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MUSHROOM-INDUCED RHABDOMYOLYSIS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ingestion of the Tricholoma equestre and Russula subnigricans mushrooms have been associated with the development of rhabdomyolysis.

Specific Substances

    A) RUSSULA SUBNIGRICANS
    1) Blackening russula
    2) Rank russula
    3) R. subnigricans
    TRICHOLOMA EQUESTRE
    1) Tricholoma flavovirens - Tricholoma equestre
    2) Man on horseback
    3) Yellow trich
    4) Yellow-knight fungus
    5) Bidau
    6) Canari
    7) Canary trich
    8) Chevalier
    9) Jaunet
    10) Riddarmusseron
    11) Shimokoshi
    GENERAL TERMS
    1) Mushrooms-Induced Rhabdomyolysis

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Tricholoma equestre and Russula subnigricans have been associated with mushroom-induced rhabdomyolysis. These mushrooms are considered to be edible in parts of Europe (eg, France, Poland), or are ingested after misidentification. Tricholoma equestre mushrooms are typically found in the United States, Canada, and France in pine forests, particularly in sandy soil, from September to November. In the southwestern United States, they commonly are found under aspen trees. The Russula subnigricans mushrooms grow in crops or alone in evergreen broad-leaf forests from summer to fall. The mushrooms have been found in the United States, Taiwan, China, and Japan.
    B) TOXICOLOGY: Tricholoma equestre contains an unidentified myotoxin which causes muscle destruction and acute myopathy. Russula subnigricans contains at least one identified myotoxin, cycloprop-2-ene carboxylic acid.
    C) EPIDEMIOLOGY: Case reports of rhabdomyolysis due to mushroom ingestion are rare in the United States, with one case reported from Alaska. Cases are more common in Europe (France, Poland, Finland) and Asia (Taiwan, Japan) although they are still rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Signs and symptoms typically develop only after repeated ingestion of these mushrooms over a short period of time (ie, several consecutive meals or over several days). Symptoms typically begin 24 hours to several days after ingestion. Symptoms are typical for toxic myopathy and rhabdomyolysis with development of fatigue, myalgias, and muscle weakness. Other effects include nausea, vomiting, diarrhea, and tachycardia.
    2) SEVERE TOXICITY: In severe cases, mushroom-induced rhabdomyolysis is associated with acute renal failure, elevated transaminases, metabolic acidosis, hyperthermia, and hypotension. Acute respiratory failure and acute myocarditis have also been described. Fatalities have occurred in patients who have eaten 3 to 10 meals consecutively.

Laboratory Monitoring

    A) In patients with a known exposure to these species of mushrooms, or in patients with exposure to unknown mushrooms and symptoms suggestive of rhabdomyolysis and myopathy, serial serum creatine kinase (CK) levels should be followed.
    B) Monitor serum electrolytes, renal function, hepatic enzymes, and urine output in symptomatic patients.
    C) Monitor ECG in patients with rhabdomyolysis.
    D) In patients with a known exposure to these mushrooms but no initial symptoms, consider following serum CK, electrolytes, and renal function tests every 24 to 48 hours for several days to detect delayed-onset myopathy and rhabdomyolysis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive care. Patients who develop rhabdomyolysis with elevated creatinine kinase (CK) and myoglobinuria will benefit from aggressive hydration with 0.9% saline to maintain urine output at 2 to 3 mL/kg/hr. Urinary alkalinization is NOT routinely recommended.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients who develop severe toxicity with hypotension should be treated first with IV fluids, with the addition of pressors (eg, dopamine or norepinephrine) if hypotension with mean arterial pressure (MAP) of less than 60 mm Hg persists. Patients with hyperthermia should be aggressively cooled, sedated with benzodiazepines, and if necessary intubated and paralyzed with a non-depolarizing paralytic agent. Patients with severe rhabdomyolysis with worsening renal function or hyperkalemia despite adequate hydration may require dialysis.
    C) DECONTAMINATION
    1) PREHOSPITAL: If the mushroom is positively identified as one of these species and ingestion has occurred within 1 hour, consider administering charcoal. However, patients typically present for evaluation only after developing symptoms of toxicity 24 hours to several days after ingestion; in these cases charcoal is not helpful.
    2) HOSPITAL: If the mushroom is positively identified as one of these species and ingestion has occurred within 1 hour, consider administering charcoal. However, patients typically present for evaluation only after developing symptoms of toxicity 24 hours to several days after ingestion; in these cases charcoal is not helpful.
    D) AIRWAY MANAGEMENT
    1) Rarely, patients with signs and symptoms of respiratory failure due to weakness from rhabdomyolysis may need intubation for respiratory support.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURES
    1) It is unknown if hemodialysis would remove the toxins causing this syndrome. Dialysis should be used for patients with worsening acute renal failure and/or hyperkalemia due to rhabdomyolysis that is not responsive to aggressive fluid hydration.
    G) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Patients with known exposure to these mushrooms, or patients with exposure to unknown mushrooms with signs and symptoms concerning for rhabdomyolysis, should be evaluated at a healthcare facility. If creatine kinase (CK), creatinine, and electrolytes are normal, patients may be discharged with outpatient follow-up in 24 to 48 hours for repeat labs to evaluate for delayed myopathy.
    2) ADMISSION CRITERIA: Patients with significantly elevated CK, elevated creatinine, or myoglobinuria should be admitted for hydration and monitoring. Patients with hypotension, hyperthermia, marked hyperkalemia, acute renal failure, or respiratory failure should be admitted to an ICU setting.
    3) CONSULT CRITERIA: Contact a medical toxicologist or your local poison center for any patient with suspected mushroom-induced rhabdomyolysis. For patients with resulting acute renal failure and/or hyperkalemia due to rhabdomyolysis, consult a nephrologist for assistance with hemodialysis if needed. A mycologist can assist with identification of the mushroom.
    H) PITFALLS
    1) Failure to follow up patients with known exposure and initial normal laboratory values to evaluate for delayed-onset rhabdomyolysis 24 hours to several days after exposure.
    I) DIFFERENTIAL DIAGNOSIS
    1) Statin-induced myopathy, red yeast rice (Monascus purpureus) toxicity, non-toxic etiologies for rhabdomyolysis, myopathy, and myositis.

Range Of Toxicity

    A) TOXICITY: Signs and symptoms typically only develop after repeated ingestion of these mushrooms over several consecutive meals or consecutive days. Rhabdomyolysis requiring supportive care for 12 to 25 days developed in one patient after ingesting 300 to 400 grams of Tricholoma equestre mushrooms daily for 4 consecutive days, and in 2 patients after ingesting 100 to 300 grams for 9 consecutive meals. Lethal exposures to Tricholoma equestre have occurred in 3 patients who had eaten at least 3 consecutive meals containing an unknown quantity and one patient who ate 300 to 400 grams for 10 consecutive meals; these patients developed renal dysfunction, myocardial lesions, and respiratory failure despite hydration and continuous venovenous hemofiltration. Several lethal ingestions of Russula subnigricans have occurred; however, the lethal dose remains unknown at this time.

Clinical Effects

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Three patients, who had eaten at least 3 consecutive meals, containing Tricholoma equestre mushrooms, developed hyperthermia, signs of acute myocarditis (cardiac dysrhythmias, QRS complex widening, and cardiovascular collapse), and acute renal insufficiency (BUN 30 to 52 mg/Dl, creatinine 1.4 to 2.5 mg/Dl) with hyperkalemia (potassium 6.0 to 7.2 mmol/L) and hypocalcemia (calcium 5.6 to 8.3 mg/dL [1.4 to 2.07 mmol/L]). The creatine kinase levels of the three patients ranged from 138,900 to 632,000 units/liter. All three patients died, despite intensive supportive care including continuous venovenous hemofiltration. Autopsy revealed myocardial lesions in one patient and renal lesions in one patient (Bedry et al, 2001).
    b) CASE REPORT: Deterioration of renal function occurred in a 60-year-old man approximately 48 hours following consumption of wild mushroom soup containing Russula subnigricans. Upon presentation to the hospital, approximately 6 hours following mushroom ingestion, the patient's BUN and serum creatinine levels were normal (17 mg/dL and 1.1 mg/dL, respectively). However laboratory data, obtained approximately 40 hours later, revealed elevated BUN and serum creatinine levels of 44 mg/dL and 2.3 mg/dL, respectively. The patient's renal function improved with supportive care and he was discharged on hospital day 33 with a serum creatinine level of 1.9 mg/dL (Lee et al, 2001).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) RESPIRATORY ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 5-year-old child developed respiratory acidosis (pH 7.28, PO2 43.9 mmHg, PCO2 59.8 mmHg, HCO3 22.9 mEq/L) after consuming 300 to 400 g of Tricholoma equestre mushrooms daily for 4 consecutive days. The patient recovered following mechanical ventilation for 34 hours (Chodorowski et al, 2003).
    b) CASE REPORT: Respiratory acidosis (pH 6.9, PO2 95 mmHg, PCO2 86 mmHg, HCO3 20 mmol/L) was reported in a 60-year-old man who consumed wild mushroom soup containing Russula subnigricans. The patient gradually recovered with supportive care (Lee et al, 2001).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Persistent leukocytosis (WBC 21,700/mm(3)) was reported in a 60-year-old man who consumed wild mushroom soup containing Russula subnigricans. The patient gradually recovered with supportive care (Lee et al, 2001).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERYTHEMA
    1) WITH POISONING/EXPOSURE
    a) Facial erythema was reported in several patients following ingestion of Tricholoma equestre mushrooms (Bedry et al, 2001).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Profuse sweating was reported in several patients who had eaten at least three consecutive meals containing Tricholoma equestre mushrooms (Chodorowski et al, 2002; Bedry et al, 2001).

Summary Of Exposure

    A) USES: Tricholoma equestre and Russula subnigricans have been associated with mushroom-induced rhabdomyolysis. These mushrooms are considered to be edible in parts of Europe (eg, France, Poland), or are ingested after misidentification. Tricholoma equestre mushrooms are typically found in the United States, Canada, and France in pine forests, particularly in sandy soil, from September to November. In the southwestern United States, they commonly are found under aspen trees. The Russula subnigricans mushrooms grow in crops or alone in evergreen broad-leaf forests from summer to fall. The mushrooms have been found in the United States, Taiwan, China, and Japan.
    B) TOXICOLOGY: Tricholoma equestre contains an unidentified myotoxin which causes muscle destruction and acute myopathy. Russula subnigricans contains at least one identified myotoxin, cycloprop-2-ene carboxylic acid.
    C) EPIDEMIOLOGY: Case reports of rhabdomyolysis due to mushroom ingestion are rare in the United States, with one case reported from Alaska. Cases are more common in Europe (France, Poland, Finland) and Asia (Taiwan, Japan) although they are still rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Signs and symptoms typically develop only after repeated ingestion of these mushrooms over a short period of time (ie, several consecutive meals or over several days). Symptoms typically begin 24 hours to several days after ingestion. Symptoms are typical for toxic myopathy and rhabdomyolysis with development of fatigue, myalgias, and muscle weakness. Other effects include nausea, vomiting, diarrhea, and tachycardia.
    2) SEVERE TOXICITY: In severe cases, mushroom-induced rhabdomyolysis is associated with acute renal failure, elevated transaminases, metabolic acidosis, hyperthermia, and hypotension. Acute respiratory failure and acute myocarditis have also been described. Fatalities have occurred in patients who have eaten 3 to 10 meals consecutively.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTHERMIA: Hyperthermia (up to 42 degrees C) was reported in several patients who ingested at least 3 consecutive meals containing Tricholoma equestre mushrooms (Bedry et al, 2001).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTENSION: Severe hypertension (182/100 mmHg) progressing to hypotension (70/40 mmHg) occurred in a 60-year-old man who consumed wild mushroom soup containing Russula subnigricans. The hypotension resolved following administration of IV fluids and dopamine (Lee et al, 2001).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hypertension (peak BP 182/100 mmHg) followed by hypotension (70/40 mmHg) was reported in a 60-year-old man following ingestion of wild mushroom soup containing Russula subnigricans. The patient's hypotension resolved with administration of IV fluids and dopamine (Lee et al, 2001).
    B) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 60-year-old man presented to the hospital with a pulse rate of 93 bpm increasing to 129 bpm approximately 6 hours after ingesting wild mushroom soup containing Russula subnigricans. A chest radiograph showed borderline cardiomegaly and an ECG revealed sinus tachycardia and left ventricular hypertrophy with strain. The patient gradually recovered with supportive care (Lee et al, 2001).
    C) MYOCARDITIS
    1) WITH POISONING/EXPOSURE
    a) Three patients, who had eaten at least 3 consecutive meals containing Tricholoma equestre mushrooms, developed hyperthermia, renal dysfunction, and signs of acute myocarditis that included cardiac dysrhythmias, QRS complex widening, and cardiovascular collapse. The creatine kinase levels of the three patients ranged from 138,900 to 632,000 units/liter (MB fraction 0.5 to 0.7 percent). All three patients died, despite intensive supportive care including continuous venovenous hemofiltration. Autopsy revealed myocardial lesions in one patient and renal lesions in one patient (Bedry et al, 2001).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) In animal studies, the mice who were given 12 g/kg/day of freshly frozen Tricholoma flavovirens mushrooms for 4 weeks had higher plasma bilirubin concentrations and higher CK and CK-MB activities than the control mice. In the histological samples, no signs of hepato- or myotoxicity were observed; however, increased incidence of pericardial inflammation in the Tricholoma flavovirens-fed mice was observed in the cardiac samples (Nieminen et al, 2008).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 5-year-old boy, who had eaten 300 to 400 g of Tricholoma equestre mushrooms daily for 4 days, developed a deep coma, acute respiratory failure, cyanosis, and seizures approximately 4 hours after the last meal. Physical examination indicated a Glasgow Coma Score (GCS) of 4, a pulse rate of 120 bpm, and a respiratory rate of approximately 6 breaths/minute. Laboratory analysis revealed an elevated ALT level of 56 units/liter (normal range 5 to 45 units/liter for a person 1- to 19-years-old) and a creatine kinase (CK) level of 306 units/liter (normal range 5 to 130 units/liter for a child). The patient also experienced muscle weakness of the pelvic girdle and bladder, requiring intermittent catheterization. He was intubated and mechanically ventilated for 34 hours. With supportive care, the symptoms of Tricholoma equestre toxicity disappeared within 12 days of hospitalization (Chodorowski et al, 2003).
    b) CASE REPORT: Respiratory failure (pH 6.9, PO2 95 mmHg, PCO2 86 mmHg, HCO3 20 mmol/L) was reported in a 60-year-old man who consumed wild mushroom soup containing Russula subnigricans. The patient gradually recovered with supportive care (Lee et al, 2001).
    c) CASE REPORT: A 72-year-old man presented with muscle weakness and myalgia approximately 24 hours after ingesting 300 to 400 grams of Tricholoma equestre mushrooms during 10 consecutive meals. Laboratory analysis revealed elevated serum creatine kinase (peak 44767 Units/liter) and liver enzyme levels (ALT and AST). On day 2 of hospitalization, he complained of pain and weakness of the muscle of the chest, shoulders and abdomen. Despite supportive therapy, the patient's condition worsened with the development of acute respiratory failure and cardiac arrest, resulting in his subsequent death several hours later (Anand et al, 2009).
    B) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Chest tightness and dyspnea have been reported following ingestion of Tricholoma equestre and Russula subnigricans mushrooms (Bedry et al, 2001; Lee et al, 2001).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 5-year-old boy, who had eaten 300 to 400 g of Tricholoma equestre mushrooms daily for 4 days, developed a deep coma, acute respiratory failure, cyanosis, and seizures approximately 4 hours after the last meal. Physical examination revealed a Glasgow Coma Score (GCS) of 4, a pulse rate of 120 bpm, and a respiratory rate of approximately 6 breaths/minute. Laboratory analysis revealed an elevated ALT level of 56 units/liter (normal range 5 to 45 units/liter for a person 1- to 19-years-old) and a creatine kinase (CK) level of 306 units/liter (normal range 5 to 130 units/liter for a child). The patient also experienced muscle weakness of the pelvic girdle and bladder, requiring intermittent catheterization. With supportive care, the symptoms of Tricholoma equestre toxicity disappeared within 12 days of hospitalization (Chodorowski et al, 2003).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 5-year-old boy, who had eaten 300 to 400 g of Tricholoma equestre mushrooms daily for 4 days, developed a deep coma, acute respiratory failure, cyanosis, and seizures approximately 4 hours after the last meal. Physical examination indicated a Glasgow Coma Score (GCS) of 4, a pulse rate of 120 bpm, and a breath rate of approximately 6 breaths/minute. Laboratory analysis revealed an elevated ALT level of 56 units/liter (normal range 5 to 45 units/liter for a person 1- to 19-years-old) and a creatine kinase (CK) level of 306 units/liter (normal range 5 to 130 units/liter for a child). The patient also experienced muscle weakness of the pelvic girdle and bladder, requiring intermittent catheterization. With supportive care, the symptoms of Tricholoma equestre toxicity disappeared within 12 days of hospitalization (Chodorowski et al, 2003).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, and watery diarrhea have been reported following ingestions of Tricholoma equestre and Russula subnigricans mushrooms (Chodorowski et al, 2002; Bedry et al, 2001; Lee et al, 2001).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Elevated liver enzyme levels (ALT, AST, LDH) occurred in several patients following ingestion of Tricholoma equestre and Russula subnigricans mushrooms (Anand et al, 2009; Chodorowski et al, 2002; Bedry et al, 2001; Lee et al, 2001).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) In animal studies, the mice who were given 12 g/kg/day of freshly frozen Tricholoma flavovirens mushrooms for 4 weeks had higher plasma bilirubin concentrations and higher CK and CK-MB activities than the control mice. In the histological samples, no signs of hepato- or myotoxicity were observed; however, increased incidence of pericardial inflammation in the Tricholoma flavovirens-fed mice was observed in the cardiac samples (Nieminen et al, 2008).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis has been reported in several patients after ingesting Russula subnigricans mushrooms (Nishiyama et al, 2010; Anand et al, 2009; Chodorowski et al, 2002; Lee et al, 2001; Bedry et al, 2001).
    b) CASE REPORT: A 72-year-old man presented with muscle weakness and myalgia approximately 24 hours after ingesting 300 to 400 grams of Tricholoma equestre mushrooms during 10 consecutive meals. Laboratory analysis revealed elevated serum creatine kinase (peak 44767 Units/liter) and liver enzyme levels (ALT and AST). On day 2 of hospitalization, he complained of pain and weakness of the muscle of the chest, shoulders and abdomen. Despite supportive therapy, the patient's condition worsened with the development of acute respiratory failure and cardiac arrest, resulting in his subsequent death several hours later (Anand et al, 2009).
    c) CASE REPORTS: Two patients, a mother and son aged 48 and 20, respectively, consumed 100 to 300 g of Tricholoma equestre mushrooms during 9 consecutive meals, and subsequently developed fatigue, muscle weakness, and myalgia of upper and lower extremities approximately 48 hours after consumption of the last meal. Both patients also experienced loss of appetite, mild nausea, and diaphoresis. Laboratory data revealed elevated serum creatine kinase levels (18,150 units/liter and 48,136 units/liter in the mother and son, respectively) and elevated ALT and AST levels. Both patients gradually recovered approximately 25 days post-ingestion (Chodorowski et al, 2002).
    d) CASE REPORT (CHILD): A 5-year-old boy developed muscle weakness of the pelvic girdle and urinary bladder, requiring intermittent catheterization, after consuming 300 to 400 g of Tricholoma equestre mushrooms daily for 4 days. Laboratory analysis revealed a mildly elevated creatine kinase level of 306 units/liter (normal range 5 to 130 units/liter for a child). The child recovered within 12 days of hospitalization (Chodorowski et al, 2003).
    e) CASE REPORT (ADULT): A 60-year-old man, with a history of hypertension, experienced nausea, vomiting, watery diarrhea, dyspnea, muscle weakness, and generalized myalgia approximately 6 hours after consuming wild mushroom soup containing Russula subnigricans. Initial laboratory analysis revealed elevated hepatic enzyme levels (AST, ALT, LDH) and a creatine phosphokinase (CK) level of 12,551 units/liter. Urinalysis showed hematuria and proteinuria. Chest radiographs revealed cardiomegaly and an ECG indicated sinus tachycardia and left ventricular hypertrophy with strain.
    1) Over the next several hours, the patient's condition continued to deteriorate, necessitating mechanical ventilation. He experienced chest tightness, neck tightness, cold limbs, drowsiness, acute respiratory failure, and hypertension (182/100 mmHg) progressing to hypotension (70/40 mmHg). Repeat laboratory analysis revealed renal dysfunction (BUN 44 mg/dL), creatinine 2.3 mg/dL), persistent leukocytosis (WBC 21,700/mm(3)), markedly elevated liver enzyme levels (AST, ALT, LDH) and CK levels (204,500 units/liter), hyperkalemia, and hypocalcemia. Following supportive care, including a 2-week course of hemodialysis, the patient was successfully extubated and was subsequently discharged 33 days post-admission with a serum creatinine of 1.9 mg/dL and a CK level of 128 units/liter (Lee et al, 2001).
    f) CASE REPORT (ADULT): A 46-year-old woman presented to the hospital with chest tightness, neck stiffness, and myalgia 6 hours after consuming wild mushroom soup containing Russula subnigricans. Laboratory analysis showed a creatine phosphokinase level of 2,225 units/liter that peaked on hospital day 2 to 14,230 units/liter. There was no evidence of renal failure and the patient recovered without sequelae (Lee et al, 2001).
    g) CASE SERIES: Twelve patients (seven women and five men) reported fatigue, muscle weakness progressing to leg stiffness, and myalgia approximately one week after consumption of at least three consecutive meals containing Tricholoma equestre mushrooms. Eight of the 12 patients also experienced facial erythema, mild nausea, and diaphoresis. Laboratory analysis of the 12 patients revealed a mean maximal serum creatine kinase level of 226,067 units/liter in the women and 34,786 units/liter in the men. Electromyography, performed in 4 patients, revealed muscle injury without peripheral nerve involvement. In 6 patients, histologic analysis was conducted on samples of quadriceps muscle. Signs of direct muscle injury were observed, including separation of muscle fibers by edema in the absence of vacuoles or the accumulation of glycogen or lipid. All but 3 patients gradually recovered, experiencing persistent muscular weakness for several weeks following hospital discharge (Bedry et al, 2001).
    3.15.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) In animal studies, the mice who were given 12 g/kg/day of freshly frozen Tricholoma flavovirens mushrooms for 4 weeks had higher plasma bilirubin concentrations and higher CK and CK-MB activities than the control mice. In the histological samples, no signs of hepato- or myotoxicity were observed; however, increased incidence of pericardial inflammation in the Tricholoma flavovirens-fed mice was observed in the cardiac samples (Nieminen et al, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) In patients with a known exposure to these species of mushrooms, or in patients with exposure to unknown mushrooms and symptoms suggestive of rhabdomyolysis and myopathy, serial serum creatine kinase (CK) levels should be followed.
    B) Monitor serum electrolytes, renal function, hepatic enzymes, and urine output in symptomatic patients.
    C) Monitor ECG in patients with rhabdomyolysis.
    D) In patients with a known exposure to these mushrooms but no initial symptoms, consider following serum CK, electrolytes, and renal function tests every 24 to 48 hours for several days to detect delayed-onset myopathy and rhabdomyolysis.
    4.1.2) SERUM/BLOOD
    A) Patients with known exposure to Tricholoma equestre or Russula subnigricans mushrooms, or patients with symptoms suggesting rhabdomyolysis (weakness, myalgia, fatigue) after ingestion of unknown mushrooms should be evaluated for rhabdomyolysis.
    1) The following tests have been used to evaluate rhabdomyolysis: serum myoglobin (sMb), and serum creatine kinase (CK). Serum CK is the most commonly used test for diagnosis. The most sensitive test used to confirm the diagnosis of muscle breakdown is CK-MM (the dominant isoform in skeletal muscle) (Grover et al, 2004).
    B) Monitor serum electrolytes, renal function, and hepatic enzymes in symptomatic patients.
    C) In patients with a known exposure to these mushrooms but no initial symptoms, consider following serum CK, electrolytes, and renal function tests every 24 to 48 hours for several days to detect delayed-onset myopathy and rhabdomyolysis.
    4.1.3) URINE
    A) Monitor urine output in patients with rhabdomyolysis.
    B) The following tests have been used to evaluate rhabdomyolysis: urine myoglobin (uMb) and urine heme pigments (uH) (Grover et al, 2004)
    4.1.4) OTHER
    A) OTHER
    1) ECG: Monitor ECG in patients with rhabdomyolysis.

Radiographic Studies

    A) MRI
    1) A 62-year-old man developed rhabdomyolysis (CK 42,689 Units/L) 20 hours after ingesting a meal containing Russula subnigricans mushrooms. MRI of the muscle showed diffuse high signal intensity in the bilateral infraspinatus and left supraspinatus muscles (Nishiyama et al, 2010).

Methods

    A) ASSAY
    1) One study evaluated the accuracy and clinical utility of microconcentrator qualitative assay for urine myoglobin (uMb) in screening patients (n=673) with rhabdomyolysis. To detect severe rhabdomyolysis (CK of greater than 10,000 units/liter), the uMb assay had a sensitivity of only 26.4% (95% CI: 23.1%-29.7%) and specificity of 96.8% (95% CI: 95.5%-98.1%). Patients with CK, uMb and uH measured in the same 24-hour period were identified. The presence of "moderate" or "large" urine hemoglobin on dipstick in the absence of hematuria on microscopy had a sensitivity of 81% in detecting severe rhabdomyolysis (Grover et al, 2004).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significantly elevated CK, elevated creatinine, or myoglobinuria should be admitted for hydration and monitoring. Patients with hypotension, hyperthermia, marked hyperkalemia, acute renal failure, or respiratory failure should be admitted to an ICU setting.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or your local poison center for any patient with suspected mushroom-induced rhabdomyolysis. For patients with resulting acute renal failure and/or hyperkalemia due to rhabdomyolysis, consult a nephrologist for assistance with hemodialysis if needed. A mycologist can assist with identification of the mushroom.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with known exposure to these mushrooms, or patients with exposure to unknown mushrooms with signs and symptoms concerning for rhabdomyolysis, should be evaluated at a healthcare facility. If creatine kinase (CK), creatinine, and electrolytes are normal, patients may be discharged with outpatient follow-up in 24 to 48 hours for repeat labs to evaluate for delayed myopathy.

Monitoring

    A) In patients with a known exposure to these species of mushrooms, or in patients with exposure to unknown mushrooms and symptoms suggestive of rhabdomyolysis and myopathy, serial serum creatine kinase (CK) levels should be followed.
    B) Monitor serum electrolytes, renal function, hepatic enzymes, and urine output in symptomatic patients.
    C) Monitor ECG in patients with rhabdomyolysis.
    D) In patients with a known exposure to these mushrooms but no initial symptoms, consider following serum CK, electrolytes, and renal function tests every 24 to 48 hours for several days to detect delayed-onset myopathy and rhabdomyolysis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: If the mushroom is positively identified as one of these species and ingestion has occurred within 1 hour, consider administering charcoal. However, patients typically present for evaluation only after developing symptoms of toxicity 24 hours to several days after ingestion; in these cases charcoal is not helpful.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) If the mushroom is positively identified as one of these species and ingestion has occurred within 1 hour, consider administering charcoal. However, patients typically present for evaluation only after developing symptoms of toxicity 24 hours to several days after ingestion; in these cases charcoal is not helpful.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive care. Patients who develop rhabdomyolysis with elevated creatinine kinase (CK) and myoglobinuria will benefit from aggressive hydration with 0.9% saline to maintain urine output at 2 to 3 mL/kg/hr. Urinary alkalinization is NOT routinely recommended.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Patients who develop severe toxicity with hypotension should be treated first with IV fluids, with the addition of pressors (eg, dopamine or norepinephrine) if hypotension with mean arterial pressure (MAP) of less than 60 mm Hg persists. Patients with hyperthermia should be aggressively cooled, sedated with benzodiazepines, and if necessary intubated and paralyzed with a non-depolarizing paralytic agent. Patients with severe rhabdomyolysis with worsening renal function or hyperkalemia despite adequate hydration may require dialysis.
    3) Save all emesis and stools in refrigerator (DO NOT FREEZE) for possible microscopic study and analysis.
    4) HISTORY OF CURRENT ILLNESS
    a) The following questions should be asked in taking the medical history regarding the exposure of the patient to the mushroom:
    1) At what time were the mushrooms eaten?
    2) When was the onset of symptoms after the ingestion?
    3) Was the mushroom eaten at more than one meal?
    4) Were the mushrooms eaten again later and, if so, were they reheated?
    5) Was the mushroom eaten raw or cooked?
    6) Was any alcohol consumed within 24 hours of the meal?
    7) Was more than one kind of mushroom ingested?
    8) How were the mushrooms stored between collection and preparation?
    9) What was the condition of the mushrooms at the time of preparation?
    10) How were the mushrooms prepared (ie, raw, sauteed, fried, soup, stew, etc.)?
    11) Are ALL persons who ate the mushroom ill?
    12) Are persons in the group who ate NONE of the mushroom ill?
    13) Other important questions regarding the mushroom include:
    a) What kind of substrate was it growing on (eg; wood, soil, etc.)?
    b) What kind of tree(s) was it growing near?
    c) What time of year was the mushroom collected?
    B) MONITORING OF PATIENT
    1) In patients with a known exposure to these species of mushrooms, or in patients with exposure to unknown mushrooms and symptoms suggestive of rhabdomyolysis and myopathy, serial serum creatine kinase (CK) levels should be followed.
    2) Monitor serum electrolytes, renal function, hepatic enzymes, and urine output in symptomatic patients.
    3) Monitor ECG in patients with rhabdomyolysis.
    4) In patients with a known exposure to these mushrooms but no initial symptoms, consider following serum CK, electrolytes, and renal function tests every 24 to 48 hours for several days to detect delayed-onset myopathy and rhabdomyolysis.
    C) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    E) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) The toxins responsible for this syndrome have not been identified; it is unknown if hemodialysis enhances their elimination. Dialysis has been used in patients with rhabdomyolysis and acute renal failure after ingestion of these mushrooms.
    2) CASE REPORT: A 60-year-old man received a 2-week course of hemodialysis after he developed hyperkalemia, hypocalcemia, elevated hepatic enzyme and creatine phosphokinase (CK) levels, ventricular tachycardia, hypotension, oliguria, and acute respiratory insufficiency several days after consuming wild mushroom soup containing Russula subnigricans mushrooms. His serum creatinine and CK levels peaked at 12.1 mg/dL and 246,600 units/liter, respectively, within 4 to 8 days after beginning dialysis, and then decreased to approximately 8.6 mg/dL and 264 units/liter, respectively, after dialysis was completed (Lee et al, 2001).

Range Of Toxicity

Summary

    A) TOXICITY: Signs and symptoms typically only develop after repeated ingestion of these mushrooms over several consecutive meals or consecutive days. Rhabdomyolysis requiring supportive care for 12 to 25 days developed in one patient after ingesting 300 to 400 grams of Tricholoma equestre mushrooms daily for 4 consecutive days, and in 2 patients after ingesting 100 to 300 grams for 9 consecutive meals. Lethal exposures to Tricholoma equestre have occurred in 3 patients who had eaten at least 3 consecutive meals containing an unknown quantity and one patient who ate 300 to 400 grams for 10 consecutive meals; these patients developed renal dysfunction, myocardial lesions, and respiratory failure despite hydration and continuous venovenous hemofiltration. Several lethal ingestions of Russula subnigricans have occurred; however, the lethal dose remains unknown at this time.

Minimum Lethal Exposure

    A) Three patients, who had eaten at least 3 consecutive meals containing an unknown quantity of Tricholoma equestre mushrooms, developed hyperthermia, signs of acute myocarditis (cardiac dysrhythmias, QRS complex widening, and cardiovascular collapse), and evidence of renal dysfunction, including elevated BUN and serum creatinine levels with hyperkalemia (6.0 to 7.2 mmol/L) and hypocalcemia (calcium 5.6 to 8.3 mg/dL [1.4 to 2.07 mmol/L). The creatine kinase levels of the three patients ranged from 138,900 to 632,000 units/liter. All three patients died, despite intensive supportive care including continuous venovenous hemofiltration. Autopsy revealed myocardial lesions in one patient and renal lesions in one patient (Bedry et al, 2001).
    B) CASE REPORT: A 72-year-old man presented with muscle weakness and myalgia approximately 24 hours after ingesting 300 to 400 grams of Tricholoma equestre mushrooms during 10 consecutive meals. Laboratory analysis revealed elevated serum creatine kinase (peak 44767 Units/liter) and liver enzyme levels (ALT and AST). On day 2 of hospitalization, he complained of pain and weakness of the muscle of the chest, shoulders and abdomen. Despite supportive therapy, the patient's condition worsened with the development of acute respiratory failure and cardiac arrest, resulting in his subsequent death several hours later (Anand et al, 2009).

Maximum Tolerated Exposure

    A) CASE REPORT (CHILD): A 5-year-old boy, who had eaten 300 to 400 grams of Tricholoma equestre mushrooms daily for 4 days, developed a deep coma, acute respiratory failure, cyanosis, and seizures approximately 4 hours after the last meal. Physical examination indicated a Glasgow Coma Score (GCS) of 4, a pulse rate of 120 bpm, and a breath rate of approximately 6 breaths/minute. Laboratory analysis revealed an elevated ALT level of 56 units/liter (normal range 5 to 45 units/liter for a person 1- to 19-years-old) and a creatine kinase (CK) level of 306 units/liter (normal range 5 to 130 units/liter for a child). The patient also experienced muscle weakness of the pelvic girdle and bladder, requiring intermittent catheterization. With supportive care, the symptoms of Tricholoma equestre toxicity disappeared within 12 days of hospitalization (Chodorowski et al, 2003).
    B) CASE REPORTS (ADULT): Two patients, a mother and son aged 48 and 20, respectively, consumed 100 to 300 grams of Tricholoma equestre mushrooms during 9 consecutive meals, and subsequently developed fatigue, muscle weakness, and myalgia of upper and lower extremities approximately 48 hours after consumption of the last meal. Both patients also experienced loss of appetite, mild nausea, and diaphoresis. Laboratory data revealed elevated serum creatine kinase levels (18,150 units/liter and 48,136 units/liter in the mother and son, respectively) and elevated ALT and AST levels. Both patients gradually recovered approximately 25 days post-ingestion (Chodorowski et al, 2002).

Pharmacology Toxicology

Toxicologic Mechanism

    A) In one study, cycloprop-2-ene carboxylic acid was identified by NMR spectroscopy as the toxic component of Russula subnigricans responsible for the development of severe rhabdomyolysis. It was revealed that polymerization of the compound at high concentrations via ene reaction abolishes its toxicity (Matsuura et al, 2009).
    B) An experiment, involving rats, was conducted to confirm the association between ingestion of Tricholoma equestre mushrooms and the development of rhabdomyolysis. Various Tricholoma equestre extracts were used in this dose-response study including 500 grams of T. equestre mixed with 200 mL of ultrapure water that was lyophilized yielding 60 grams of powder, a concentrate of 1.35 grams of cold aqueous extract obtained from 5 grams of powdered T. equestre, a concentrate of 1.65 grams of boiled aqueous extract obtained from 5 grams of powdered T. equestre, and a concentrate of 1.3 grams obtained from 10 grams of powdered T. equestre after chloroform-methanol (vol/vol) extraction. The results of the study showed that all mice treated with T. equestre developed elevated serum creatine kinase levels, tachypnea, reduced motor activity, and occasional diarrhea. Light microscopy of muscle fibers showed disorganization. Although the toxic component of T. equestre has not yet been identified, it is clear that the toxic compound is extracted equally well by water and chloroform-methanol (Bedry et al, 2001).
    C) Six chlorinated phenyl ethers, identified as russuphelins A, B, C, D, E, and F, have been isolated from the mushroom Russula subnigricans Hongo. Russuphelin A exhibited cytotoxicity against various solid tumor cells, and russuphelins B, C, and D exhibited cytotoxicity in vitro against P38 leukemic cells; however, the causal relationship between the russuphelins and development of rhabdomyolysis, following ingestion of R. subnigricans, has not been established (Lee et al, 2001; Takahashi et al, 1993).

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