystole. On arterial hibits generation of adenosine triphosphate, which provides blood gas analysis, his arterial carboxyhemoglobin was 1.5%, energy for many cellular functions. Most organ systems are indicating that he had not developed carbon monoxide poi - susceptible to the effect of H 2S, particularly mucous mem - soning. He was treated with cardiopulmonary resuscitation branes and tissues that demand the most oxygen. H 2S stops cel - and received an intravenous infusion of 2.5 g of hydroxo - lular respiration at high concentrations. The mechanism of cobalamin as an antidote for H2S poisoning. However, he died toxicity of H 2S is similar to that of cyanide. Increased exposure of H2S poisoning 42 min after arrival at the hospital (8:01 concentrations of H 2S are associated with adverse effects of in - a.m.) in spite of the staff’s efforts. creased severity: conjunctival irritation occurs at about 50 ppm, irritation of the respiratory tract at 50–100 ppm, loss of smell at 100–200 ppm, pulmonary edema at 250–500 ppm, and con - centrations greater than 500 ppm—often called the “knock Methods down concentration”—can cause respiratory arrest, collapse, and death within minutes (10). Although H 2S has a character - Analytical procedures for sulfide and thiosulfate istic “rotten egg” scent, its odor cannot be always identified, be - Extraction of sulfide and thiosulfate from serum and deriva - cause the exposure to > 150 ppm paralyzes olfactory nerves. tization of those were performed according to the method de - In acute H 2S poisoning, victims should be immediately trans - ferred to fresh air and cardiopulmonary resuscitation started for victims with no heartbeat. Therapy for acute H 2S poisoning is supportive care. Although effective protocols for acute H 2S poi - soning are not established, nitrate therapy, such as inhaled amyl nitrate and intravenous sodium nitrate, and hyperbaric oxygen therapy may be useful for certain patients. Nitrates detoxify H 2S poisoning by inducing the formation of methe - moglobin, which has a higher affinity for H 2S than does cy - tochrome oxidase; methemoglobin then binds H 2S, decreasing its toxicity. Truong et al. (11) recently reported that hydroxo - cobalamin (Figure 2), which is part of the antidote kit for cyanide poisoning, is useful as an antidote against H 2S poi - soning in animal experiments; a cyanide antidote kit might be useful for emergency treatment of acute H 2S poisoning. Hy - droxocobalamin is thought to detoxify H 2S poisoning by forming a complex with H 2S, which metabolizes to thiosulfate and sulfate. To help establish an effective therapy for acute H 2S poisoning, we report here on a fatal case of acute hydrogen sulfide poi - soning, and serum concentrations of sulfide and thiosulfate before and after administration of hydroxocobalamin. This pa - tient committed suicide using H 2S made from two commercial products. Recently, H 2S created from mixing two commercial products has been used as a tool for suicide in Japan (7−9,12). Figure 2. Structural formula of hydroxocobalamin. We think that case reports can offer useful information on 120 Fujita.qxd:JATLynneTemplate 1/24/11 1:01 PM Page 3 Journal of Analytical Toxicology, Vol. 35, March 2011 scribed by Kage et al. (13,14). Sulfide was detected as bis(pentafluorobenzyl)sulfide. A serum sample (0.2 mL) was added to the mixture solution: 0.8 mL of 5 mM tetradecyl-dimethyl-benzyl ammonium chloride solution in oxygen-free water saturated with sodium tetraborate, 0.5 mL of 20 mM pentafluorobenzyl bromide (PFBBr) solution in ethyl acetate, and 2.0 mL of internal standard (IS) solution (10 μM 1,3,5-tribromobenzene (TBB) in ethyl acetate). The preparation was vortex mixed for 1 min, and about 0.1 g of potas - sium dihydrogen phosphate was added. The preparation was again vortex mixed for 10 s and centrifuged at 2500 rpm for Downloaded from https://academic.oup.com/jat/article/35/2/119/773132 by guest on 01 October 2021 10 min. An aliquot of the organic phase was injected onto a gas chromatograph – mass spectrometer (GC –MS). Thiosulfate was detected as bis(penta- fluorobenzyl)disulfide. A serum sample (0.2 mL) was added to the mixture solu - tion: 0.05 mL of 200 mM L-ascorbic acid solution, 0.05 mL of 5% sodium chlo - ride, and 0.5 mL of 20 mM PFBBr solu - tion in acetone. The preparation was vortex mixed for 1 min; 2.0 mL of 25 mM iodine solution in ethyl acetate and 0.5 mL of IS solution (40 μM TBB in Figure 3. Selected ion-monitoring chromatograms (SIM) of sulfide and thiosulfate in serum. Sulfide and ethyl acetate) were added.