Research poisoning and treatment with in the Australian Capital Territory and New South Wales

Darren M Roberts manita phalloides (“deathcap” Abstract PhD, FRACP, Clinical Toxicology Fellow1 or “whitecap”) is a cyclopep- Objectives: To report the frequency and clinical outcomes of Amanita phalloides A tide variety of mushroom poisoning in the Australian Capital Territory and New South Wales, and the Michael J Hall FACEM, that is responsible for more than 90% treatments used (including silibinin). Clinical Director, of mushroom-related fatalities; one Design, setting and patients: Retrospective case series of patients admitted to Department of Emergency Medicine2 mushroom cap can cause fulminant public hospitals in Canberra and Sydney for suspected A. phalloides poisoning hepatic failure and death in an adult.1 between 1999 and 2012 (identified from hospital records and calls to the New Morna M Falkland South Wales Poisons Information Centre). BPharm, Most reported A. phalloides poison- Senior Pharmacist, ings occur in . In , Main outcome measures: Frequency of poisoning and the clinical outcomes. Medicines Information Centre2 most occur in Canberra as A. phal- Results: Twelve patients presented with a history suggesting A. phalloides loides grows in the Australian Capital poisoning, 10 with probable poisoning and two with possible poisoning. Eight of Simone I Strasser those with probable poisoning developed significant hepatotoxicity and four MD, FRACP, Territory, particularly in the older died. Silibinin was administered to nine of those with probable poisoning (the Clinical Associate Professor suburbs of Canberra (which has been and Hepatologist3 other presented before 2005). Maintaining silibinin supply became a challenge attributed to imported oak trees). during two clusters of poisoning. Eight of the patients with probable poisoning Nick A Buckley Cases have also been reported in MD, FRACP, were not long-term residents of the ACT, and six were immigrants from . 1 Clinical Toxicologist, and Victoria. Public health campaigns are Conclusions: The mortality rate due to A. phalloides poisoning in this case series Professor4 commonplace in the ACT in summer was high despite treatment according to current standards, including use of and autumn (“mushroom season”). silibinin, and the frequency of hepatotoxicity was more than double that for the 1 New South Wales Poisons Amatoxin is the most potent hepa- previous decade. Ongoing public health campaigns are required. Information Centre, Children’s Hospital at totoxin in cyclopeptide mushrooms; Westmead, Sydney, NSW. it irreversibly binds to RNA polymer- action and some supporting evidence poisoning who were treated at pub- 2 Canberra Hospital, 1 Canberra, ACT. ase II, causing hepatic necrosis. The from animal studies, and silibinin is lic hospitals in Canberra and the 3 Australian National clinical features of A. phalloides poi- regarded as the standard of care in Australian National Liver Trans- Transplantation Unit, Royal soning are well described (Box 1). Europe. In 2010, the silibinin stock plantation Unit at Royal Prince Prince Alfred Hospital, Sydney, NSW. The most recent report of A. phal- level at Canberra Hospital was Alfred Hospital between January 4 Professorial Medicine loides poisonings in Australia was increased so that there was sufficient 1999 and May 2012. Patients were Unit, Prince of Wales Hospital, University of New from the ACT over 10 years ago, stock to treat two patients and, in identified from clinical databases in South Wales, Sydney, NSW. describing seven poisonings that Sydney, Royal Prince Alfred Hospital departments of emergency medicine [email protected] occurred between 1988 and 1998.5 also stocked it. and clinical toxicology in the ACT Since then, a chemically modified Here, we review cases of A. phal- and from call records of the New MJA 2013; 198: 43–47 derivative of silibinin (silibinin-C- loides poisoning that occurred in the South Wales Poisons Information doi: 10.5694/mja12.11180 2',3-dihydrogen succinate, disodium ACT and New South Wales between Centre. A diagnosis of A. phalloides salt [Legalon SIL, Madaus], referred 1999 and 2012, including patients poisoning was suspected on the to hereafter as silibinin) — a pur- treated with silibinin. basis of a history of mushroom ported antidote to A. phalloides poi- ingestion and subsequent delayed soning that is derived from the milk Methods onset of gastroenteritis and hepati- — has been tis; blood tests confirming the pres- stocked by hospitals in the ACT. In We reviewed the clinical records of ence of amatoxin are not available in 2005, Canberra Hospital imported patients with possible A. phalloides Australia. The Medical Journalsilibinin of Australia for use ISSN: as 0025-an antidote 729X 21 Januarythrough 2013 198 the 1 43-47Special Access Scheme ©The Medicalof Journal the Therapeutic of Australia Goods 2013 Adminis- 1 Clinical features of acute Amanita phalloides poisoning1-4 www.mja.com.autration because it is not registered Research 0 to 6–18 hours after ingestion: Asymptomatic for use in Australia. Sufficient stock 6–24 hours after ingestion: Gastroenteritis, including abdominal pain, nausea, vomiting, was purchased to treat one patient diffuse diarrhoea, dehydration with or without hypotension, metabolic acidosis and for at least 96 hours at a dosage of electrolyte disturbance; normal or mildly deranged renal function and levels of hepatic 20 mg/kg/24 h, given in 6-hourly enzymes doses. This decision was made 1–7 days after ingestion: Resolving gastrointestinal symptoms, but progressive hepatic (despite a lack of good-quality evi- failure, coagulopathy, kidney injury (including hepatorenal syndrome); possible progression to dence of efficacy) because there was multisystem organ failure and a 10%–30% mortality rate no approved treatment in Australia, > 7 days after ingestion: Complete resolution of symptoms occurs in most survivors over weeks or months; chronic hepatitis may persist ◆ there was a plausible mechanism of

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2 Patients with a history suggesting Amanita phalloides poisoning, Australian Capital Teritory and New South Wales, 1999–2012*

No. of Peak abnormal results mushrooms Onset of of renal and liver Predicted Patient ingested symptoms function tests Treatment to die† Outcome A 1 8.5 h Cr, 137 mol/L; ALT, IV fluids, analgesia, antiemetics, MDAC, NAC, No Survived, no sequelae 7814 U/L; INR, 3.4; La, penicillin, silibinin (36 h after ingestion) then 4.6 mmol/L silymarin, ICU admission, care by liver transplantation unit B 10 9 h Cr, 192 mol/L; ALT, IV fluids, penicillin, silibinin (23 h after ingestion) No Died 6 days after ingestion 3914 U/L; INR, 2.2; La, then silymarin, ICU admission, care by liver (shock, acute abdomen and 16 mmol/L transplantation unit cerebral oedema; hepatic failure was resolving) C 1 8.5 h Cr, 98 mol/L; ALT, IV fluids, antiemetics, analgesia, MDAC, NAC, No Survived, no sequelae 4913 U/L; INR, 1.7; La, penicillin, silibinin (46 h after ingestion) 1.6 mmol/L D211hCr, 88mol/L; ALT, IV fluids, penicillin, silibinin (21 h after ingestion), No Survived 3701 U/L; INR, 1.7; La, cimetidine, antibiotics and antifungal, care by liver 2.3 mmol/L transplantation unit E Unclear, 25 h after first Cr, 73 mol/L; ALT, IV fluids, MDAC, acetylcysteine, silibinin (31 h after No Survived, persistent but various meal; 9 h after 7067 U/L; INR, 2.6; La, second meal), ICU admission, care by liver asymptomatic hepatitis at last mushrooms second meal 4.4 mmol/L transplantation unit review (5 days after ingestion) ingested in two meals F Unclear; 10 h Cr, 179 mol/L; ALT, IV fluids, NAC, MDAC, silibinin (19 h after No (died Died 2.5 days after ingestion, perhaps 8–10 7253 U/L; INR, 8.4; La, ingestion), ICU admission, care by liver early) fulminant hepatic failure and 18 mmol/L transplantation unit, plasma products lactic acidosis G Unclear Unknown; had Cr, 232 mol/L; ALT, IV fluids, then heparin and interhospital transfer for Yes Died 4 days after suspected time symptoms for 3793 U/L; INR, 12.6; La, investigation and treatment of an ischaemic foot of ingestion, fulminant hepatic 48 h before 13.4 mmol/L that resolved without other intervention‡ failure and lactic acidosis presentation H Unclear; 10 h Cr, 119 mol/L; ALT, IV fluids, NAC, MDAC, silibinin (19 h after Yes (based Died 3 days after ingestion, perhaps 8–10 7511 U/L; INR, >12; La, ingestion), ICU admission, care by liver on terminal fulminant hepatic failure and 22 mmol/L transplantation unit, plasma products blood test lactic acidosis results) I Unclear 14 h Cr, 77 mol/L; ALT, IV fluids, MDAC, NAC, silibinin (23 h after No Survived, no sequelae 63 U/L; INR, 1.0; La, ingestion), ICU admission 1.3 mmol/L J 510hCr, 111mol/L; ALT, IV fluids, MDAC, NAC, silibinin (33 h after No Survived 52U/L; INR, 1.1; La, ingestion), ICU admission 1.5 mmol/L K Part of a 12 h Urea and ALT levels Observed for 4 h, no follow-up No Survived mushroom mildly elevated L 1 6 h (very mild) No changes Observed overnight, no progression of symptoms No Survived

ALT= serum alanine aminotransferase (reference interval, < 55 U/L). Cr = serum creatinine (reference interval, 60–110 mol/L). ICU = intensive care unit. INR = international normalised ratio (reference interval, 0.8–1.2). IV = intravenous. La = blood lactate (reference interval, < 2.5 mmol/L). MDAC = multiple doses of activated charcoal. NAC = acetylcysteine. * Poisoning was probable in Patients A–J (clinical or mycological features confirmed that A. phalloides had been ingested) and possible in Patients K and L (very mild symptoms and non-significant biochemical changes). † Based on prognostication tools. ‡ Patient G presented before 2005, so did not receive silibinin. ◆

De-identified demographic, clini- criteria is variable (sensitivity 1.0 and pital (Box 2). The median age of the cal and treatment data were specificity 0.98 in a study of 198 patients was 36 years (interquartile 8 extracted and two prognostic tools patients; sensitivity 0.75 and specifi- range, 27–51 years; range, 2–88 2 for predicting death (or liver trans- city 0.90 in a study of 27 patients; years) and eight patients were male. ) due to acute A. phalloides poi- sensitivity 0.57 and specificity 1.0 in a Eight of those with probable poison- study of 10 patients6). soning were considered. ing (based on clinical and mycologi- • Onset of diarrhoea < 8 hours after Ethics approval cal features) were not long-term mushroom ingestion or INR у 6 on residents of the ACT and seven were This study was approved by the Day 4. These criteria are supported immigrants (six from Asia, one from Human Research Ethics Committees by a study of 27 patients (sensitivity Europe). of ACT Health, Calvary Health Care 1.0 and specificity 0.68 for diarrhoea; All the patients had ingested wild sensitivity 1.0 and specificity 1.0 for ACT, Royal Prince Alfred Hospital and mushrooms. One had presented to a INR)2 and a study of 10 patients the Children’s Hospital at Westmead. (sensitivity 1.0 and specificity 1.0 for Sydney hospital after picking mush- diarrhoea; sensitivity 0.71 and speci- rooms in Canberra, transporting ficity 1.0 for INR),6 but they have Results them home and then incorporating been criticised because the support- them into a meal. Two had consumed ing studies classified liver transplant Over the 12-year study period, 12 mushrooms for recreational purposes recipients as deaths in their analysis.7 patients presented with a history after they had been misidentified as a • INR у 2.5 and serum creatinine suggesting A. phalloides poisoning; hallucinogenic variety. Another had level > 106 mol/L from Day 3. The they all developed clinical features of consumed mushrooms believed to be reported predictive utility of these poisoning and were admitted to hos- A. phalloides (based on information in

44 MJA 198 (1) · 21 January 2013 Research

public health campaigns) for self- venous penicillin (given in high 3 Temporal changes in INR, serum ALT levels and blood poisoning. doses [0.25–1.0 million units/kg/ lactate levels in patients with probable Amanita phalloides Two patients had very mild symp- day]). Patients also received multiple poisoning toms and non-significant biochemi- doses of activated charcoal (50 grams Survived (n=5) cal changes, so A. phalloides 6-hourly by enteral administration). Died; no plasma products given (n=2) poisoning was considered possible. Maintaining a supply of silibinin Died; plasma products given (n=2)* The other 10 had probable A. phal- to treat patients was a challenge due loides poisoning owing to marked to the clustering of events. Of the 10 14 † symptoms and the characteristics of probable poisonings, nine occurred 12 the ingested mushroom; eight devel- over the last 4 years of the study oped significant hepatotoxicity period. In six of these cases, the 10 (alanine aminotransferase [ALT] level patients presented on a public holi- 8 more than 10 times the upper limit of day (New Year’s Day) — two on one the reference interval) and seven occasion and four on another. Addi- INR 6 were admitted to an intensive care tional stock was urgently required 4 unit. One patient presented to hospi- for the cluster of four patients, tal after 48 hours of gastroenteritis which required close communica- 2 but the history of mushroom inges- tion with pharmacy, clinical toxicol- 0 tion was not noted until about 4 ogy and liver transplant centre 12345678 hours before she died. Six patients colleagues in other states, and with 10 000 Survived (n=5) were transferred from the ACT to the the importing company (which Died (n=4) Australian National Liver Transplan- promptly mobilised sufficient stock). 8000 tation Unit in Sydney. Four of the However, one of only three hospitals patients with probable A. phalloides that stocked silibinin during the 6000 poisoning died. study period is in South Australia, Temporal changes in INR, serum but this was not known by anyone 4000 † ALT (U/L) ALT ALT levels and blood lactate levels within the Poisons Information Cen- are shown in Box 3. In most patients, tre network when treatment for the 2000 marked changes in INR and ALT cluster of four patients was urgently levels did not occur until at least 24 being sought. 0 hours after mushroom ingestion. In From our experience, elevated INR 12345678 and blood lactate levels appeared to two of the patients who died rapidly, 25 the rate of increase of INR was more be the best prognostic markers. Survived (n=5) Other prognostic tools (listed in the Died (n=4) marked compared with that in survi- 20 vors, but the same was not observed Methods) did not provide useful with ALT levels. The rate of increase advance warning of death — they 15 in blood lactate levels was also more met criteria only within several † marked in patients who died com- hours of death in the four patients 10 pared with those who survived. The who died. One death is notable onset of increased INR and ALT lev- because the INR values and ALT (mmol/L) Lactate 5 els appears to have been delayed for levels suggested resolution of one of the patients who died and had hepatic injury, but the patient had 0 not received silibinin (Patient G); progressive severe metabolic acido- 12345678 however, the time of mushroom sis and hypoalbuminaemia and, 6 Number of days since ingestion by this patient was impre- days after mushroom ingestion, ingestion of mushrooms cisely documented. developed an acute abdomen and subsequently died of cerebral ALT = alanine aminotransferase. INR = international normalised ratio. Multiple therapies were adminis- * Change from solid blue line to dashed blue line indicates start of tered, including silibinin to all but oedema. The three patients who treatment with plasma products. † Time of ingestion unclear, so times are estimates. ◆ one patient with probable A. phal- died rapidly with hepatic failure also loides poisoning. Silibinin supply was had very severe lactic acidosis (Box exhausted during the treatment of 3). Severe gastrointestinal tract tox- one patient, who was subsequently icity may be a significant contribu- Discussion given oral silymarin (Legalon tory cause of death and may 9 [140 mg silymarin capsules], complicate liver transplantation. This case series shows that A. phal- Madaus; a standardised extract of Toxicity progressed rapidly in two loides poisoning is an ongoing public milk thistle seeds that contains sili- patients who were thought to have health concern. It is also the first binin). Other purported antidotes ingested the largest doses (about 8– report of silibinin use in Australia for that were administered included 10 mushrooms). Because of the small A. phalloides poisoning. Despite intravenous acetylcysteine (given number of patients, it was not poss- availability of silibinin, multiple according to dosing guidelines for ible to explore the effectiveness of ingestions from 2000 to 2012 led to paracetamol poisoning) and intra- treatments. severe poisoning, including four

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deaths. Compared with data from transplantation should be delayed A blood test that detects amatoxin the previous decade,5 the number of until at least 2–4 days after poisoning would be useful to confirm exposures patients with hepatotoxicity more to allow elimination of amatoxin to for epidemiological purposes. If rap- than doubled and the number of prevent graft poisoning.12 Early pre- idly available, a quantitative assay deaths quadrupled. However, the dictors of severe poisoning (but not might assist existing prognostic tests, events were clustered and sporadic. necessarily death) may also help although more research is first People who do not reside in the ACT decision making regarding transfer to required to guide interpretation of appear to be at higher risk, as do specialised liver units. these results — for example, to immigrants (six victims had recently Multiple antidotes are currently develop a nomogram for risk stratifi- arrived from Asia, where consump- used to treat patients with A. phal- cation, similar to the approach used tion of wild mushrooms is common- loides poisoning.1,10 The evidence of for paracetamol poisoning. An ama- place, and had limited English efficacy is limited for all treatments, toxin assay may also be useful for language skills). Those who consume largely due to the difficulties associ- determining when the blood concen- mushrooms for recreational purposes ated with human studies of an infre- tration of amatoxin is sufficiently low may also be vulnerable. quent and sporadic type of poisoning. in an individual patient to allow liver Ongoing review of public health Two analyses of observational studies transplantation to proceed, when campaigns and existing treatment in human poisonings have supported required, without subsequent poi- protocols is occurring and appears to the role of silibinin and acetyl- soning of the graft. be warranted. However, increased cysteine;10,13 however, positive find- Management is controversial in awareness of the toxicity of A. phal- ings are limited by potential patients who present early after loides may have the counter-effect of publication bias.10,13 None of the ingestion of mushrooms that may be prompting its use for self-harm, treatments have been subjected to A. phalloides but do not have clinical which is concerning given the low dose–response or controlled trials in features of significant poisoning. We efficacy of existing treatments. humans. Many animal studies are of identified two such patients with The approach to treating patients limited clinical relevance because favourable outcomes (although A. with suspected A. phalloides poison- treatments are not delayed. Further, phalloides ingestion was not con- ing includes prompt consideration of in-vitro studies have demonstrated firmed). In such cases, the risk of A. the diagnosis and identification of effects of benzylpenicillin, acetyl- phalloides ingestion should be clari- the mushroom if a fresh specimen or cysteine and silibinin in human cul- fied by consulting a mycologist and/ a sample of gastric contents is avail- tured hepatocytes,14-16 but not canine or conducting a Meixner test. Early able. This requires liaison with a hepatocytes.17 A study in pigs demon- intervention, including decontami- mycologist and performance of the strated no beneficial effects of sili- nation and antidotes, should be con- Meixner test. The Meixner test is binin, acetylcysteine, benzylpenicillin, sidered after consulting a Poisons conducted by adding hydrochloric cimetidine or thioctic acid adminis- Information Centre. acid to a sample of mushroom placed tered 4 hours after poisoning.18 In our Clinical trials on antidotes for A. on newspaper; a blue colour change case series, four out of 10 patients phalloides poisoning would be suggests the presence of amatoxin, with clinically significant poisoning extremely helpful as there are no although false positive results have died, despite the use of intravenous treatments with good evidence, and been reported.1 Treatment includes silibinin and other treatments in nine there may be as yet unknown but supportive care and gastrointestinal of them. The optimal doses and tim- cheaper and more widely available decontamination, and antidote use ing of antidotes, and the range of alternatives to silibinin. An observa- should be considered.10 Fluid resus- amatoxin ingestion for which anti- tional study of silibinin (Clinical- citation is required during the gas- dotes are effective, are unknown. Trials.gov Identifier, NCT00915681) troenteritis phase to restore Despite these limitations, silibinin is underway, but no randomised con- haemodynamic stability and main- continues to be imported into Aus- trolled trials are currently registered tain renal perfusion. Amatoxin is tralia and is widely used elsewhere. and most guidelines follow the subject to enterohepatic recircula- Decisions regarding stock holdings accepted standard practice in Europe. tion, so multiple doses of activated of silibinin require consideration of A. phalloides poisoning is a public charcoal should be given to limit cost (about $1400/day/patient), stock health problem in Australia, particu- reabsorption. Nasobiliary drainage expiration, and time to obtain larly the ACT, and the mortality rate has also been employed to reduce replacement or additional stock is potentially high. Based on cur- enterohepatic recirculation.11 Extra- (potentially long, as it is not mar- rently available data, we recommend corporeal treatments have been tri- keted in Australia). Our experience treatment with supportive care, mul- alled, but efficacy is inadequately suggests that Poisons Information tiple doses of activated charcoal, quantified. Centre knowledge of silibinin stocks, intravenous silibinin, and acetyl- Electrolyte abnormalities should and rapid communication with the cysteine, as well as consideration of be corrected, and liver enzyme levels, distributor and hospitals is required. liver transplantation. INR, and lactate levels should be A coordinated national approach (eg, Acknowledgements: We thank Emily Diprose for helpful monitored for prognosticative pur- a national inventory of antidotes) comments on this article. poses. Indications for liver transplan- may be useful given that A. phalloides Competing interests: No relevant disclosures. tation are debated. Where possible, poisoning is not limited to the ACT. Received 26 Jul 2012, accepted 3 Dec 2012.

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1 Berger KJ, Guss DA. Mycotoxins revisited: part I. amatoxin poisoning: some critical comments. multivariate statistic analysis. Toxicon 2010; 55: J Emerg Med 2005; 28: 53-62. J Hepatol 2007; 47: 424-425. 1338-1345. 2 Escudié L, Francoz C, Vinel JP, et al. Amanita 8 Ganzert M, Felgenhauer N, Zilker T. Indication of 14 Magdalan J, Piotrowska A, Gomulkiewicz A, et phalloides poisoning: reassessment of liver transplantation following amatoxin al. Benzylpenicyllin and acetylcysteine prognostic factors and indications for intoxication. J Hepatol 2005; 42: 202-209. protection from -amanitin-induced apoptosis emergency liver transplantation. J Hepatol 9 Pinson CW, Daya MR, Benner KG, et al. Liver in human hepatocyte cultures. Exp Toxicol 2007; 46: 466-473. transplantation for severe Amanita phalloides Pathol 2011; 63: 311-315. 3 Giannini L, Vannacci A, Missanelli A, et al. mushroom poisoning. Am J Surg 1990; 159: 15 Magdalan J, Ostrowska A, Piotrowska A, et al. Amatoxin poisoning: a 15-year retrospective 493-499. Benzylpenicillin, acetylcysteine and silibinin as antidotes in human hepatocytes intoxicated analysis and follow-up evaluation of 105 10 Enjalbert F, Rapior S, Nouguier-Soulé J, et al. with alpha-amanitin. Exp Toxicol Pathol 2010; patients. Clin Toxicol (Phila) 2007; 45: 539-542. Treatment of amatoxin poisoning: 20-year 62: 367-373. 4 Krenová M, Pelclová D. Potential hepatotoxic retrospective analysis. J Tox icol Clin Toxicol 2002; and nephrotoxic substances reported to the 40: 715-757. 16 Magdalan J, Piotrowska A, Gomulkiewicz A, et Czech Toxicological Information Centre in the al. Influence of commonly used clinical 11 Madhok M, Scalzo AJ, Blume CM, et al. Amanita antidotes on antioxidant systems in human past 3 years. J Toxicol Clin Toxicol 2004; 42: 498. bisporigera ingestion: mistaken identity, dose- hepatocyte culture intoxicated with alpha- 5 Trim GM, Lepp H, Hall MJ, et al. Poisoning by related toxicity, and improvement despite amanitin. Hum Exp Toxicol 2011; 30: 38-43. Amanita phalloides (“deathcap”) mushrooms in severe hepatotoxicity. Pediatr Emerg Care 2006; 17 Magdalan J, Ostrowska A, Piotrowska A, et al. the Australian Capital Territory. Med J Aust 1999; 22: 177-180. Failure of benzylpenicillin, N-acetylcysteine and 171: 247-249. 12 Jaeger A, Jehl F, Flesch F, et al. Kinetics of silibinin to reduce alpha-amanitin 6 Ferreira R, Romãozinho JM, Amaro P, et al. amatoxins in human poisoning: therapeutic hepatotoxicity. In Vivo 2009; 23: 393-399. Assessment of emergency liver transplantation implications. J Tox icol Clin Toxico l 1993; 31: 18 Tong TC, Hernandez M, Richardson WH 3rd, et criteria in acute liver failure due to Amanita 63-80. al. Comparative treatment of alpha-amanitin phalloides. Eur J Gastroenterol Hepatol 2011; 23: 13 Poucheret P, Fons F, Doré JC, et al. Amatoxin poisoning with N-acetylcysteine, 1226-1232. poisoning treatment decision-making: benzylpenicillin, cimetidine, thioctic acid, and 7 Ganzert M, Felgenhauer N, Zilker T. pharmaco-therapeutic clinical strategy silybin in a murine model. Ann Emerg Med 2007; Reassessment of predictors of fatal outcome in assessment using multidimensional 50: 282-288. ❏

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