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Home , Coprine, Gyromitrin, Mushroom poisoning, Tricholoma equestre

Syndromic diagnosis and management of confirmed

James H. Diaz, MD, DrPH, FCCM

Objective: To assess the evolving global epidemiology of early syndromes (four neurotoxic, two gastrointestinal, two aller- mushroom and to identify new and emerging mush- gic); three late syndromes (hepatotoxic, accelerated nephrotoxic, room poisonings and their treatments, a descriptive analysis and ); and three delayed syndromes (delayed nephro- review of the world’s salient scientific literature on mushroom toxic, delayed neurotoxic, ). Four new was conducted. poisoning syndromes were classified including accelerated neph- Data Source: Data sources from observation studies conducted rotoxicity ( proxima, Amanita smithiana), rhabdomyolysis over the period 1959–2002, and describing 28,018 mushroom ( equestre, subnigricans), erythromelalgia poisonings since 1951, were collected from case reports, case ( amoenolens, Clitocybe acromelalgia), and delayed neu- series, regional descriptive studies, meta-analyses, and labora- rotoxicity (Hapalopilus rutilans). In addition, data sources were tory studies of mushroom poisonings and the toxicokinetics of stratified by three chronological time periods with >1,000 con- . firmed mushroom ingestions reported and tested for any statis- Study Selection: Studies included in the review were selected tically significant secular trends in case fatalities from mushroom by a MEDLINE search, 1966–2004, an Ovid OLDMEDLINE search, ingestions over the entire study period, 1951–2002. 1951–1965, and a medical library search for sources published Conclusions: Since the 1950s, reports of severe and fatal before 1951. mushroom poisonings have increased worldwide. Clinicians must Data Extraction: To better guide clinicians in establishing consider mushroom poisoning in the evaluation of all patients diagnoses and implementing therapies, despite confusing inges- who may be intoxicated by natural substances. Since information tion histories, data were extracted to permit an expanded syn- on natural exposures is often insufficient and incorrect, a new dromic classification of mushroom poisoning based on presenta- syndromic classification of mushroom poisoning is recommended tion timing and target organ systemic . to guide clinicians in making earlier diagnoses, especially in Data Synthesis: The final 14 major syndromes of mushroom cases where only advanced critical care, including organ trans- poisoning were stratified first by presentation timing and then by plantation, may be life saving. (Crit Care Med 2005; 33:427–436) target organ systemic toxicity and included early (<6 hrs), late KEY WORDS: mushrooms, poisonous; fungi, poisonous; - (6–24 hrs), and delayed syndromes (>1 day). There were eight ing, food

EARLY-ONSET TOXICITY Amanita (A. muscaria [Fly erases, and its peripheral cholinergic effects (<6 HRS) Amanita], A. pantherina [Panther often last for several hours following inges- Amanita]) contain limited quantities of tion of raw or cooked -contain- Peripheral Cholinergic muscarine, only Clitocybe (Funnel ing mushrooms. Caps) and mushrooms contain Since significant toxicity and fatalities enough muscarine to cause an acute are uncommon, the treatment of musca- Muscarine, a quaternary ammonium peripheral cholinergic syndrome within rine poisoning is primarily supportive compound, is similar structurally to acetylcholine and can stimulate periph- 30 mins to 2 hrs of (Table 1). with fluid rehydration and secretion con- eral muscarinic, cholinergic receptors. Muscarine-containing mushroom poison- trol with intravenous boluses, Muscarine cannot stimulate nicotinic ing is characterized by salivation, lacrima- 0.01–0.02 mg/kg (1). Other than atro- cholinergic receptors or cross the tion, urination, , and emesis, often pine, there are no specific for blood-brain barrier to cause a central with miosis, bronchorrhea, and bronchos- muscarine and no commonly available cholinergic syndrome (1). Although pasm. Unlike acetylcholine, muscarine is analytical techniques to identify musca- many mushroom species, including not hydrolyzed by plasma acetylcholinest- rine in body fluids.

From Programs in Community Preventive Medicine tional sources and by a state grant from the Health MD, DrPH, FCCM, Louisiana State University Health and in Environmental and Occupational Health Sciences, Education Fund (HEF) of the Board of Regents, State of Sciences Center, 1600 Canal Street, Suite 800, New School of Public Health, and the Departments of Anes- Louisiana, entitled The Assessment and Remediation Orleans, LA 70112. E-mail: [email protected]. thesiology, Emergency Medicine, and Family Medicine, of Public Health Impacts due to Hurricanes and Major Copyright © 2005 by the Society of Critical Care School of Medicine, Louisiana State University Health Flooding Events, Grant Award HEF (2001–2006) 01. Medicine and Lippincott Williams & Wilkins Sciences Center, New Orleans, LA. The author has no financial interests to disclose. DOI: 10.1097/01.CCM.0000153531.69448.49 Supported, in part, by departmental and institu- Address requests for reprints to: James H. Diaz,

Crit Care Med 2005 Vol. 33, No. 2 427 Table 1. Onset time and target system classification of mushroom poisoning by common mushroom -Induced species Epileptogenic Neurotoxicity

Early-Onset Toxicity Late-Onset Toxicity Delayed-Onset Toxicity The gyromitrin-containing, false mo- (Ͻ6 Hrs) (Within 6–24 Hrs) (Ն1 Day) rel mushrooms ( brunnea, G. Neurotoxic Hepatotoxic Nephrotoxic californica, G. esculenta, G. infula) rarely Cholinergic Amatoxic cause mushroom poisoning in the United Clitocybe species Amanita species species States but frequently cause mushroom (Funnel Caps) species (Corts) poisoning in Europe and Scandinavia, Inocybe species species Rhabdomyolytic Glutaminergic Nephrotoxic Tricholoma equestre where they are commonly mistaken for Amanita proxima (Yellow Trich) the prized, edible morel ( escu- (Fly Amanita) Amanita smithiana Russula subnigricans lenta, also known as the conifer edible (Toxic Lepidella) (Blackening Russula) morel) (1). Since gyromitrin is water- (Panther Amanita) Erythromelalgia Neurotoxic soluble and highly volatile, vigorous boil- Epileptogenic Clitocybe acromelalga Hapalopilus rutilans Gyromitra species Clitocybe amoenolens (Purple-Dye Polypore) ing followed by prolonged drying will (False Morels) (Poison Dwarf Bamboo Mushroom) render Gyromitra mushrooms edible, but Hallucinogenic amateur mushroom foragers rarely prac- species tice these detoxifying steps (3). Karlson- (Mellow Mushrooms) Allergic Stiber and Persson (3) reported that the Immunohemolytic Swedish Poison Information Centre re- ceived 706 telephone inquiries on human (Poison Pax) exposures to Gyromitra esculanta during Pneumonic the period 1994–2002. Clinical manifes- Lycoperdon species (Puffballs) tations were mainly gastrointestinal and Gastrointestinal neurologic, including , , nys- Disulfiram reaction tagmus, , and (3). The Coprinus atramentarius Swedish Centre recorded no fatalities ( Inky Caps) Miscellaneous from Gyromitra mushroom ingestions gastrointestinal over the 50 yrs from 1952 to 2002 (4). Boletus species Gyromitrin-containing mushroom Chlorophyllum species poisoning is characterized by self-limited Entoloma species , weakness, , , abdominal cramping, and diarrhea, within 4–6 hrs of ingestion (3). This sub- Glutaminergic Neurotoxicity following unintentional ingestions of ibo- acute onset of gastrointestinal (GI) toxic- tenic acid-containing mushrooms (2). ity may, rarely, be followed by epilepto- Several of the most brightly colored The excitatory manifestations of ibotenic genic neurotoxicity, with vertigo, (red, pink, gold, blue-gray) Amanita , , , and , es- acid poisoning, which can be reversed mushrooms (A. muscaria, A. pantherina) pecially in the elderly and in patients on with intravenous , in- are featured prominently in illustrated prophylaxis or treatment for tu- clude hyperactivity, hyperreflexia, myoc- children’s books (A. muscaria in Alice in berculosis (3–5). Epileptogenic neurotox- lonus, and seizures. In 1992, Benjamin Wonderland) and are often accidentally icity results from gyromitrin’s activation (2) reported the clinical features and ingested by children because of their fa- by phase 1 hydrolysis to its active, management of nine cases of mushroom miliar bright colors or intentionally in- primary neurotoxic metabolite, monom- gested for their hallucinogenic effects (2). poisoning from A. pantherina (Panther ethylhydrazine, which, like isoniazid, in- ϭ Their isoxazol-derived constituents, ibo- Amanita, n 8) and A. muscaria (Fly hibits , a decar- ϭ tenic acid and , cause the stim- Amanita, n 1) admitted to the Seattle boxylase cofactor, with diminished ulatory and hallucinogenic effects of Children’s Hospital. Most ingestions oc- production of GABA, a central inhibitory these mushrooms. resem- curred in male toddlers with onset of (3, 5). Thus, isoniazid’s bles glutamic acid structurally and can neurotoxicity within 30–180 mins. Clin- side effects, including central neurotox- stimulate central glutaminergic recep- ical features included ataxia, hyperkinetic icity manifesting as seizures, and, possi- tors (2). Muscimol resembles ␥-aminobu- behavior, intermittent hysteria, halluci- bly, peripheral neurotoxicity manifesting tyric acid (GABA) structurally and can nations, and waxing and waning obtun- as peripheral neuropathies, may be un- stimulate central GABA receptors (1). dation. Seizures and myoclonic twitching masked and potentiated by gyromitrin Within 30 mins to 2 hrs following large occurred in four of nine patients and poisoning and further pyridoxine inhibi- ingestions, adults will experience a pre- were controlled with anticonvulsants. tion. dominance of muscimol-mediated Vomiting was rare. Recovery was rapid and Hepatocellular damage, presumably GABAergic effects including , complete in all nine children. Besides ben- from the formation of free methyl radi- somnolence, delirium, dysphoria, and zodiazepines for control, the treat- cals, may follow gyromitrin-induced sei- (1). On the other hand, ment of ibotenic acid poisoning is support- zures and is manifested by elevated he- children often experience a preponder- ive; central toxicity is patic transaminases and hyperglycemica, ance of glutaminergic excitatory effects short-lived, and fatalities are rare (2). often followed by rebound

428 Crit Care Med 2005 Vol. 33, No. 2 (3, 4). From 1 to 3 days following evi- occurred after mixed mushroom inges- Allergic Pneumonic Syndrome dence of hepatic damage, intravascular tions, often with alcohol and other drugs, (Lycoperdonosis) with may and intravenous injections of hallucino- occur and possibly cause renal damage genic mushroom extracts (8–11). Mixed Lycoperdonosis is an acute allergic (3). Fulminant hepatic failure and death psilocybin-containing mushroom intoxi- bronchoalveolitis that is not related to are rare following gyromitrin poisoning cations are usually characterized by anx- production, as in hemorrhagic (3, 4). iety, , tachycardia, hyperten- pulmonary stachybotryotoxicosis, or to systemic mycosis, as in pulmonary blas- Although there are no specific diag- sion, dysphoria, hallucinations, tremor, tomycosis and histoplasmosis (15, 16). nostic tests for gyromitrin poisoning, and dyskinesias (11). In 1998, Beck and Although not a true poisoning, but an both chromatography and mass spec- others (12) used gas chromatography- acute bronchopneumonic syndrome, ly- trometry may identify monomethylhydr- mass spectrometry to identify large azine and its neurotoxic metabolites (3). coperdonosis may follow the accidental amounts of phenylethylamine in Psilo- The treatment of gyromitrin poisoning or intentional inhalation or insufflation cybe semilanceata (Liberty Cap Psilo- includes initial GI decontamination with of spores from Lycoperdon species puff- cybe) mushrooms ingested by three ado- oral activated charcoal, 1 g/kg of body balls, including L. gemmatum (Golden weight, and seizure control with titrated lescent males, later hospitalized for Puffball), L. perlatum (Common Puff- intravenous doses of benzodiazepines and adverse reactions. The authors suggested ball), and L. pyriforme (Stump Puffball) repeated intravenous boluses of pyridox- that phenylethylamine, a sympathomi- (15, 16). ine, 25 mg/kg, a specific monomethylhy- metic amine, could be responsible for the Puffballs are often edible in the fall but drazine (3). adverse adrenergic reactions, notably hy- dry out and decay over the winter and pertension and tachycardia, following release massive quantities of spores in Hallucinogenic Neurotoxicity Psilocybe mushroom ingestions (12). explosive aerosols when bitten or crushed Management of hallucinogenic mush- in the spring and summer. Aerosols of An acute hallucinogenic or psilocin room poisoning is mainly supportive, puffball spores have often been used as syndrome, resembling lysergic acid di- with benzodiazepines reserved for myoc- folk-healing therapies for asthma and ethylamide (LSD)-induced hallucinations lonus, hyperkinesias, and seizures. bronchitis, for hallucinogenic experi- and characterized by ataxia, hallucina- mentation by adolescents, and as explod- tions, and hyperkinesis, can be caused by ing “land mines” and slingshot-propelled a large variety of psilocybin-containing Paxillus Involutus “grenades” by pranksters. mushrooms or mellow mushrooms Immunohemolytic Syndrome Lycoperdonosis is characterized by the within minutes of ingestion (6). Common acute onset of nausea, vomiting, and na- psilocybin-containing mushrooms in- The Paxillus syndrome is a rare, and sopharyngitis, followed within days by fe- clude (San Isidro Psi- potentially fatal, immunoallergic reac- ver, malaise, dyspnea, and inflammatory locybe), P. cyanescens (Common Wood- tion that may follow the consumption of pneumonitis with diffuse reticulonodular Chip Psilocybe), P. semilanceata (Liberty many common, but inedible, mushroom infiltrates on chest radiograph (15, 16). Cap Psilocybe), cyanopus species, including Paxillus involutus Patients treated with steroids and anti- (Deadly Conocybe), Gymnopilus spect- (Poison Pax) and possibly Boletus luridus fungals, such as amphotericin B, usually abili (Big Laughing Gym), and Psa- (Stem Net Bolete) and Clitocybe clavi- recover without chronic bronchopulmo- thyrella foenisecii (Lawn Mower’s Mush- ceps (Alcohol Funnel Cap) (13, 14). The nary sequelae (15, 16). Mechanical venti- room) (3, 6). Psilocybin-containing Paxillus syndrome occurs most com- lation for respiratory failure may be indi- mushrooms are frequently cultivated do- monly after the repeated ingestion of cated in some cases (15, 16). mestically, particularly P. cubensis (San Paxillus involutus and is characterized by Isidro Psilocybe), for their hallucinogenic an acute onset of nausea, vomiting, epi- Disulfiram Reaction effects with spores sold in drug parapher- gastric pain, and diarrhea within 30 mins nalia stores (“head shops”), mail-order to 3 hrs of ingestion (13, 14). An acute Many Coprinus species or inky cap kits, and over the Internet. In 1988, immune complex-mediated hemolytic mushrooms, especially C. atramentarius, Schwartz and Smith (7) reported that with hemoglobinuria, oliguria, the ubiquitous alcohol inky caps, contain among 174 adolescents self-identified as , an amino acid that inhibits anuria, and acute renal failure from im- substance abusers, 45 (26%) reported in- and causes mune-complex nephritis may follow, pos- gesting hallucinogenic mushrooms acetaldehyde poisoning, a disulfiram-like sibly initiated by an allergic response to a (mean, 2–4 mushrooms per episode), effect, on ingestion of ethyl alcohol (34). usually in combination with alcohol, common Paxillus and Boletus antigenic Coprine poisoning usually occurs when marijuana, and other drugs. protein constituent, involutin (13, 14). C. atramentarius (Alcohol Inky Cap) is Psilocybin and its primary metabolite, Convalescent serum immunoglobulin G mistaken for the edible C. comatus psilocin, are centrally acting indoles that antibodies to a Paxillus extract contain- (Shaggy-Mane Edible Inky Cap) (1, 17, resemble LSD and serotonin stereo- ing involutin have been detected by hem- 18). Alcohol and raw or cooked C. atra- chemically. Psilocybin can act as both a agglutination inhibition testing in several mantarius co-consumption does not re- serotonin agonist and antagonist. Al- patients with the acute Paxillus syn- sult in an immediate disulfiram effect be- though the hallucinogenic effects of psi- drome (13, 14). Treatment of the Paxillus cause of coprine’s delayed inhibition of locybin-containing mushrooms are syndrome is entirely supportive and in- acetaldehyde dehydrogenase over 30 short-lived and fatalities are rare, renal cludes hemoperfusion or , mins to 2 hrs (17, 18). Investigators now failure, seizures, and cardiac arrest have and death is rare (13, 14). speculate that coprine’s primary metabo-

Crit Care Med 2005 Vol. 33, No. 2 429 lite, 1-aminocyclopropanol, and not A. ocreata, A. phalloides, A. suballiacea, 22, 29). Without intensive care, often in- coprine, is actually responsible for the A. tenuifolia, A. verna, A. virosa); b) Gale- cluding urgent liver transplantation, delayed disulfiram-like effect (19). Alco- rina (G. autumnalis, G. marginata, G. phase 3 may cause death within a week of hol consumption within 2 hrs of a venenata); and c) Lepiota (L. brunneoin- ingestion (30, 31). coprine-containing mushroom meal will carnata, L. chlorophyllum, L. helveola, In 2003, Forro and Mandli (32) de- result in tachycardia, facial flushing, dia- L. josserandii). , the scribed their experiences in providing an- phoresis, chest pain, nausea, and projec- ubiquitous Death Cap (Death Angel) esthetics and critical care to three pa- tile vomiting, often mimicking an acute Amanita, is generally considered the tients undergoing liver transplantation myocardial infarction (17–19). In addi- most toxic of the world’s cyclopeptide- for fulminant hepatic failure following tion to coprine-containing inky caps, containing Amanita mushrooms, with the ingestion of A. phalloides mushrooms some prized, edible mushrooms, notably Galerina species being the least toxic of in Hungary. All three patients developed the prized black morel (Morchella angus- the cyclopeptide-containing mushrooms an unanticipated constellation of acute ticeps), may also cause a mild disulfiram (3, 22). In Eastern Europe, however, Klan ischemic pancreatitis, disseminated in- reaction if consumed with alcohol (1) (23) found that among 22 species of ama- travascular coagulation, acute renal fail- (Table 1). The acute disulfiram syndrome toxic mushrooms (three Amanita, eight ure, and gastrointestinal bleeding in the is short-lived over a few hours, and treat- Galerina, and 11 Lepiota species), Gale- perioperative period. The authors also ment is entirely supportive with anti- rina sulcipes was the most lethal species suggested that may have direct emetics and fluid rehydration. Fatalities in humans followed by A. phalloides, A. cardiovascular effects in addi- are possible from acetaldehyde poisoning virosa, G. marginata, and L. brunneoin- tion to their hepatotoxic and nephrotoxic with tachyarrhythmias and cardiovascu- carnata (Table 1). effects and concluded that liver trans- lar collapse but are exceedingly rare. The cyclopeptides are divided into plantation comprised only a small part of three classes of high molecular weight the complex critical care management of Miscellaneous Gastrointestinal peptides: amatoxins, , and vi- A. phalloides poisoned patients (32). Toxicity Alone rotoxins (24). The amatoxins, principally In 1997, Skaare (33) recommended ␣-amanitin, are the most toxic cyclopep- that the following conditions be included The most common type of mushroom tides and may be enterohepatically recir- in the differential diagnosis of acute ful- poisoning worldwide is a syndrome of culated (25). Amatoxins cause delayed he- minant liver failure, potentially requiring malaise, epigastric pain, nausea, vomit- patorenal failure by inactivating RNA liver transplantation: a) acetaminophen ing, and diarrhea that occurs within 30 polymerase II and inhibiting protein syn- poisoning; b) acute fatty liver of preg- mins to 3 hrs of ingesting a wide variety thesis (26). The amatoxins exhibit limited nancy; c) viral hepatidides; d) ischemic of inedible mushrooms and even some protein binding; are eliminated in urine, hepatitis; e) acute Budd-Chiari syndrome; edible mushrooms, especially those that vomitus, and feces; and may be detected and f) amatoxic mushroom poisoning. In have recently decomposed in the field or in both bodily fluids and hepatorenal bi- addition, acute fulminant liver failure re- in storage. Gastrointestinal toxin-con- opsies by chromatography, radioimmu- quiring liver transplantation has oc- taining mushrooms may come from noassay, and enzyme-linked immunosor- curred following overdoses with the illicit several genera including Boletus, Chloro- bent assay (27). The phallotoxins, amphetamine, 3,4-methylenedioxymeth- phyllum, Entoloma, Lactarius, Ompha- principally phalloidin, are rapidly acting amphetamine (Ecstasy). For amatoxic lotus, and Tricholoma (1, 20). The exact but not highly absorbed and cause sub- mushroom poisoned patients, Skaare GI have not been identified, lead- acute GI toxicity by reducing mucosal (33) recommended early and frequent ing some investigators to speculate that cell membrane integrity (28). The viro- evaluation of liver function and coagula- either allergy or malabsorption may toxins have not been implicated in hu- tion status and early referral to a liver cause the clinical manifestations (20). man toxicity (24). transplant center. Resolution of symptoms occurs rapidly As noted, cyclopeptide poisoning may In the United States, Klein and col- over 6–24 hrs, and treatment is nonspe- be divided into three phases with phase 1 leagues’ (34) criteria are often used to cific and entirely supportive with anti- occurring 6–24 hrs after mushroom in- evaluate hepatic dysfunction and to rec- emetics and fluid rehydration. gestion and presenting a nonspecific, ommend liver transplantation in ama- phalloidin-mediated toxidrome of nausea, toxic mushroom-poisoned patients. Klein LATE- AND DELAYED-ONSET vomiting, abdominal cramps, and watery and colleagues’ (34) criteria are com- TOXICITY diarrhea, which mimics self-limited food posed of any two of the following condi- poisoning, cholera, or viral gastroenteri- tions: a) grade 2 or higher hepatic en- Late-Onset Toxicity (>6 hrs) tis (21). Since phase 2 is characterized by cephalopathy; b) prothrombin time twice transient clinical improvement with de- normal despite procoagulant therapy; c) Amatoxic . A triphasic layed, asymptomatically rising liver en- hypoglycemia requiring continuous glu- onset of subacute GI toxicity, followed by zymes 18–36 hrs after ingestion, patients cose infusion; and c) hyperbilirubinemia a false recovery period, and, subse- with phase 2 cyclopeptide poisoning may Ͼ25 mg/dL (425 mmol/L). In European quently, late-onset hepatic failure is pa- be discharged home, only to return jaun- centers, however, other criteria are often thognomonic of poisoning with cyclopep- diced with hepatorenal failure within 2–6 used to evaluate hepatic dysfunction and tide-containing mushrooms (21). Most days of mushroom ingestion (21, 22). to predict the need for liver transplanta- mushroom fatalities worldwide continue Phase 3 is characterized by severe gastro- tion in mushroom poisoning, which oc- to be caused by cyclopeptide-containing enteritis, significantly elevated liver en- curs more frequently than in the United species from three major genera: a) zymes, and evidence of hepatic, renal, States. Amanita (A. bisporigera, A. hygroscopia, and, often, pancreatic insufficiency (21, In 1989, O’Grady and colleagues (35)

430 Crit Care Med 2005 Vol. 33, No. 2 from the Liver Unit, King’s College encephalopathy, peaking liver enzymes, Since most patients with School of Medicine, in London, were hyperbilirubinemia, acute azotemia, and poisoning are hospitalized after onset of among the first investigators to recognize prolonged thromboplastin times were of gastrointestinal symptoms, gastric de- the need for early prognostic indicators little prognostic value when applied to contamination by lavage has little useful- to select those patients most likely to their series of 12 amatoxic mushroom- ness beyond 6 hrs postingestion. Al- benefit from orthotopic liver transplanta- poisoned patients with fulminant liver though multiple-dose activated charcoal tion for fulminant liver failure from acet- failure. In 1997, Beckurts and coinvesti- (1 g/kg initially, followed by 0.5 g/kg), aminophen poisoning, infectious hepati- gators (39) from Munich recommended administered orally or by gastric tube tis, drug reactions, and a variety of applying the following prognostic criteria during the first 3 days postingestion, and miscellaneous causes of acute liver fail- (the Munich criteria) to reliably predict a intensive care, including fluid resuscita- ure, including amatoxic mushroom poi- lethal from a nonlethal course following tion and possibly liver transplantation, sonings. The King’s College Hospital amatoxic mushroom poisoning: a) pro- remain the standard of care for amatoxin prognostic criteria for the selection of thrombin time 20% greater than normal; poisoning, many untested, unapproved patients with fulminant, nonacetamino- b) creatinine concentration Ͼ1.4 mg/dL therapies have been used over the years. phen-induced liver failure for orthotopic (133 mmol/L) after correcting for all wa- Although not specific antidotes, thioctic liver transplantation included prothrom- ter and electrolyte abnormalities; c) se- acid (41), a free radical scavenger, benzyl Ͼ Ͼ bin time 100 secs (International Nor- rum bilirubin 4.6 mg/dL (78.2 mmol/ penicillin (penicillin G) (42), silibinin Ͼ malized Ratio 6.5), irrespective of the L); and d) progressing hepatic (43), N-acetylcysteine (NAC) (43), and ci- grade of hepatic encephalopathy, or any encephalopathy. Despite differing evalua- metidine (44) have all been used in the of the three following variables, also irre- tion criteria for liver transplantation fol- pharmacologic management of amatoxin spective of the grade of hepatic encepha- lowing amatoxic mushroom poisoning in poisoning with varying success. In a Ͻ Ͼ lopathy: a) age 10 or 40 yrs; b) dura- the United States and Europe, all authors meta-analysis of 2,108 patients hospital- tion of before onset of hepatic agree that constant monitoring of he- ized in North America and Europe for Ͼ encephalopathy 7 days; and c) pro- patic, neurologic, clotting, and renal management of amatoxin poisoning, En- thrombin time Ͼ50 secs (International functions is essential in the critical care Ͼ jalbert and coauthors (45) noted that Normalized Ratio 3.5) and serum bili- management of all patients with fulmi- benzyl penicillin alone, or in combina- rubin Ͼ17.5 mg/dL (300 mmol/L) (35). nant liver failure from amatoxic mush- tion with the other drug therapies noted, In 2000, Shakil and coauthors (36) at the room poisoning. was the most frequently used chemother- Thomas E. Starzl Transplantation Insti- Although Galerina mushroom-poi- apy but demonstrated little efficacy. A tute, University of Pittsburgh School of soned patients usually recover after gas- survival analysis suggested that silibinin Medicine, reassessed the validity of the trointestinal phase 1, amatoxin poisoning administered either alone or in combina- King’s College Hospital criteria in 177 following ingestion of Lepiota mush- tion or NAC administered alone offered patients with fulminant liver failure eval- rooms may, like Amanita phalloides in- the most effective therapeutic outcomes uated for possible orthotopic liver trans- gestion, also result in fulminant hepati- (45). plantation and concluded that the King’s tis, liver failure, and death (40). In 1993, College Hospital criteria provided valu- Ramirez and others (40) reported the Unlike thioctic acid, both intravenous able early prognostication in making de- health outcomes in ten patients who had benzyl penicillin and silibinin have cisions regarding orthotopic liver trans- ingested Lepiota species mushrooms in shown some hepatic protection in ama- plantation for patients with fulminant Spain. Seven patients had ingested Lepi- toxin-poisoned mouse models, and cime- liver failure (36). In addition, the authors ota helveola, and the remaining three tidine may offer hepatoprotection by in- noted that fulfillment of the King’s Col- patients had ingested Lepiota brunneoin- hibiting of lege Hospital criteria usually predicted carnata (Deadly Lepiota) (40). Of the ten amatoxins, not phallotoxins (42–45). poor outcome regardless of treatment for patients, five recovered completely after Recommended by European experts as liver failure (high specificity and positive gastrointestinal phase 1, and the other safe and effective, intravenous benzyl predictive value), but that lack of fulfill- five developed hepatic insufficiency (40). penicillin, 1 million units/kg/day, may ment did not reliably predict survival Of the five with hepatic involvement, displace amanitin from albumin, block its (low negative predictive value) (36). three patients developed fulminant hepa- uptake by hepatocytes, and prevent In 1991, Ronzoni and coauthors (37) titis, and two of these died of adult respi- amanitin from binding to and inhibiting in Milan managed two amatoxic mush- ratory distress syndrome (40). The pa- RNA polymerase II (31, 42, 45). room-poisoned patients who satisfied tient with fulminant hepatitis who Silibinin, an extract from the milk Klein and colleagues’ (34) criteria for survived later developed chronic active thistle, Silybum marianum, may occupy liver transplantation with intensive care hepatitis 1 yr after Lepiota ingestion (40). cell membrane binding sites and block and without liver transplantation. Both Finally, five of the surviving eight pa- amanitin’s hepatocellular penetration if patients awakened from hepatic coma tients subsequently developed chronic administered during the first 3 days and recovered completely from amatoxin mixed polyneuropathies within the first postingestion (43, 45). Silibinin is not poisoning (37). At 1-yr follow-up, both year after Lepiota poisoning (40). The easily available in the United States, and patients were in excellent health with authors concluded that liver transplanta- its dosage recommendations remain em- normal liver function and no neurologic tion might have prevented the two deaths pirical and not evidence-based. Current sequelae of hepatic encephalopathy or hy- from liver failure with adult respiratory recommendations for silibinin treatment poglycemia (37). distress syndrome and the single case of include an intravenous loading dose of 5 In 1996, Bektas and coauthors (38) in chronic active hepatitis following Lepiota mg/kg administered over 1 hr, followed Hanover, Germany, reported that hepatic poisoning (40). by a continuous intravenous infusion of

Crit Care Med 2005 Vol. 33, No. 2 431 20 mg/kg/day for the first 3 days after to a regional liver transplantation center peritoneal allenic norleucine, the amino amatoxic mushroom ingestions (43–47). for intensive care. acid nephrotoxin of A. smithiana, than Since amatoxins, like acetaminophen, Accelerated Acute Renal Failure. In with orellanine, the interstitial and tubu- undergo hepatic biotransformation to October 1992, Leray and coauthors (59) lar nephrotoxin of Cortinarius mush- glutathione-binding, free radical toxic in- managed five cases of acute renal insuf- rooms (61–63). termediates, NAC, a glutathione precur- ficiency following accidental ingestion of Treatment of suspected A. proxima sor, was considered initially as a poten- Amanita proxima mushrooms by forag- and A. smithiana poisoning is primarily tially effective antidote for amanitin ers seeking edible Amanita ovoidae supportive and should include GI decon- poisoning. Although offering effective mushrooms. All cases were characterized tamination with activated charcoal, al- hepatoprotection in acetaminophen poi- by initial GI toxicity, followed by cytolytic though of no proven benefit in absorbing soning, NAC has only demonstrated effec- hepatitis and acute renal failure (59). Al- allenic norleucine in patients manifesting tiveness in amatoxin poisoning in one though temporary hemodialysis was re- acute GI toxicity (60, 61). In addition, the case series (44–47). In an amatoxin- quired in four patients, all patients made combination of acute GI distress and re- poisoned mouse model, Schneider and favorable recoveries within 3 wks without nal insufficiency following mushroom in- coinvestigators (47) found that NAC (1.2 evidence of chronic hepatic or renal dam- gestion should alert clinicians to the pos- g/kg) produced no change in survival or age (59). In 1998, deHaro and coauthors sibility of A. proxima poisoning in in elevation of hepatic enzyme levels (60) reviewed 31 cases of Amanita prox- Europe, or A. smithiana in the United compared with control mice not receiv- ima poisoning reported to the Marseille States, and the need for early institution ing NAC. Poison Center and determined that the of venovenous charcoal hemoperfusion Plasmapheresis, hemofiltration, he- initial case was reported in 1968 and that or hemodialysis (60, 61). ϭ moperfusion, and hemodialysis also have most (n 26) cases (83%) resulted from Erythromelalgia. Erythromelalgia is a not demonstrated any effectiveness in re- confusion with edible Amanita ovoidae painful peripheral, inflammatory condi- versing fulminant hepatic failure in phase mushrooms. The mean onset to clinical tion characterized by intense burning 3 cyclopeptide poisoning (48–51). Al- manifestations was 13 hrs and 12 mins; pain, redness, and edema of the hands though the extracorporeal bioartificial all patients had gastrointestinal toxicity, and feet, often intensified by heat and liver has been successful in reversing he- and oliguria or anuria occurred within a relieved by cold. Transient erythromelal- few days of ingestion in 14 patients (60). gia has followed the oral administration patic failure in acetaminophen poisoning, Ten patients had laboratory evidence of of several prescription drugs including it has not been tested in human cyclopep- hepatic insufficiency, and 11 of 14 pa- bromocriptine (64), verapamil (65), and tide poisoning but could serve as an ef- tients with renal insufficiency required nifedipine (66). The histopathologic ex- fective artificial bridge to hepatic trans- temporary hemodialysis (60). Recovery amination of skin biopsies in drug- plantation (52). was uniformly favorable in all 31 patients induced erythromelalgia has demon- In a series of laboratory experiments without long-term sequelae (60). strated perivascular mononuclear in mice, Floersheim (53–56) demon- Between 1992 and 1998, 13 patients in infiltration and prominent perivascular strated that pretreatment with sublethal the U.S. Pacific Northwest developed an- dermal edema without vasculitis (64, 65). doses of phalloidin, alone, and orexia, malaise, nausea, vomiting, ab- In 1918, Ichimura (67) first described lyophilized preparations of A. phalloides dominal cramping, diarrhea, diaphoresis, mushroom-induced erythromelalgia in and kutkin, a mixture of glycosides from and vertigo within 30 mins to 12 hrs of Japan within 3 days of consuming Clito- the roots of Picrorhiza kurroa, offered consuming either raw or cooked Amanita cybe acromelalga mushrooms, which re- some protection against lethal challenges smithiana (Toxic Lepidella Amanita) sembled the prized , of amatoxins and phallotoxins, possibly mushrooms (61). Many of the poisoned Lepista inversa (Edible Blewit). In 2001, by increasing hepatic microsomal detox- patients were apparently seeking the ed- Saviuc and co-authors (68) reported the ification of amatoxins and phallotoxins. ible white mushroom, Tri- first European observations of mush- In a similar experiment, Zanoli (57) choloma magnivalere,anA. smithiana room-induced erythromelalgia in seven showed that 2,4-monofurfurylidene- look-alike in the U.S. Pacific Northwest French patients within one to several tetra-O-methyl sorbitol also offered some (61). All patients were either oliguric or days of consuming Clitocybe amoenolens protection against lethal challenges of anuric on presentation and manifested (Poison Dwarf Bamboo Mushroom) amatoxins in mice. In 1977, Floersheim acute renal insufficiency with rising se- mushrooms, which resemble the edible (58) demonstrated that cytochrome c rum blood urea and creatinine mushrooms Lepista inversa (Edible Ble- alone or combined with benzyl penicillin levels within a week of mushroom inges- wit) and Clitocybe gibba (Common Fun- completely reversed hepatotoxicity in tion (61). In addition, both serum alanine nel Cap), in the high alpine meadows of mice after supralethal doses of ␣-aman- aminotransferase and lactic dehydroge- France. itin, even up to 12 hrs postpoisoning. nase were frequently elevated, whereas All of the French patients with eryth- Although the search for specific antidotes other hepatic enzymes and liver function romelalgia were characterized by numb- to amatoxins continues, any patient with tests usually remained normal (61). Al- ness, burning pain, paresthesias, and red- a mushroom ingestion history and phys- though none of the A. smithiana-poi- dish edema in the fingers and toes with ical and laboratory findings suggestive of soned patients died, several required he- some proximal extension within Ն1 day amatoxin poisoning from Amanita, Gale- modialysis up to three times per week for of mushroom ingestions (68). There were rina,orLepiota species mushrooms up to 1 month following ingestion (61). no associated GI symptoms, and the se- should be initially managed with multi- Subsequent in vitro investigations in rum electrolytes and liver enzymes re- ple-dose activated charcoal and support- mice models demonstrated a more rapid mained normal. In most cases, the pain ive therapy and immediately transferred onset of renal tubular damage with intra- was worst at night, intensified by heat,

432 Crit Care Med 2005 Vol. 33, No. 2 and relieved by ice-cold water immersion. rius-poisoned patients may develop Cortinarius mushroom ingestion. Most Although recovery usually occurred chronic renal failure and require chronic of the patients included in the meta- within 8 days to 5 months without resid- hemodialysis or renal transplantation analysis came from Poland and included ual effects, one patient in the French se- (72–74). Grzymala’s patients and other Polish pa- ries developed self-induced trench foot In 1957, Grzymala (73) reported a se- tients (n ϭ 135); patients from France (n from prolonged ice-water immersion and ries of 102 Polish patients with orellanine ϭ 45), Sweden (n ϭ 26), and Austria (n ϭ suffered continuing paresthesias in both poisoning following the ingestion of Cor- 16); and patients from several other west- feet for 3 yrs (68). Treatment of eryth- tinarius orellanus (Deadly Cort) mush- ern European countries (72, 73). The re- romelalgia is entirely supportive with rooms. In this initial report of human sponsible Cortinarius species mush- acetylsalicylic acid, opioids, and analgesic Cortinarius poisoning, there were 11 rooms were identified by experts in 90 adjuvants, including clonazepam and clo- deaths, for a case fatality rate of 11% (73). patients and included Cortinarius orella- mipramine (68). The exact toxicokinetic In 1990, Bouget and others (74) reported nus in 58.9%, Cortinarius speciosissimus mechanisms of erythromelalgia remain a series of 26 French patients hospitalized in 20%, Cortinarius splendens henrici in unknown but may result from acromelic for periods of 10–12 days following C. 15.6%, Cortinarius cinnamomeus in acid activation of peripheral glutamate orellanus ingestions. Twelve patients pre- 1.1%, and unspeciated Cortinarius mush- pain receptors, including N-methyl-D- sented with acute tubulo-interstitial ne- rooms in 5.6% (72, 73). aspartate, amino-5-methyl-4-isoxazole- phritis and acute renal failure, requiring The mean onset time to initial pre- proprionic acid, and kainite subtype re- hemodialysis in eight patients, and 14 senting, mainly GI, symptoms was 3 days ceptors (68–71). Japanese toxicologists patients presented with normal renal (72). In the prerenal phase, vomiting oc- have now been identified acromelic acids function, although 12 had initial leuko- curred in 62.7% of 82 patients, polydipsia A–E as the toxic constituents in Clitocybe cyturia (74). In this series, the incidence in 45.8%, flank pain in 36.1%, nausea in acromelalgia mushrooms (68–71). of end-stage renal failure requiring he- 36.1%, and abdominal pain in 24.1% modialysis and subsequent renal trans- (72). The renal phase of orellanine poi- Delayed-Onset Toxicity (≥1 Day) plantation was 8%, similar to the 11% soning was delayed by a mean period of case fatality rate reported by Grzymala in 8.5 days in all patients and was charac- Delayed Renal Failure. Cortinarius Poland during the prerenal transplant era terized by leukocyturia in 50% of 62 pa- mushrooms (Corts) can cause renal fail- (73, 74). In a 2001 review of 90 patients tients, hematuria in 45.2%, proteinuria ure following ingestions worldwide (3, hospitalized after Cortinarius ingestions, in 30.6%, and leukocytosis in 17.7% (72). 72). Cortinarius mushrooms contain Danel and coauthors (72) reported acute Histopathologic features on initial renal orellanine, a nephrotoxic bipyridine N- renal failure with progression to chronic biopsies in 36 patients at a mean posting- oxide. Orellanine inhibits protein synthe- renal failure in half of the patients, with estion time of 25 days demonstrated tu- sis, generates free oxygen radicals, and intermittent hemodialysis or renal trans- bular damages (lesions, necrosis, atro- causes tubulo-interstitial nephritis in ro- plantation required in 70% of those pa- phy) in 77.8%, inflammatory infiltrates in dent models and in humans (3, 72). The tients. In a 1995 review of 22 patients 69.4%, interstitial edema in 55.6%, and orellanine-containing Cortinarius mush- treated for Cortinarius ingestions in Swe- rooms include C. cinnamomeus, C. hen- den over the period 1979–1993, Holm- fibrosis in 38.9% (72). rici (C. splendens henrici [Lovely Poi- dahl and Blohmé (75) reported that nine As in other reported series of Cortina- soned Cort]), C. orellanoides, C. of 22 patients (41%) developed chronic rius poisonings, there were no clinical or orellanus (Deadly Cort), C. rainierensis, renal failure requiring hemodialysis or laboratory indications of liver injury in and C. speciosissimus (3, 72). In North renal transplantation. any patient (72–75). Neuromuscular America, Cortinarius poisoning predom- Although orellanine can be detected symptoms were, however, observed in inantly follows ingestion of C. rainieren- by thin-layer chromatography on renal 20% of the patients, preceded the renal sis (3, 72). In Europe, Cortinarius poison- biopsy specimens for months after Corti- phase, and included limb paresthesias, ing predominately follows ingestion of narius poisoning, there are no specific muscle cramps, and myalgias. Although either C. orellanus or C. speciosissimus laboratory tests to predict outcomes after there was no reported laboratory evi- (3, 72–74). Cortinarius ingestions (74, 75). Only the dence (elevated serum creatine phos- Cortinarius mushrooms grow in de- onset times of GI toxicity and subsequent phokinase [CPK] levels) of rhabdomyoly- ciduous forests and mountainous regions nephrotoxicity will assist clinicians in dif- sis in Cortinarius-poisoned patients, throughout the temperate world, includ- ferentiating A. smithiana from Cortina- neuromuscular symptoms in the prerenal ing Australia, Europe, North America, rius poisoning (3, 62, 72, 74–76). Acute phase could mimic Tricholoma equestre and the United Kingdom. Cortinarius- GI toxicity within 6 hrs followed by sub- (Yellow Trich) or Russula subnigricans poisoned patients will typically present acute nephrotoxicity within 24–36 hrs (Blackening Russula) poisoning with my- with anorexia, headache, nausea, vomit- suggests A. smithiana poisoning (3, 61). algias and rhabdomyolysis (72, 74, 75, 77, ing, gastritis, and chills within 24–36 hrs Subacute GI toxicity within 24–36 hrs 78). Health status and treatment out- of ingestion (72–74). Oliguric renal fail- followed days to weeks later (mean, 8.5 comes in 62 patients with acute renal ure due to interstitial nephritis and tubu- days) by nephrotoxicity suggests Cortina- failure included 32 patients with chronic lar necrosis with later fibrosis will de- rius poisoning (62, 72, 74–76). renal insufficiency with most patients velop in most cases days to weeks In a meta-analysis of 245 patients with (69%) requiring hemodialysis or perito- following mushroom ingestion (72–74). 90 patients analyzed in precise detail, neal dialysis, and of these, 12 patients Although most patients regain near- Danel and coauthors (72) described the required renal transplantation. There normal renal function following short- main clinical and histopathologic fea- were five deaths among 90 Cortinarius- term hemodialysis, 40–60% of Cortina- tures of orellanine poisoning following poisoned patients, primarily in those (n

Crit Care Med 2005 Vol. 33, No. 2 433 poisoned patients (80). The management Tricholoma species have now been iso- of Hapalopilus poisoning is supportive lated, the toxic compound in T. equestre linicians must with gastric decontamination by orogas- remains to be identified (77, 81–84). consider mush- tric lavage, if within 6 hrs of ingestion, The subacute onset of fatigue and multiple-dose activated charcoal, restora- muscle weakness with little GI distress room poisoning tion of fluid and electrolyte balance, and following yellow mushroom consump- C short-term hemoperfusion, peritoneal di- tion should arouse suspicion of T. eques- in the evaluation of all pa- alysis, or hemodialysis for acute renal in- tre poisoning (77). All patients should be sufficiency (79, 80). hospitalized for supportive care, serum tients who may be intoxi- Delayed Myotoxicity With Subsequent CPK monitoring, and forced alkaline di- cated by natural substances. Rhabdomyolysis. Between 1992 and uresis for renal protection from myoglo- 2003, 12 patients in southwestern France binuria (77, 81–82). (Bordeaux) developed fatigue, muscle Although some Tricholoma species weakness, and proximal myalgia 24–72 are consumed in the United States and in ϭ 62) with renal failure, for a case fatality hrs after consuming at least three con- Japan, particularly Tricholoma magni- rate of 5.6% (72). secutive, cooked meals of the edible yel- valere (T. matsutake), the white mat- Early treatment of known Cortinarius low mushroom, Tricholoma equestre sutake mushroom, many Tricholoma ingestions should include immediate gas- (also known as the Yellow Trich or Tri- species mushrooms can cause mild, self- tric emptying and GI decontamination choloma flavovirens) (77). Over the next limited GI toxicity, with nausea, vomit- with activated charcoal, which has not 4 days, all patients developed worsening ing, abdominal cramps, and diarrhea (75, been proven to absorb either orelline or weakness, especially in the quadriceps, 83–86). is collo- orellanine (72). Early secondary decon- facial erythema, nausea without vomit- quially called the “dirty Trich” mush- tamination by either plasmapheresis or ing, and diaphoresis without (77). room in the United States because of its hemoperfusion is also of no proven ben- All patients were hospitalized and dem- frequent association with GI toxicity (86). efit in removing orellanine and prevent- onstrated evidence of severe rhabdomyol- The French cluster of 12 mushroom ing renal failure after Cortinarius inges- ysis with mean maximum serum CPK poisonings by T. equestre was particu- tions (3, 72, 74, 75). The treatment levels of 22,067 units/L in women (n ϭ 7) larly exceptional for several reasons in- protocol for Cortinarius ingestions and 34,786 units/L in men (n ϭ 5) (77). cluding a) it had a high case fatality rate should include hemoperfusion for renal Electromyography demonstrated muscle of 25%; b) it involved a unique onset of insufficiency, hemodialysis or peritoneal injury without peripheral nerve involve- myotoxicity followed by rhabdomyolysis dialysis for short-term renal failure, and ment, and quadriceps muscle biopsies without vomiting, severe GI toxicity, or chronic hemodialysis or renal transplan- were consistent with direct muscle dam- hepatorenal failure; and c) it involved a tation for chronic renal failure (3, 72, 74, age (77). In 2002, another two cases of T. popular, edible mushroom that later be- 75). Renal transplantation should not be equestre with rhabdomyolysis were re- came highly toxic only after cooking and performed too early in the course of ill- ported from Poland (81). An outbreak of repeated consumption (77). In summary, ness, as complete renal recovery may oc- delayed rhabdomyolysis with acute renal no wild or uncultivated mushroom cur in 40–60% of Cortinarius-poisoned insufficiency in the most severely poi- should ever be eaten raw or consumed in patients (3). In the series reported by soned patients was also reported from large quantities as main courses. Even Danel and coauthors (72), the median Taiwan in 2001, following the ingestion some edible mushrooms, such as the mo- time to renal transplantation was 10 of Russula subnigricans (Blackening rel-like (Wrinkled Cap months (range, 6–30 months). Russula) (82). Bell Morel), may cause GI toxicity when Delayed Fail- Three of the French patients died de- cooked, especially if eaten in excess (1). ure. In the 1990s, three people in Ger- spite intensive care, including veno- many developed decreased visual acuity, venous hemofiltration, after developing CONCLUSIONS somnolence, weakness, and reduced mo- severe hyperthermia (to 42°C), dyspnea tor tone and activity Ն24 hrs following at rest, acute myocarditis, and QRS com- Several new toxidromes, some with fa- the ingestion of Hapalopilus rutilans plex widening without severe acidosis tal outcomes, have been described in the (Purple-Dye Polypore) mushrooms (79, (77). Postmortem examinations demon- United States and Europe, including sub- 80). Laboratory studies demonstrated strated myocardial lesions similar to the acute myopathy with subsequent rhabdo- electrolyte abnormalities and hepatorenal striated muscle biopsy lesions in one pa- myolysis following ingestion of Tri- insufficiency (80). In 1998, Kraft and co- tient, renal lesions in one patient, and no choloma equestre, acute renal failure investigators (80) in Germany identified hepatic lesions (77). In the nine survi- following ingestion of Amanita proxima polyporic acid, a dihydroorotate dehydro- vors, the serum CPK levels normalized or A. smithiana, erythromelalgia follow- genase inhibitor, as the toxic constituent over 2 wks, but muscular weakness per- ing ingestion of Clitocybe amoenolens, in Hapalopilus rutilans, using rodent sisted for several weeks (77). French in- and delayed central nervous system fail- models. Rats developed reduced locomo- vestigators were later able to demonstrate ure following ingestion of Hapalopilus tor activity, depressed visual placing re- increased CPK levels and similar ob- rutilans. sponses, electrolyte disturbances, and he- served muscle weakness and myopathic Gastrointestinal mushroom poisoning patorenal failure within Ն24 hrs of lesions in mice receiving equivalent hu- continues to occur commonly, as more polyporic acid administration, with all man doses of T. equestre extracts (77). amateur mushroom hunters are fooled by symptoms and laboratory derangements Although the yellow pigment of T. eques- look-alikes, consume wild mushrooms resembling those observed in the three tre and several metabolites from various raw, or overindulge on cooked mush-

434 Crit Care Med 2005 Vol. 33, No. 2 rooms, often with alcohol. Hallucino- 14. Flammer R: Paxillus syndrome: Immunohe- toxin mushroom poisoning: Myths and ad- genic mushroom poisoning is also occur- molysis following repeated mushroom inges- vances in therapy. Med Toxicol 1987; 2:1–9 ring more commonly with more fatalities tion. Schweiz Rundsch Med Prax 1985; 74: 32. Forro M, Mandli T: Liver transplantation af- as adolescents and young adults are en- 997–999 ter Amanita phalloides poisoning from the couraged to experiment with natural 15. Respiratory illness associated with inhalation viewpoint of anesthesia and intensive care of three cases. Orvosi Hetilap 2003; 144: by peers, spore-selling push- of mushroom spores—Wisconsin 1994. MMWR Morb Mortal Wkly Rep 1994; 43: 269–273 ers, enticing Web sites, and drug para- 525–526 33. Skaare VK: Mushroom poisoning: An indica- phernalia shopkeepers. Clinicians must 16. Strand RD, Neuhauser EBD, Sornberger CF: tion for liver transplantation. J Transplant consider mushroom poisoning in the Lycoperdonosis. N Engl J Med 1967; 227: Coordination 1997; 7:141–143 evaluation of all patients who may be 89–90 34. Klein AS, Brems JJ, Goldstein L, et al: Aman- intoxicated by natural substances. Since 17. Tottmar O, Lindberg P: Effect on rat liver ita poisoning: treatment and the role of liver information on natural exposures is often acetaldehyde dehydrogenase in vivo and in transplantation. Am J Med 1989; 86:187–193 insufficient and incorrect, a new tox- vitro by coprine, the disulfiram-like constit- 35. O’Grady JG, Alexander GJ, Hayllar KM, et al: idromic classification of mushroom poi- uent of Coprinus atramentarius. Acta Phar- Early indicators of prognosis in fulminant soning is recommended to guide clini- macol Toxicol 1977; 40:476–481 hepatic failure. Gastroenterology 1989; 97: 439–445 cians in making earlier diagnoses, 18. Carlson A, Henning P, Lindberg P, et al: On the disulfiram-like effect of coprine, the 36. Shakil AO, Kramer D, Mazariegos GV, et al: especially in cases where only advanced : Clinical features, outcome care, such as liver or transplanta- pharmacologically active principle of Copri- nus atramentarius. Acta Pharmacol Toxicol analysis, and applicability of prognostic cri- tion, may be life saving (Table 1). 1978; 42:292–297 teria. Liver Transplantation 2000; 6:163–169 19. Marchner H, Tottmar O, Astenklyft PH, et al: 37. Ronzoni G, Vesconi S, Radrizzani D, et al: REFERENCES A comparative study of disulfiram, cyana- recovery after serious mushroom poisoning mide, and 1-aminocyclopropanol on the ac- (grade IV encephalopathy) with intensive 1. Goldfrank LR: Mushrooms. In: Goldfrank’s etaldehyde metabolism in rats. Acta Pharma- care support and without liver transplanta- Toxicologic Emergencies. Seventh Edition. col Toxicol 1978; 43:219–232 tion. Minerva Anestesiologica 1991; 57: Goldfrank LR, Flomenbaum NE, Lewin NA, 20. Stenklyft PH, Augenstein WL: Chlorophyl- 383–387 et al (Eds). Stamford, CT, Appleton & Lange, lum molybdites: Severe mushroom poison- 38. Bektas H, Schlitt HJ, Boker K, et al: Indica- tions for liver transplantation in severe 2003, pp 1115–1128 ing in a child. J Toxicol Clin Toxicol 1990; Amanita phalloides mushroom poisoning. 2. Benjamin DR: Mushroom poisoning in in- 28:159–168 Chirurg 1996; 67:996–1001 fants and children: The Amanita pantherina/ 21. Becker CE, Tong TG, Boerner U: Diagnosis 39. Beckurts KT, Holscher AH, Heidecke CD, et muscaria group. J Toxicol Clin Toxicol 1992; and treatment of Amanita phalloides-type al: The role of liver transplantation in the 30:13–22 mushroom poisoning: Use of thioctic acid. treatment of acute liver failure following 3. Karlson-Stiber C, Persson H: Cytotoxic fun- West J Med 1976; 125:100–109 gi—An overview. Toxicon 2003; 42:339–349 Amanita phalloides poisoning. Deutsche 22. Yamada EG, Mohle Boetani J, Olson KR, et 4. Lampe KF: Toxic fungi. Annu Rev Pharmacol Medizinische Wochenschrift 1997; 122: al: Mushroom poisoning due to amatoxin: Toxicol 1979; 19:85–104 351–355 Northern California, winter 1996–1997. 5. Michelot D, Toth B: —A 40. Ramirez P, Parilla P, Sanchez Bueno F, et al: West J Med 1998; 169:380–384 review. J Appl Toxicol 1991; 11:235–243 Fulminant hepatic failure after Lepiota 23. Klan J: A review of mushrooms containing 6. Hatfield GM, Brady LR: Toxins of higher mushroom poisoning. J Hepatol 1993; 19: amanitins and phalloidins. Casopis Lekaru fungi. Lloydia 1975; 38:36–55 51–54 Ceskych 1993; 132:449–451 7. Schwartz RH, Smith DE: Hallucinogenic 41. Kubicka J: Neue Moglichkeiten in der Behan- 24. Wieland TH, Faulstich H: Amatoxins, phallo- mushrooms. Clin Pediatr 1988; 27:70–73 dlung von vergiftung mit dem grumen Knol- toxins, phallolysin, and antamanide: The bi- 8. Borowiak KS, Ciechanowski K, Waloscyzk P: lenblatterpilz—Amanita phalloides. Mykol ologically active components of poisonous (Psilocybe semi- Mitteil 1963; 7:92–94 Amanita mushrooms. CRC Crit Rev Biochem lanceata) intoxication with myocardial in- 42. Floersheim GL, Schneeberger J, Bucher K: farction. J Toxicol Clin Toxicol 1998; 36: 1978; 5:182–260 Curative potencies of penicillin in experi- 47–49 25. Busi C, Fuime L, Costantino D, et al: Aman- mental Amanita phalloides poisoning. 9. Franz M, Regele H, Kirchmair M, et al: Magic ita toxins in the gastroduodenal fluid of the Agents & Actions 1971; 2:138–141 mushrooms: Hope for a “cheap high” result- patient poisoned by the mushroom Amanita 43. Vogel G, Tuchweber B, Trost W, et al: Pro- ing in end-stage renal failure. Nephrol Dial phalloides. N Engl J Med 1979; 300:800 tection by silibinin against Amanita phal- Transplant 1996; 11:2324–2327 26. Lindell TJ, Weinberg F, Morris PW, et al: loides poisoning in beagles. Toxicol Appl 10. Raff E, Halloran PF, Kjellstrand CM: Renal Specific inhibition of nuclear RNA polymer- Pharmacol 1984; 73:355–362 failure after eating “magic” mushrooms. Can ase II by alpha-amanitin. Science 1970; 170: 44. Schneider SM, Borochovitz D, Krenzelok EP: Med Assoc J 1992; 147:1339–1341 447–449 Cimetidine protection against alpha-aman- 11. Curry SC, Rose MC: Intravenous mushroom 27. Jaeger A, Jehl F, Flesch F, et al: Kinetics of itin hepatotoxicity in mice: A potential model poisoning. Ann Emerg Med 1985; 14: amatoxins in human poisoning: Therapeutic for the treatment of Amanita phalloides poi- 900–902 implications. J Toxicol Clin Toxicol 1993; soning. Ann Emerg Med 1987; 16:1136–1140 12. Beck O, Helander A, Karlson-Stiber C, et al: 31:63–80 45. Enjalbert F, Rapior S, Nouguier-Soulé J, et Presence of phenylethylamine in hallucino- 28. Schneider SM, Vanscoy G, Michelson EA: al: Treatment of amatoxin poisoning: 20-year genic Psilocybe mushroom: Possible role in Failure of cimetidine to affect phalloidin tox- retrospective analysis. J Toxicol Clin Toxicol adverse reactions. J Anal Toxicol 1998; 22: icity. Vet Hum Toxicol 1991; 33:17–18 2002; 40:715–757 45–49 29. Floersheim GL: Treatment of mushroom 46. Montanini S, Sinardi D, Practico C, et al: Use 13. Winkelmann M, Stangel W, Schedel I, et al: poisoning. JAMA 1984; 252:3130–3132 of acetylcysteine as the life-saving antidote in Severe hemolysis caused by antibodies 30. Amanita phalloides mushroom poisoning— Amanita phalloides (death cap) poisoning. against the mushroom Paxillus involutus Northern California, January 1997. MMWR Case report on 11 patients. Arzneimittel For- and its therapy by plasma exchange. Klin Morb Mortal Wkly Rep 1997; 46:489–492 schung 1999; 49:1044–1047 Wochenschr 1986; 64:935–938 31. Floersheim GL: Treatment of human ama- 47. Schneider SM, Michelson EA, Vanscoy G:

Crit Care Med 2005 Vol. 33, No. 2 435 Failure of N-acetylcysteine to reduce alpha ima poisoning: Experience of the poison cen- Cortinarius orellanus. Intensive Care Med amanitin toxicity. J Appl Toxicol 1992; 12: ter of Marseille. Néphrologie 1998; 19:21–24 1990; 16:506–150 141–142 61. Warden CR, Benjamin DR: Acute renal fail- 75. Holmdahl J, Blohmé I: Renal transplantation 48. Piqueras J, Duran-Suarez JR, Massnet L, et ure associated with suspected Amanita smi- after Cortinarius speciosissimus poisoning. al: Mushroom poisoning: Therapeutic thiana ingestions: A case series. Acad Emerg Nephrol Dial Transplant 1995; 10: or forced diuresis. Transfusion Med 1998; 5:808–812 1920–1922 1987; 27:116–117 62. Pelizzari V, Feifel E, Rohrmoser MM, et al: 76. Rohrmoser M, Kirchmair M, Feifel E, et al: 49. Vesconi S, Langer M, Ipichino G, et al: Ther- Partial purification and characterization of a Orellanine poisonings: Rapid detection of the apy of cytotoxic mushroom intoxication. Crit toxic component of Amanita smithiana. My- fungal toxin in renal biopsy material. J Toxi- Care Med 1985; 13:402–406 cologia 1994; 86:555–560 col Clin Toxicol 1997; 35:63–66 50. Jaeger A, Jehl F, Flesch F, et al: Kinetics of 63. Schumacher T, Hoiland K: Mushroom poi- 77. Bedry R, Baudrimont I, Deffieux G, et al: amatoxin in human poisoning: Therapeutic soning caused by species of the genus Corti- Wild mushroom intoxication as a cause of implications. J Toxicol Clin Toxicol 1993; narius. Arch Toxicol 1991; 33:17–18 rhabdomyolysis. N Engl J Med 2001; 345: 31:63–80 64. Eisler T, Hall RP, Kalavar KA, et al: Eryth- 798–802 51. Mullins ME, Horowitz BZ: The futility of romelalgia-like eruption in parkinsonian pa- 78. Vannacci A, Baronti R: Mushroom-induced hemoperfusion and hemodialysis in Amanita tients treated with bromocriptine. Neurology rhabdomyolysis: Cortinarius or Tricholoma? phalloides poisoning. Vet Hum Toxicol 2000; 1981; 31:1368–1370 Toxicon 2002; 40:1063 42:90–91 65. Drenth JP, Michiels JJ, VanJoost T, et al: 79. Saviuc P, Flesch F: Acute higher fungi mush- 52. Detry O, Arkadopoulos N, Ting P, et al: Clin- Verapamil-induced secondary erythermalgia. room poisoning and its treatment. Presse ical use of a bioartificial liver in the treat- Br J Derm 1992; 127:292–294 Medicale 2003; 32:1427–1435 ment of acetaminophen-induced fulminant 66. Sunahara JF, Gora-Harper ML, Nash KS: 80. Kraft J, Bauer S, Keilhoff G, et al: Biological hepatic failure. Ann Surg 1999; 65:934–938 Possible erythromelalgia-like syndrome asso- effects of the dihydroorotate dehydrogenase 53. Floersheim GL, Bianchi L: Ethanol dimin- ciated with nifedipine in a patient with inhibitor polyporic acid, a toxic constituent ishes the toxicity of the mushroom Amanita Raynaud’s phenomenon. Ann Pharmaco- of the mushroom Hapalopilus rutilans,in phalloides. Experentia 1984; 40:1268–1270 therapy 1996; 30:484–486 rats and humans. Arch Toxicol 1998; 72: 54. Floersheim GL: Protection by phalloidin 67. Ichimura J: A new poisonous mushroom. Bot 711–721 against lethal doses of phalloidin. Agents & Gaz (Tokyo) 1918; 65:109–111 81. Chodorowski Z, Waldman W, Sein Anand J: Actions 1976; 6:490–492 68. Saviuc PF, Danel VC, Moreau PA, et al: Acute poisoning with Tricholoma equestre. 55. Floersheim GL: Ethanol and tolerated doses Erythromelalgia and mushroom poisoning. Przegl Lek 2002; 59:386–387 of Amanita phalloides protect against lethal J Toxicol Clin Toxicol 2001; 39:403–407 82. Lee PT, Wu ML, Tsai WJ, et al: Rhabdomyol- effects of the mushroom. Agents & Actions 69. Konno K, Hashimoto K, Ohfune Y, et al: ysis: An unusual feature with mushroom poi- 1977; 7:171–173 Acromelic acids A and B: Potent neuroexci- soning. Am J Kidney Dis 2001; 38:E17 56. Floersheim GL, Bieri A, Koenig R, et al: Pro- tatory amino acids isolated from Clitocybe 83. Steglich W, Topfer E, Reininger W, et al: tection against Amanita phalloides by the acromelalgia. J Am Chem Soc 1988; 110: Isolation of flavomannin-6,6'-dimethyl ether iridoid glycoside mixture of Picrorhiza kur- 4807–4815 and one of its racemates from higher fungi. roa (kutkin). Agents & Actions 1990; 29: 70. Fushiya S, Sato S, Kazasawa T, et al: Ac- Phytochemistry 1972; 11:3299–3304 386–387 romelic acid C. A new toxic constituent of 84. Gluchoff K, Arpin N, Dangy-Caye MP, et al: 57. Zanoli P: Mechanism of protection with 2.4- Clitocybe acromelalgia: An efficient isolation Recherches chimiotaxinomiques sur les monofurfurylidene-tetra-O-methyl sorbitol of acromelic acids. Tetrahedon Lett 1990; champignons: Sur le 7,7' bi-physicon bi- (MSF) against Amanita phalloides toxicity in 31:3901–3904 anthraquinone obtenue à partir de Tri- mice. Arznemittel Forschung 1979; 29: 71. Fushiya S, Sato S, Kera Y, et al: Isolation of choloma equestre L. per Fr. (basidiomycete, 1885–1889 acromelic acids D and E from Clitocybe ac- agaricale). CR Acad Sci [D] (Paris) 1972; 274: 58. Floersheim GL: Cytochrome c as an antidote romelalgia. Heterocycles 1992; 34: 1739–1742 in mice poisoned with the mushroom toxin 1277–1280 85. Ohnuma N, Amemiya K, Kakuda R, et al: alpha-amanitin. Curr Prob Clin Biochem 72. Danel VC, Saviuc PF, Garon D: Main features Sterol constituents from two edible mush- 1977; 7:59–74 of Cortinarius spp. poisoning: A literature rooms, Lentinula edodes and Tricholoma 59. Leray H, Canaud B, Andary C, et al: Amanita review. Toxicon 2001; 39:1053–1060 matsutake. Chem Pharm Bull (Tokyo) 2000; proxima poisoning: A new cause of acute 73. Grzymala S: Massenvergiftungen durch den 48:749–751 renal insufficiency. Néphrologie 1995; 16: orangefuchsigen Hautkopf. Z Pilzkd 1957; 86. Lincoff GH, Mitchell DH: Toxic and Halluci- 341 23:139–142 nogenic Mushroom Poisoning: A Handbook 60. deHaro L, Jouglard J, Arditti J, et al: Acute 74. Bouget J, Bousser J, Pats B, et al: Acute renal for Physicians and Mushroom Hunters. New renal insufficiency caused by Amanita prox- failure following collective intoxication by York, Van Nostrand Reinhold, 1997

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