Int J Legal Med DOI 10.1007/s00414-015-1156-8

CASE REPORT

Systemic inflammatory response due to chloroform intoxication—an uncommon complication A. Dettling & K. Stadler & C. Eisenbach & G. Skopp & H. T. Haffner

Received: 17 July 2014 / Accepted: 29 January 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Well-known adverse effects of chloroform are drowsiness, nausea, and liver damage. Two cases with an uncommon complication due to chloroform intoxication are presented. In the first case, a general physician, because of nausea and dyspnea, admitted a 34-year-old woman to hospital. She developed a toxic pulmonary edema requiring mechanical ventilation for a few days, and a systemic inflammatory response syndrome (SIRS) with elevated white blood cell counts, a moderate increase of C-reactive protein, and slightly elevated procalcitonin levels. There were inflammatory altered skin areas progressing to necrosis later on. However, bacteria could be detected neither in blood culture nor in urine. Traces of chloroform were determined from a blood sample, which was taken 8 h after admission. Later, the husband confessed to the police having injected her chloroform and put a kerchief soaked with chloroform over her nose and mouth. In the second case, a 50-year-old man ingested chloroform in a suicidal attempt. He was found unconscious in his house and referred to a hospital. In the following days, he developed SIRS without growth of bacteria in multiple blood

A. Dettling : G. Skopp : H. T. Haffner Institute of Forensic Medicine and Traffic Medicine, University Hospital, Heidelberg, Germany C. Eisenbach Department of Internal Medicine, University Hospital, Heidelberg, Germany K. Stadler Institute of Forensic Medicine, University Hospital, Munich, Germany A. Dettling (*) Institute of Legal Medicine and Traffic Medicine, University Hospital, Voss-Str. 2, 69115 Heidelberg, Germany e-mail: [email protected]

cultures. He died several days after admission due to multiorgan failure. SIRS in response to chloroform is a rare but severe complication clinically mimicking bacterial-induced sepsis. The mechanisms leading to systemic inflammation after chloroform intoxication are currently unclear. Possibly, chloroform and/or its derivates may interact with pattern recognition receptors and activate the same pro-inflammatory mediators (cytokines, interleukins, prostaglandins, leukotrienes) that cause SIRS in bacterial sepsis.

Keywords Chloroform . Injection . Ingestion . Systemic inflammatory response syndrome

Introduction Following its discovery in 1831, chloroform has been administered to patients as an anesthetic in 1848 for the first time [1]. It was not until the late 1970s that its use during surgery has been discontinued [2]. Exposure to chloroform produces a deep sleep and has a relatively minor impact on the respiratory center. Nevertheless, severe and life-threatening adverse effects have precluded its use in medicine. Exposure resulted in injury of the liver, cardiac arrhythmias [3], as well as in gastrointestinal disturbances such as nausea and vomiting [2]. A carcinogenic potential has been proven in animal experiments [4]. Today, chloroform is still used as a solvent in the laboratory and as a reagent in organic synthesis. Accidental, intentional, or even forced inhalation of chloroform has been reported in a few cases only, whereas incorporation as a liquid seems to be exceptional [5]. Two cases of systematic inflammatory response due to acute chloroform exposure by injection and ingestion are presented.

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Case reports The first victim was a 34-year-old woman. Her husband informed the medical emergency service after she manifested nausea, shortness of breath, and general debility. The emergency physician admitted her to the hospital. On arrival at the emergency room, she showed a mild hypotension (105/ 85 mmHg) with tachycardia (106/min). The blood pH was 7.2 and the base excess −10 in the venous blood. Rapidly, she developed a toxic lung edema requiring artificial respiration for several days. In the x-ray of the thorax, she showed changes compatible with lung edema soon after admission. Skin alterations were present at both elbows seemingly being reminiscent of sepsis, which progressed to necrosis during the following days. The ultrasound scan of the veins of the upper extremities showed thrombosis of both cubital veins. Leukocyte count increased up to 36,000/μl on the first day after admission; in addition, there was an increase of the Creactive protein and procalcitonin levels to maximum values of 116 mg/l and 0.37 ng/ml, respectively, on the fourth day. Nevertheless, bacteria could be detected neither in blood cultures nor in urine. The cultures covered all aerobic and anaerobic bacteria. Liver enzymes were increased already a few hours after the incidence (maximum values: AST 64 U/l, ALT 59 U/l, lactate dehydrogenase 427 U/l) and reached the maximum in-between the second to eighth day. In addition, an elevation of the creatine kinase up to 1700 U/l was seen on the fourth day, a decrease of Quick’s test to 65 %, and an elevation of the D-dimer up to 4.16 mU/l. All the other diagnostics showed normal findings. Headspace/gas chromatography confirmed chloroform being present in a blood sample, which was taken approximately 8 h after admission to hospital, and in a urine specimen, which was not otherwise specified. Both samples were taken as usual in a clinical setting without headspace sampling. Briefly, 1 g of anhydrous sodium sulfate was added to 1 ml of blood or urine in a glass vial made airtight with a crimped-on rubber stopper. Gas chromatography/head space analysis (Clarus 500, PerkinElmer, Rodgau, Germany) was performed following separation of the vapor by a widebore capillary column (DB-1701, 60 m×0.32 mm inner diameter, 1 μm film thickness, Agilent, Waldbronn, Germany); volatiles were detected using a flame ionization detector. The lower limits of detection and quantitation were 0.3 and 1.0 μg chloroform/ml blood or urine, respectively; peaks were amounting to the lower limit of quantitation in both body fluids. Amitriptyline (161 ng/ml), nortriptyline (132 ng/ml), and diphenhydramine (>2400 ng/ml, above the upper limit of detection) were determined from urine following a general unknown screening and subsequent quantitation of both compounds by in-house methods using liquid chromatography/ tandem mass spectrometry and gas chromatography/mass spectrometry, respectively. Amitriptyline, nortriptyline, and diphenhydramine were not detectable in the blood specimen

at detection limits of 2 and 5 ng/ml, respectively. Later on, when the police saw him, the husband confessed that he had soaked a kerchief with chloroform, put it on his wife’s mouth and nose, and injected her chloroform into both elbows. The woman recovered from the Bchemical^ attack. In the second case, a 50-year-old man ingested a larger quantity of chloroform in his residence in a suicidal attempt. He was still responsive at arrival of the emergency physician and told them that he drunk about 1 l of chloroform he had at his home. Resuscitation was afforded upon admission to the hospital, where he developed a systemic inflammatory response syndrome (SIRS). During hospitalization, leukocyte counts increased up to 37,000/μl on the eleventh day, Creactive protein and procalcitonin levels increased to maximum values of 145 mg/land 5.46 ng/ml, respectively on the fifth and tenth day. As experienced in the first case, blood cultures and urine tested negative for bacteria. In this case, cultures covered aerobic and anaerobic bacteria just like in the first case. A few hours after admission, liver enzyme activities significantly increased and reached maximum levels on the third day (maximum values: AST 9775 U/l, ALT 3900 U/l, gamma-GT 84 U/l, lactate dehydrogenase 5340 U/l). The levels of carbon monoxide-hemoglobin elevated up to 2.4 %, while methemoglobin levels adhered the normal range. He died a few days following hospitalization due to multi-organ failure. His medical history revealed alcohol misuse, hemiparalysis due to cerebral stroke, and dissection of the arteria carotis interna as well as epilepsia. A death investigation has not been performed. Unfortunately, blood and urine specimens had not been submitted to toxicological analyses.

Discussion Although chloroform is not any longer used as an anesthetic agent, it is still available as a solvent or chemical intermediate. As a result, poisoning due to chloroform has been reported from time to time in suicide [1, 6–8] as well as in homicide cases [9–11]. Exposure occurs preferably to chloroform vapor promoting its rapid absorption into blood and distribution into fatty tissue where it tends to accumulate. According to some few reports, chloroform is also rapidly absorbed and distributed to adipose tissue following administration by the oral route [12–16]. However, the potentially lethal dose of orally administered chloroform is significantly higher, and adverse effects are delayed compared to inspiration [9]. According to literature, oral doses of as little as 10 ml of chloroform resulted in fatal poisoning [2]. An intravenous application can be considered as exceptional. There are some 1909 case reports and the report of Rao et al. [8] where intravenously administered chloroform in patients undergoing anesthesia exhibited similar effects compared to inhalation [8, 17].

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About 18–67 % of a single dose of chloroform is eliminated unchanged in the expired air. The absorbed quantity undergoes considerable biotransformation in man; major products are carbon dioxide and hydrochloric acid. During surgery, average concentrations of chloroform in brain, lungs, and liver of 126, 100, and 64 mg/kg, respectively, have been determined from death cases unrelated to chloroform’s toxicity [2]. During anesthesia, blood concentrations of the anesthetic agent ranged from 20 to 232 mg/l [9]. In the presented first case, only traces of chloroform were detectable. The short elimination half-life (1.5 h in man) and the sampling of blood a few hours following admission to the hospital into a suboptimal vial are a likely explanation for this finding. Chloroform has not been determined from the second case; however, unequivocal evidence was given that the deceased had ingested chloroform. Acute hepatotoxic reactions have been described in literature following ingestion of chloroform during a suicidal attempt [18]. In similar cases, liver damage occurred within 2 to 5 h after acute exposure to chloroform [2]. This is in line with respective findings in both presented cases where abnormal liver enzyme activities could be noticed a few hours following injection or ingestion of the solvent. In addition, acute poisoning produced local inflammatory reactions [19]; furthermore, exposure caused moderate submucosal hemorrhage of the trachea and esophagus [20] as well as edema of the lips, lungs, and brain [11]. In these cases, the concentration of chloroform in blood ranged from 5 to 115 μg/ml. Edema of the lungs may result from a systemic inflammatory response. Complications with regard to pulmonary function such as the adult respiratory distress syndrome have been related to sepsis [21]. There are only few cases describing a SIRS in combination with an exogenous intoxication. Gergely et al. [22] reported a SIRS in rats after treatment with carbon tetrachloride. In addition, Lovas et al. [23] described a case of amphetamine intoxication with an extreme elevation of procalcitonin without bacterial infection. SIRS appears to be a rare, yet harmful condition, which obviously can be associated to chloroform intoxication for the first time. Currently, no case report has been published describing coincidence of chloroform poisoning and SIRS. Usually, bacteria, parts of them, or their toxins cause sepsis. The type of organism causing sepsis, its load and virulence, as well as the patient’s precondition, coexisting illnesses, and genetic characteristics are important determinants of the outcome. The response is initiated by interaction between different receptor types that recognize pathogen-associated molecular patterns, resulting in an up-regulation of immune responses [21]. The pathogenesis of sepsis involves complex interactions including cytokines, reactive oxygen, and nitrogen species as well as eicosanoids [24]. The lipid A part of lipopolysaccharide is considered the most potent microbial mediator of the

pathogenesis of clinical features such as hypotension and edema [24]. The intricate pathogenesis of sepsis and the symptoms in both cases strongly indicating toward a clinical manifestation of sepsis suggest chloroform as a triggering agent. It may be a subject of debate whether chloroform or its degradation products interact with pattern recognition receptors activating the same pro-inflammatory responses such as interleukins cytokines, prostaglandins, or leukotrienes, which cause SIRS in bacterial sepsis. It is well-known that trichloromethanol and phosgene are formed from chloroform besides carbon dioxide and hydrochloric acid [25, 26]. Fawell [26] suggested that phosgene might react with cysteine or glutathione. Depletion of glutathione may give rise to the activation of systemic inflammatory responses. On the other hand, the recognition pattern of bacteria or their toxins largely differ, and the progress of sepsis is not restricted to specific molecular patterns. Consequently, chloroform or its degradation products may trigger the immunological response by themselves. Although the underlying mechanisms of chloroform toxicity are not yet clear, it should be kept in mind that chloroform intoxication is able to precipitate harmful complications such as SIRS. Considering the coincidence of chloroform poisoning and SIRS in the two presented cases, it may be speculated whether this complication occurs more often and causes lethal effects of chloroform intoxication.

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Int J Legal Med 12. Moffat AC, Jackson JV, Moss MS, Widdop B (1986) Clarke’s isolation and identification of drugs, 2nd edn. The Pharmaceutical Press, London, pp 450–451 13. Dell'Aglio D, Sutter M, Schwartz M, Koch D, Algren D, Morgan B (2010) Acute chloroform ingestion successfully treated with intravenously administered N-acetylcysteine. J Med Toxicol 6:143–146 14. Hakim A, Jain AK, Jan R (1992) Chloroform ingestion causing toxic hepatitis. J Assoc Physicians India 40:477 15. Choi SH, Lee SW, Hong YS, Kim SJ, Moon SW, Moon JD (2006) Diagnostic radiopacity and hepatotoxicity following chloroform ingestion: a case report. Emerg Med J 23:394–395 16. Boyer E, Larson SC, Perrone J, De Roos F (1998) Limited hepatotoxicity following a massive chloroform ingestion treated with oral N-acetyl-cysteine. J Toxicol Clin Toxicol 36:440 17. Burkhardt L (1909) Über Chloroform- und Äthernarkose durch intravenöse Injektion. Arch Exp Pathol Pharmacol 61:323–342 18. Kim H (2008) A case of acute toxic hepatitis after suicidal chloroform and dichloromethane ingestion. Am J Emerg Med 26:1073.e3–1073.e6 19. Ago M, Hayashi T, Ago K, Ogata M (2011) Two fatalities associated with chloroform inhalation. Variation of toxicological and pathological findings. Legal Med 13:156–160

20. Harada K, Ichiyama T, Ikeda H, Ishihara T, Yoshida K (1997) An autopsy case of acute chloroform intoxication after intermittent inhalation for years. Jpn J Legal Med 51:319–323 21. Angus DC, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med 369:840–851 22. Gergely J, Sipka S, Csipo J, Udvardy M, Szegedi GY, Kulcsar A (1997) Systemic inflammatory response syndrome (SIRS) induced by carbon tetrachloride in rats. Mediat Inflamm 6:73–74 23. Lovas A, Agoston Z, Kesmarky K, Hankovszky P, Molnar Z (2014) Extreme procalcitonin elevation without proven bacterial infection related to amphetamine abuse. Case Rep Crit Care 1–3 24. Tunctan B, Korkmaz B, Sari AN, Kacan M, Unsal D, Serin MS, Buharalioglu CK, Sahan-Firat S, Schunck WH, Falck JR, Malik KU (2012) A novel treatment strategy for sepsis and septic shock based on the interactions between prostanoids, nitric oxide, and 20hydroxyeisosatetraenoic acid. Antiinflamm Antiallergy Agents Med Chem 11:121–150 25. Van Dyke RA, Chenoweth MB (1965) Metabolism of volatile anesthetics. Anesthesiology 26:348–357 26. Fawell J (2000) Risk assessment case study—chloroform and related substances. Food Chem Toxicol 38:S91–S95

Systemic inflammatory response due to chloroform intoxication--an uncommon complication.

Well-known adverse effects of chloroform are drowsiness, nausea, and liver damage. Two cases with an uncommon complication due to chloroform intoxicat...
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