Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

ATRACTYLIS GUMMIFERA

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Atractylis gummifera is a toxic plant which is widely distributed in Mediterranean countries. Ingestion of the root extracts, where the toxic glucosides are found, produces toxicity, with the liver as the main target organ. Fatalities have resulted from plant ingestions. Toxicity may be induced by the oral, respiratory, and cutaneous routes. Prognosis has generally been poor following poisonings.
    B) Atractyloside, the toxic diterpenoid glycoside first isolated from the plant, Atractylis gummifera, has more recently been isolated from other plant sources; one in particular, Callilepis laureola, has been responsible for poisonings in Africa. The major source of human exposure to atractyloside is through herbal remedies.

Specific Substances

    1) Atractylis gummifera
    2) Atractylis gummifera L.
    3) Birdlime thistle
    4) White chameleon
    5) ATRACTYLIS GUMMIFERA (L) (BOTANIC NAME)
    6) CHAMELEON, WHITE (COMMON NAME FOR ATRACTYLIS GUMMIFERA)
    7) WHITE CHAMELEON (COMMON NAME FOR ATRACTYLIS GUMMIFERA (L)

Available Forms Sources

    A) FORMS
    1) The plant secretes a whitish-yellowish, glue-like substance that is often used as a chewing gum (Schiano, 1998).
    B) SOURCES
    1) The two principle toxic glycosides of the plant (Atractylis gummifera) are atractyloside and carboxyatractyloside which are mainly found in the root extracts, and are most toxic in the springtime (Calmes et al, 1994; Schiano, 1998; Georgiou et al, 1988).
    C) USES
    1) Human exposures are mainly from herbal remedies (Obatomi & Bach, 1998) Watson et al, 1979). Parts of the plant have traditionally been used as a purgative, emetic, diuretic, and antipyretic (Hamouda et al, 2004; Schiano, 1998). Other uses have included treatment of syphilitic ulcers, bleaching teeth, and as an abortifacient(Georgiou et al, 1988). Nogue et al (1992) reported treatment of chronic lumbar back pain as another traditional use of this plant. A gum secretion from leaves of the plant has been used as chewing gum in Mediterranean countries (Stewart & Steenkamp, 2000).

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: Atractylis gummifera is a type of thistle; the common name is white chameleon. Various species have been used as a herbal remedy for various indications, as a purgative, analgesic, emetic, diuretic, antipyretic, for bleaching teeth, and as an abortifacient. The leaf produces a glue-like substance and is used as a chewing gum.
    B) TOXICOLOGY: Two glucosides, atractyloside and carboxyatractyloside, are responsible for the plant's toxicity. They inhibit mitochondrial oxidative phosphorylation and can also cause hepatotoxicity and renal failure. The root or root extracts are primarily responsible for the plant's toxicity. The root is harvested, and most toxic, in the spring.
    C) EPIDEMIOLOGY: Atractylis gummifera is a thistle mostly found in the Mediterranean region, including Greece, Italy, Sicily, Spain, Portugal and North Africa. Toxicity is uncommon, but severe effects and deaths have been reported.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: After ingestion, gastrointestinal symptoms typically occur within 24 hours of ingestion. GI effects include vomiting, nausea, abdominal pain, esophagitis, and dysphagia. It can also produce hematemesis. These effects are followed by dizziness and weakness. Renal failure can develop early in the clinical course.
    2) SEVERE TOXICITY: More severe events include: hepatitis, hypoglycemia, coagulopathies, renal failure, metabolic acidosis, and CNS depression. Death can occur in hours to days depending on the amount ingested, usually due to hepatic failure.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Respiratory rate may be increased, with hypertension followed by hypotension in progressive cases. Tachycardia has been reported.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Transient hypertension, followed by severe hypotension is commonly seen following ingestions. Cardiac dysrhythmias have been reported.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression, necessitating mechanical ventilation, may occur in severe toxicities.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Initial presentation of gastrointestinal effects and weakness is often followed by rapid onset of coma and CNS depressant effects. Seizures and CNS hemorrhages may occur.
    2) EEG may be abnormal.
    3) Muscle weakness and decreased reflexes have been reported.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Epigastric pain with copious vomiting and diarrhea is normally reported within the first 24 hours of ingestion.
    0.2.9) HEPATIC
    A) WITH POISONING/EXPOSURE
    1) The hallmark of poisoning is hepatic dysfunction progressing to fulminant hepatic failure and death.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Renal dysfunction, leading to renal failure in severe cases of toxicity, has been reported.
    0.2.11) ACID-BASE
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may occur in severe poisonings.
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Coagulopathies have been reported in human poisonings.
    0.2.16) ENDOCRINE
    A) WITH POISONING/EXPOSURE
    1) Hypoglycemia, often severe, is a common toxic effect of Atractylis gummifera.
    0.2.20) REPRODUCTIVE
    A) A 28-year-old woman, who ingested an unknown amount of atractylis gummifera in her 24th week of pregnancy, subsequently delivered, at 39 weeks, a healthy baby boy .

Laboratory Monitoring

    A) Monitor vital signs and mental status in all poisoning cases.
    B) With significant ingestions, obtain a CBC, electrolytes, liver enzymes and renal function. Monitor coagulation studies in patients with hepatic injury.
    C) Monitor oxygen saturation and administer oxygen as required.
    D) Obtain a urinalysis and monitor urine output.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Administer IV fluids and antiemetics as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Continue supportive care. Hypotension: Treatment includes IV fluid resuscitation, followed by vasopressors, if hypotension persists. Seizures: Administer benzodiazepines. For CNS depression or respiratory failure, airway protection and ventilation may be needed. Treat hypoglycemia with IV dextrose. Hemodialysis may be required in cases of renal failure. Liver transplant has been suggested for hepatic failure.
    C) DECONTAMINATION
    1) PREHOSPITAL: Decontamination is unlikely to be necessary because significant vomiting may develop after ingestion.
    2) HOSPITAL: Patients generally present late after ingestion with significant vomiting so GI decontamination is likely of limited utility. Activated charcoal should be administered in any patient with a recent ingestion who is not vomiting, and awake and able to maintain their airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is usually not necessary, but may be indicated in cases of CNS depression or respiratory failure.
    E) ANTIDOTE
    1) There is no known antidote for atractylis gummifera.
    F) ENHANCED ELIMINATION
    1) Enhanced elimination is usually not necessary; however, hemodialysis may be needed in cases of renal failure.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Children with taste exposures and asymptomatic adults can probably be monitored at home.
    2) OBSERVATION CRITERIA: Any symptomatic ingestion, or self-harm attempt ingestion should be evaluated in the emergency department. Children with more than taste exposures should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Patients with persistent symptoms, those with laboratory evidence of renal or hepatic injury, metabolic acidosis or hypoglycemia, and those with altered mental status, hypotension or persistent vomiting should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity.
    H) PITFALLS
    1) Failure to recognize the potential severity of toxicity from the ingestion.
    I) PHARMACOKINETICS
    1) Rapid oral absorption has been described, but the pharmacokinetics are not well studied. Toxicity has been reported from absorption through burned skin.
    J) DIFFERENTIAL DIAGNOSIS
    1) Other related triterpenoid glycosides which include: Callilepis laureola, Xanthium atrumarium, Coffea Arabica, Weidelia gluaca, Wedelia asperrima, Atractylis carduus, Atractylodes lancea, and lphiona aucheri.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Maximum tolerated dose and minimal lethal human dose has not been delineated. Ingestion of the root or a root extract, especially if harvested in the spring may be toxic.
    B) THERAPEUTIC DOSE: The estimated dose used as an alternative medicine is 67 micrograms atractyloside in an adult.

Clinical Effects

Summary Of Exposure

    A) USES: Atractylis gummifera is a type of thistle; the common name is white chameleon. Various species have been used as a herbal remedy for various indications, as a purgative, analgesic, emetic, diuretic, antipyretic, for bleaching teeth, and as an abortifacient. The leaf produces a glue-like substance and is used as a chewing gum.
    B) TOXICOLOGY: Two glucosides, atractyloside and carboxyatractyloside, are responsible for the plant's toxicity. They inhibit mitochondrial oxidative phosphorylation and can also cause hepatotoxicity and renal failure. The root or root extracts are primarily responsible for the plant's toxicity. The root is harvested, and most toxic, in the spring.
    C) EPIDEMIOLOGY: Atractylis gummifera is a thistle mostly found in the Mediterranean region, including Greece, Italy, Sicily, Spain, Portugal and North Africa. Toxicity is uncommon, but severe effects and deaths have been reported.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: After ingestion, gastrointestinal symptoms typically occur within 24 hours of ingestion. GI effects include vomiting, nausea, abdominal pain, esophagitis, and dysphagia. It can also produce hematemesis. These effects are followed by dizziness and weakness. Renal failure can develop early in the clinical course.
    2) SEVERE TOXICITY: More severe events include: hepatitis, hypoglycemia, coagulopathies, renal failure, metabolic acidosis, and CNS depression. Death can occur in hours to days depending on the amount ingested, usually due to hepatic failure.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Respiratory rate may be increased, with hypertension followed by hypotension in progressive cases. Tachycardia has been reported.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Initially, respiratory rate may be increased. Following the onset of CNS depression, respiratory depression may occur, requiring mechanical ventilation (Georgiou et al, 1988).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Hypothermia was reported in 6 children in a family following ingestion of the plant (Lemaigre et al, 1975).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Initially, hypertension may be present(Nogue et al, 1992; Lemaigre et al, 1975). Following disease progression, hypotension occurs (Georgiou et al, 1988; Schiano, 1998).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Tachycardia may be a common initial clinical presentation (Lemaigre et al, 1975).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Mydriasis is commonly seen in severe, progressive cases of toxicity (Lemaigre et al, 1975; Georgiou et al, 1988).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Transient hypertension, followed by severe hypotension is commonly seen following ingestions. Cardiac dysrhythmias have been reported.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Transient hypertension has been reported as an initial effect in poisonings. With disease progression, a severe refractory hypotension generally occurs (Nogue et al, 1992; Lemaigre et al, 1975; Georgiou et al, 1988; Schiano, 1998). This is seen most commonly following ingestions of the raw root extract when it is harvested in springtime (Larrey & Pageaux, 1995).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Cardiac dysrhythmias have been reported in serious poisonings (Georgiou et al, 1988).
    b) CASE REPORT: A 30-month-old boy was admitted to a pediatric ICU in a coma following the application of an occlusive dressing saturated in a liquid containing A. gummifera; the root was boiled in 1L of water. According to the parents, the dressing was changed every 12 hours to treat a burn for 6 days prior to admission. Shortly after admission he developed ventricular tachycardia secondary to severe hyperkalemia (potassium 7.4 mmol/L) with hypotension. Treatment included immediate cardioversion and peritoneal dialysis. His clinical course was complicated by hepatorenal injury and acute renal failure. A urine screen was positive for A. gummifera. The child gradually improved and was discharged to home on day 16 with persistent renal insufficiency (Bouziri et al, 2010).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression, necessitating mechanical ventilation, may occur in severe toxicities.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Increased respiratory rate may be seen on initial presentation to the ED. With disease progression, CNS depression with coma and respiratory depression may develop, necessitating mechanical ventilation (Georgiou et al, 1988). Early mechanical ventilation following poisoning appears to delay the onset of nephrotoxicity (Obatomi & Bach, 1998).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Initial presentation of gastrointestinal effects and weakness is often followed by rapid onset of coma and CNS depressant effects. Seizures and CNS hemorrhages may occur.
    2) EEG may be abnormal.
    3) Muscle weakness and decreased reflexes have been reported.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) Within the first 24 hours of a toxic ingestion the patient generally exhibits vomiting and diarrhea with vertigo and weakness. Rapid onset of coma follows, sometimes with encephalopathy, seizures, CNS hemorrhages, and respiratory depression (Hamouda et al, 2004; Steenkamp et al, 1999; Georgiou et al, 1988; Cardevielle & Darracq, 1980; Watson et al, 1979).
    b) CASE REPORT: A 30-month-old boy was admitted to a pediatric ICU in a coma following the application of an occlusive dressing saturated in a liquid containing A. gummifera; the root was boiled in 1L of water. According to the parents, the dressing was changed every 12 hours to treat a burn for 6 days prior to admission. Shortly after admission he developed ventricular tachycardia secondary to severe hyperkalemia (potassium 7.4 mmol/L) with hypotension. Treatment included immediate cardioversion and peritoneal dialysis. His clinical course was complicated by hepatorenal injury and acute renal failure. A urine screen was positive for A. gummifera. The child gradually improved and was discharged to home on day 16 with persistent renal insufficiency (Bouziri et al, 2010).
    c) CASE REPORT: Impaired consciousness with a Glasgow Coma Scale score of 11 was reported in a 28-year-old woman, in her 24th week of pregnancy, who ingested an unknown amount of atractylis gummifera. The patient also developed vomiting, abdominal pain, bloody diarrhea, and elevated liver enzyme levels. With supportive care, the patient recovered and, in her 39th week of pregnancy, delivered a healthy baby boy (Madani et al, 2006).
    B) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Patients often present within the first 24 hours with vertigo, headache, extreme weakness, and generalized myalgias(Nogue et al, 1992; Georgiou et al, 1988; Cardevielle & Darracq, 1980).
    C) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Abnormal EEG has been reported in severe toxicity (Cardevielle & Darracq, 1980; Georgiou et al, 1988). In one case EEG was suggestive of general cerebral edema (Georgiou et al, 1988).
    D) HYPOREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) Decreased, sluggish or absent reflexes were reported in at least 2 children of a family who all ingested Atractylis gummifera (Lemaigre et al, 1975).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Epigastric pain with copious vomiting and diarrhea is normally reported within the first 24 hours of ingestion.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Initial presenting clinical effects, occurring within the first 24 hours of ingestion, include epigastric pain with copious vomiting and diarrhea, which may be bloody (Hamouda et al, 2004; Steenkamp et al, 1999; Schiano, 1998; Larrey & Pageaux, 1995; Georgiou et al, 1988; Cardevielle & Darracq, 1980; Lemaigre et al, 1975).
    b) CASE REPORT: A 28-year-old pregnant woman, in her 24th week of pregnancy, experienced vomiting, abdominal pain, and bloody diarrhea after ingesting an unknown amount of atractylis gummifera. The patient recovered following symptomatic treatment and subsequently delivered a healthy baby boy in her 39th week of pregnancy (Madani et al, 2006).
    B) GASTROINTESTINAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Gastrointestinal hemorrhage has been reported following poisoning. This is most likely due to coagulopathies caused by hepatic dysfunction (Steenkamp et al, 1999).

Hepatic

    3.9.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) The hallmark of poisoning is hepatic dysfunction progressing to fulminant hepatic failure and death.
    3.9.2) CLINICAL EFFECTS
    A) HEPATIC FAILURE
    1) WITH POISONING/EXPOSURE
    a) Severe poisonings result in increasing hepatic dysfunction, with elevated serum liver enzymes (ALT and AST), elevated serum bilirubin, elevated NH3, and coagulopathies, including prolonged PT and PTT (Madani et al, 2006; Steenkamp et al, 1999; Schiano, 1998; Nogue et al, 1992; Georgiou et al, 1988; Cardevielle & Darracq, 1980; Lemaigre et al, 1975). Elevated ALT and AST, up to 800-fold, has been associated with a 50% reduction of prothrombin index and severe centrilobular hepatocellular necrosis (Obatomi & Bach, 1998). Hepatic failure is a poor prognostic indicator, with death occurring within a few days (typically less than 4 days) (Hamouda et al, 2004; Stewart & Steenkamp, 2000).
    1) Jaundice may be a rare finding due to the rapid onset of hepatotoxicity and rapid progression to death (Stewart & Steenkamp, 2000).
    2) Hepatic necrosis, due to prolonged ischemia, has been observed during postmortem examinations (Hamouda et al, 2004).
    b) CASE REPORT: A 30-month-old boy was admitted to a pediatric ICU in a coma following the application of an occlusive dressing saturated in a liquid containing A. gummifera; the root was boiled in 1L of water. According to the parents, the dressing was changed every 12 hours to treat a burn for 6 days prior to admission. He developed elevated liver enzymes, cholestasis, decreased prothrombin level, and increased creatinine. A urine screen was positive for A. gummifera. There was no evidence of viral hepatitis. The child gradually improved and was discharged to home on day 16 with persistent renal insufficiency (Bouziri et al, 2010).
    c) CASE REPORT: Georgiou et al (1988) reported a poisoning in a 7-year-old boy who developed fulminant hepatic failure and death after drinking an extract made from the plant root. Postmortem examination revealed diffuse necrosis of the hepatic parenchyma and collapse of the interstitial connective tissue with accumulation of macrophages containing ceroid. Intrahepatic cholestasis was also reported.
    d) CASE REPORT: Following Callilepis laureola poisoning, a 21-year-old woman died 3 days after hospital admission. Postmortem examination revealed edematous portal tracts and severe ductal metaplasia. Acute submassive necrosis of the parenchyma, involving all hepatic zones, was notable (Steenkamp et al, 1999).
    e) CASE SERIES: Four children died following ingestion of Atractylis gummifera. On macroscopic examination of the livers, fulminant hepatitis with marked necrosis was seen. Histologic examination of the livers revealed massive eosinophilic necrosis, centrilobular necrosis, and marked congestion and thickening of the central lobular veins (Lemaigre et al, 1975).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC FAILURE
    a) Liver histology in rats and mice given 5 mg/kg orally twice daily as a 10% solution for 10 to 12 days revealed destruction of nuclei in periportal cells, nuclear pleomorphism, mixed inflammatory infiltrates, and diffuse hyperplasia of Kupffer cells (Martin et al, 1985).
    b) In rat studies, liver necrosis was a striking feature of atractyloside toxicity. Evidence of early renal tubular necrosis was noted where liver necrosis was established; however, it was seldom comparable in severity (Wainwright et al, 1977).
    c) IN-VITRO toxicity of Callilepis laureola in human hepatoblastoma Hep G2 cells was reported. Cytotoxicity was produced in a concentration-dependent manner and was significant at all concentrations tested. 100% toxicity was observed at a concentration of 6.7 mg/mL at 6 hours. Toxicity was found to be time-dependent, with significantly higher toxicity after 24 hours of incubation than 48 hours (Popat et al, 2001).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Renal dysfunction, leading to renal failure in severe cases of toxicity, has been reported.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Severe poisonings progress from mild renal insufficiency to renal failure, with increased BUN and creatinine, albuminuria, hematuria, and oliguria or anuria (Hamouda et al, 2004; Cardevielle & Darracq, 1980; Nogue et al, 1992; Georgiou et al, 1988; Lemaigre et al, 1975; Schiano, 1998). Renal biopsies have shown tubular-nephritic lesions in 2 postmortem cases (Lemaigre et al, 1975), tubular necrosis with marked interstitial infiltration in one case (Nogue et al, 1992) and renal congestion and petechial bleeding as well as renal tubular lesions in another fatality (Georgiou et al, 1988). Nephrotoxicity often begins with increased serum creatinine, increased urine output, and progresses to hyperkalemic acute renal failure within 24 hours after an acute ingestion (Obatomi & Bach, 1998). Renal tubular necrosis is commonly observed at postmortem examinations when renal failure was an early clinical finding (Hamouda et al, 2004; Stewart & Steenkamp, 2000).
    b) CASE REPORT: A 30-month-old boy was admitted to a pediatric ICU in a coma following the application of an occlusive dressing saturated in a liquid containing A. gummifera; the root was boiled in 1L of water. According to the parents, the dressing was changed every 12 hours to treat a burn for 6 days prior to admission. He developed elevated liver enzymes, cholestasis, decreased prothrombin level, and an increased creatinine (482 micromol/L; normal 60 to 120 micromol/L). A urine screen was positive for A. gummifera. His creatinine improved to 250 micromol/L prior to discharge. He gradually improved and was discharged on day 16 with persistent renal insufficiency (Bouziri et al, 2010).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL TUBULAR NECROSIS
    a) Histology of the renal system of rats and mice given 5 mg/kg orally twice daily as a 10% solution for 10 to 12 days revealed tubular hyalinization, interstitial inflammatory infiltrates, and tubular necrosis (Martin et al, 1985).

Acid-Base

    3.11.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may occur in severe poisonings.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis may be expected to occur in severe poisonings with renal failure and respiratory depression. Accumulation of lactic acid in tissues and blood has been reported in animal studies (Hamouda et al, 2004; Stewart & Steenkamp, 2000; Georgiou et al, 1988; Watson et al, 1979; Chardon et al, 1964).

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Coagulopathies have been reported in human poisonings.
    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION PATHWAY FINDING
    1) WITH POISONING/EXPOSURE
    a) Coagulopathies may be common in severe overdoses, with prolongation of INR and PTT (Georgiou et al, 1988). This is particularly evident in cases of progressive hepatic dysfunction.
    b) Petechial bleeding of the viscera (stomach, intestine, lungs, kidneys, peritoneum, and brain) has been found at necropsy in fatal cases (Steenkamp et al, 1999; Georgiou et al, 1988). Hemorrhagic syndrome is reported (Cardevielle & Darracq, 1980).
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) In a case series of 50 children with atractyloside poisoning, 80% were reported to have leukocytosis (total wbc greater than 11 x 10(9)/L) (Watson et al, 1979).

Endocrine

    3.16.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypoglycemia, often severe, is a common toxic effect of Atractylis gummifera.
    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Hypoglycemia, often severe, is common in poisonings due to inhibition of glycogen synthesis and oxidative phosphorylation (Madani et al, 2006; Stewart & Steenkamp, 2000; Cardevielle & Darracq, 1980; Chardon et al, 1964). A possible direct action on cellular metabolism of glucose has been speculated (Cardevielle & Darracq, 1980). Hypoglycemia often appears before a nephrotoxic reaction (Wainwright et al, 1977). Death has occurred within a few hours from hypoglycemic coma (Stewart & Steenkamp, 2000).
    b) In a case series of 50 children with atractyloside poisoning, 93% were reported to be hypoglycemic (Watson et al, 1979).

Reproductive

    3.20.1) SUMMARY
    A) A 28-year-old woman, who ingested an unknown amount of atractylis gummifera in her 24th week of pregnancy, subsequently delivered, at 39 weeks, a healthy baby boy .
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY OUTCOME
    1) CASE REPORT - A 28-year-old woman, in her 24th week of pregnancy, developed vomiting, abdominal pain, bloody diarrhea, impaired consciousness (GCS 11), and elevated liver enzyme levels after ingesting an unknown amount of atractylis gummifera. She recovered with symptomatic treatment. In her 39th week of pregnancy, the patient vaginally delivered a healthy baby boy. At birth, his Apgar score was 10 with a normal physical exam and normal lab values. One week later, a repeat exam and laboratory testing of the infant continued to yield normal results with no evidence of toxicity (Madani et al, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status in all poisoning cases.
    B) With significant ingestions, obtain a CBC, electrolytes, liver enzymes and renal function. Monitor coagulation studies in patients with hepatic injury.
    C) Monitor oxygen saturation and administer oxygen as required.
    D) Obtain a urinalysis and monitor urine output.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor hepatic function closely. Progressive liver dysfunction, with abnormal liver enzymes, bilirubin, and coagulopathies may progress to fulminant liver failure in severe cases (Georgiou et al, 1988; Cardevielle & Darracq, 1980; Nogue et al, 1992; Lemaigre et al, 1975; Schiano, 1998).
    2) Renal function should be monitored in all symptomatic patients. Severe poisonings progress from mild renal insufficiency to renal failure, with increased BUN and creatinine, albuminuria, hematuria, and oliguria or anuria (Cardevielle & Darracq, 1980; Nogue et al, 1992; Georgiou et al, 1988; Lemaigre et al, 1975; Schiano, 1998).
    3) Monitor electrolytes in symptomatic patients.
    4) No studies are available applying severity of acute atractyloside toxicity to plasma or urinary concentrations of parent compound or metabolites (Stewart & Steenkamp, 2000; Obatomi & Bach, 1998).
    B) COAGULATION STUDIES
    1) Progressive toxic cases often develop hepatic dysfunction and coagulopathies. Monitor PT or INR and PTT.
    C) HEMATOLOGY
    1) Complete blood count should be monitored in all symptomatic patients.
    4.1.4) OTHER
    A) OTHER
    1) OXYGEN SATURATION
    a) Monitor oxygen saturation with pulse oximetry and arterial blood gases as needed in all symptomatic patients.
    2) OTHER
    a) In severe symptomatic poisonings, with decreased levels of consciousness and hepatic failure, monitor for cerebral edema.
    b) Once the patient is stabilized, an electroencephalogram (EEG) may be useful in severe cases.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) If respiratory tract irritation is present, monitor chest x-ray.

Methods

    A) CHROMATOGRAPHY
    1) Calmes et al (1994) reported a reversed-phase high-performance liquid chromatographic method, with light-scattering detection, for the quantitative determination of the toxic glucosides, atractyloside and carboxyatractyloside, in a 60% methanolic extract of the plant roots. This procedure has not been used in the clinical setting.
    2) A thin-layer chromatographic method for the detection of atractyloside, after Callilepis laureola poisoning, in urine was developed. A limit of detection was reported as 500 ng (Steenkamp et al, 1999).
    3) A gas chromatographic-mass spectrometric (GC-MS) method, with single ion monitoring mode, for the detection of atractyloside in human biological fluid has been developed. A limit of detection of 0.0451 mmol/L was reported (Laurens et al, 2001).
    B) HIGH PERFORMANCE LIQUID CHROMATOGRAPHY
    1) High performance liquid chromatography with high-resolution tandem mass spectrometry was used to quantify atractyloside (ATR) and carboxyatractyloside (CATR) in the blood and urine of a woman who had ingested extracts of atractylis gummifera. The method was validated in whole blood with quantification limits 0.17 and 0.15 mcg/L for ATR and CATR, respectively (Carlier et al, 2014).
    C) IMMUNOASSAY
    1) Bye et al (1990) developed an enzyme immunoassay for the detection of atractyloside in fluid samples. Thin layer chromatography confirmed the results. Methanol did not interfere with the assay. Toxin levels were not quantified in the samples (Bye et al, 1990).

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 persistent symptoms, those with laboratory evidence of renal or hepatic injury, metabolic acidosis or hypoglycemia, and those with altered mental status, hypotension or persistent vomiting should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children with taste exposures and asymptomatic adults can probably be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any symptomatic ingestion, or self-harm attempt ingestion should be evaluated in the emergency department. Children with more than taste exposures should be referred to a healthcare facility.

Monitoring

    A) Monitor vital signs and mental status in all poisoning cases.
    B) With significant ingestions, obtain a CBC, electrolytes, liver enzymes and renal function. Monitor coagulation studies in patients with hepatic injury.
    C) Monitor oxygen saturation and administer oxygen as required.
    D) Obtain a urinalysis and monitor urine output.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Decontamination is unlikely to be necessary because significant vomiting can develop after ingestion.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Patients generally present late after ingestion with significant vomiting so GI decontamination is likely of limited utility. Activated charcoal should be administered in any patient with a recent ingestion who is not vomiting, and awake and able to maintain their airway.
    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).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. No antidote is available for poisoning with this plant.
    2) This agent can cause hepatotoxicity and renal toxicity. Monitor liver and renal function tests for patients with significant exposure.
    3) Monitor for CNS and respiratory depression.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status. With significant ingestions, obtain a CBC, electrolytes, liver enzymes and renal function. Coagulation studies may be indicated.
    2) Obtain a urinalysis and monitor urine output.
    C) AIRWAY MANAGEMENT
    1) Maintain adequate ventilation and oxygenation with close monitoring of arterial blood gases.
    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).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis has been advocated and may be useful in a patient unresponsive to normal supportive care or in whom renal failure and acid-base or fluid and electrolyte problems may become uncontrollable.

Range Of Toxicity

Summary

    A) TOXICITY: Maximum tolerated dose and minimal lethal human dose has not been delineated. Ingestion of the root or a root extract, especially if harvested in the spring may be toxic.
    B) THERAPEUTIC DOSE: The estimated dose used as an alternative medicine is 67 micrograms atractyloside in an adult.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) Callilepis laureola - When an herbal remedy is prepared from tubers of C. laureola, it is estimated that each dose contains approximately 67 micrograms atractyloside, equivalent to 1 microgram/kilogram body weight for a 70-kilogram adult. Chronic administration may cause severe liver or kidney damage over time (Obatomi & Bach, 1998).

Minimum Lethal Exposure

    A) PEDIATRIC
    1) CASE REPORT: A 30-month-old boy was admitted to a pediatric ICU in a coma following the application of an occlusive dressing saturated in a liquid containing A. gummifera; the root was boiled in 1L of water. According to the parents, the dressing was changed every 12 hours to treat a burn for 6 days prior to admission. Shortly after admission he developed ventricular tachycardia secondary to severe hyperkalemia (potassium 7.4 mmol/L) with hypotension. Treatment included immediate cardioversion and peritoneal dialysis. Other clinical events included cholestasis, hepatorenal injury and acute renal failure. A urine screen was positive for A. gummifera. The child gradually improved and was discharged to home on day 16 with persistent renal insufficiency (Bouziri et al, 2010).
    2) CASE SERIES: Ten children, all in the same family, ingested unknown quantities of Atractylis gummifera. Four of the children died prior to hospital admission. Four of 6 children taken to the hospital died. Only 2 children survived. Clinical symptoms reported in the hospitalized children included coma, hypertension, severe vomiting and epigastric pain, sluggish or absent reflexes, mydriasis, jaundice, elevated liver function tests, tachycardia and hypothermia. Autopsy reports on 4 of the deceased children revealed fulminant hepatitis with marked hepatic necrosis. Tubular nephritic lesions of the kidneys were seen in 2 of the children (Lemaigre et al, 1975)

Maximum Tolerated Exposure

    A) ADULT
    1) CASE REPORT: A 40-year-old woman, taking an oral solution containing Atractylis gummifera daily for chronic back pain, reported vomiting, vertigo, extreme weakness, and generalized myalgia beginning on day 3 of therapy. Atractylis gummifera was stopped that day. She was hospitalized 9 days after the first dose due to ongoing symptoms. On admission, vital signs revealed an increased blood pressure (170/110 mmHg). Anuria was observed, along with renal and hepatic dysfunction. Renal biopsy revealed tubular necrosis and marked interstitial infiltration. Following symptomatic therapy, including hemodialysis, the patient fully recovered and was discharged after 7 days of hospitalization (Nogue et al, 1992).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)RAT:
    a) 431 mg/kg (Budavari, 2001)

Pharmacology Toxicology

Toxicologic Mechanism

    A) The isolated glucosides, atractyloside (or atractyline) and carboxyatractyloside (or gummiferin) have been shown to be specific inhibitors of oxidative phosphorylation of liver mitochondrial adenine nucleotide translocation by binding with high affinity with the protein component of the mitochondrial ADP-carrier (Stanislas M & Vignais P, 1964; (Georgiou et al, 1988). A disruption of glucose metabolism with inhibition of glycogen synthesis, particularly inhibition of oxidative phosphorylation, has been described (Chardon et al, 1964; Cardevielle & Darracq, 1980).
    1) At concentrations of 20 micromoles, atractyloside inhibited mitochondrial adenine nucleoside translocation, specifically blocking oxidative phosphorylation and Krebs cycle oxidative reactions. Atractyloside selectively binds to the phosphoryl transferase (nucleoside monophosphokinase) in the outer mitochondrial membranes of animal liver, kidney and heart (Obatomi & Bach, 1998).
    2) In cases of human hepatotoxicity, histologic examinations have shown the characteristic pattern of necrosis associated with other active radical-producing toxins is NOT evident in atractyloside poisoning. Hepatotoxicity may be the result of a symbiotic effect of more than one toxin or metabolite of atractyloside (Stewart & Steenkamp, 2000).
    3) Hedili et al (1989) demonstrated in rat studies a decrease in cytochrome P450 and cytochrome b5 following doses of the plant glucosides. The decrease in these cytochromes was related to morphological changes in the endoplasmic reticulum in the rat liver as well as centrilobular liver necrosis.

Physicochemical

Physical Characteristics

    A) Atractyloside, a highly toxic glucoside isolated from the thistle Atractylis gummifera, is a crystalline structure with a strychnine-like action; it produces seizures of a hypoglycemic nature (Budavari, 2001).

Molecular Weight

    A) 803.00 - Atractyloside (Budavari, 2001)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    3) Bouziri A , Hamdi A , Menif K , et al: Hepatorenal injury induced by cutaneous application of Atractylis gummifera L. Clin Toxicol (Phila) 2010; 48(7):752-754.
    4) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    5) Budavari S: The Merck Index, 13th ed, Merck & Co, Inc, Whitehouse Station, NJ, 2001.
    6) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    7) Bye SN, Coetzer THT, & Dutton MF: An enzyme immunoassay for atractyloside, the nephrotoxin of Callilepis laureola (impila). Toxicon 1990; 28:997-1000.
    8) Calmes M, Crespin F, & Maillard C: High-performance liquid chromatographic determination of atractyloside and carboxyatractyloside from Atractylis gummifera L. J Chromatography 1994; 663:119-122.
    9) Caravati EM, Knight HH, & Linscott MS: Esophageal laceration and charcoal mediastinum complicating gastric lavage. J Emerg Med 2001; 20:273-276.
    10) Cardevielle P & Darracq R: L'Intoxication par le chardon a glu (Atractylis gummifera L.). Med Tropicale 1980; 40(2):137-142.
    11) Carlier J, Romeuf L, Guitton J, et al: A validated method for quantifying atractyloside and carboxyatractyloside in blood by HPLC-HRMS/MS, a non-fatal case of intoxication with Atractylis gummifera L. J Anal Toxicol 2014; 38(9):619-627.
    12) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    13) Chardon G, Viala A, & Vignais P: L'Intoxication par le chardon a glu, atractylis gummifera L. Therapie 1964; 19:1313-1322.
    14) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    15) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    16) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    17) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    18) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    19) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    20) Georgiou M, Sianidou L, & Hatzis T: Hepatotoxicity due to Atractylis gummifera-L. Clin Toxicol 1988; 26(7):487-493.
    21) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    22) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    23) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    24) Hamouda C, Hedhili A, Ben-Salah N, et al: A review of acute poisoning from Atractylis gummifera L. Vet Hum Toxicol 2004; 46(3):144-146.
    25) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    26) Hedili A, Warnet JM, & Thevenin M: Biochemical investigation of Atractylis Gummifera L. hepatotoxicyty in the rat. Biological Monitoring of Exposure and the Response at the Subcellular Level to Toxic Substances. Arch Toxicol 1989; Suppl 13:312-315.
    27) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    28) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    29) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    30) Larrey D & Pageaux GP: Hepatotoxicity of herbal remedies and mushrooms. Semin Liver Dis 1995; 15(3):183-188.
    31) Laurens JB, Bekker LC, & Steenkamp V: Gas chromatographic-mass spectrometric confirmation of atractyloside in a patient poisoned with Callilepis laureola. J Chromatogr B 2001; 765:127-133.
    32) Lemaigre G, Tebbi Z, & Galinsky R: Hepatite fulminante par intoxication due au chardon a glu (Atractylis gummifera-L). Nouvelle Presse Med 1975; 4(40):2865-2868.
    33) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    34) Madani N, Sbai H, Harandou M, et al: [Atractylis gummifera poisoning in a pregnant woman]. Presse Med 2006; 35(12 Pt 1):1828-1830.
    35) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    36) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    37) Nogue S, Sanz P, & Botey A: Insuffisance renale aigue due a une intoxication par le chardon a glu (Atractylis gummifera - L) (letter). Presse Med 1992; 21(3):130.
    38) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    39) Obatomi DK & Bach PH: Biochemistry and toxicology of the diterpenoid glycoside atractyloside. Food Chem Toxicol 1998; 36:335-346.
    40) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    41) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    42) Popat A, Shear NH, & Malkiewicz I: The toxicity of Callilepis laureola, a South African traditional herbal medicine. Clin Biochem 2001; 34:229-236.
    43) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    44) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    45) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    46) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    47) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    48) Schiano TD: Drug-induced liver disease: liver injury from herbs and other botanicals. Clinics in Liver Dis 1998; 2(3):607-630.
    49) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    50) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    51) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    52) Steenkamp V, Stewart MJ, & Zuckerman M: Detection of poisoning by impila (Callilepis laureola) in a mother and child. Hum Exper Toxicol 1999; 18:594-597.
    53) Stewart MJ & Steenkamp V: The biochemistry and toxicity of atractyloside: a review. Ther Drug Monit 2000; 22:641-649.
    54) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    55) Vale JA, Kulig K, American Academy of Clinical Toxicology, et al: Position paper: Gastric lavage. J Toxicol Clin Toxicol 2004; 42:933-943.
    56) Vale JA: Position Statement: gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997; 35:711-719.
    57) Wainwright J, Schonland MM, & Candy HA: Toxicity of Callilepis laureola. S Afr Med J 1977; 52:313-315.
    58) Watson AR, Coovadia HM, & Bhoola KD: The clinical syndrome of impila (Callilepsis laureola) poisoning in children. S Afr Med J 1979; 55:290-292.