Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

TOAD TOXINS

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) There are several types of toxic substances found in the venom of toads.
    1) CARDIOACTIVE SUBSTANCES: Bufagins (bufandienolides) are cardioactive substances found in toad venom. They have effects similar to the cardiac glycosides found in plants.
    a) Bufotoxins are the conjugation products of the specific bufagin with one molecule of suberylargine (Chen & Kovarikova, 1967).
    b) Bufotoxins were originally isolated from the parotoid glands of toads, but have since been seen in various plants and mushrooms (Siperstein et al, 1957; Lincoff & Mitchel, 1977; Kibmer & Wichtl, 1986).
    2) CATECHOLAMINES: There are also several catecholamines in toad venom. Epinephrine has been found in as high a concentration as 5% in the venom of several species. Norepinephrine has also been found (Chen & Kovarikova, 1967).
    3) INDOLEALKYLAMINES: Chemicals found include several bufotenines. Bufotenines are organic bases containing an indole ring and have primarily oxytocic actions and often pressor actions (Palumbo et al, 1975).
    a) Specific substances include bufothionine, serotonin, cinobufotenine, bufotenine, and dehydrobufotenine (Chen & Kovarikova, 1967).
    b) Bufotenine is the 5-hydroxy derivative of N,N-dimethyltryptamine and is a hallucinogen (Gilman et al, 1985).
    4) NONCARDIAC STEROLS: The sterols found in toad venom include cholesterol, provitamin D, gamma sitosterol, and ergosterol. They do not appear to have a significant role in toxicity (Chen & Kovarikova, 1967; Palumbo et al, 1975).
    5) TETRODOTOXIN: Tetrodotoxin and tetrodotoxin analogues have been isolated from the toad Atelopus oxyrhynchus, Bufonidae family (Yotsu-Yamashita, 1992).

Specific Substances

    A) GENERAL TERMS
    1) Toads
    2) Bufo Species
    3) Toad Toxins
    4) Toxins, Toads
    NON-AMERICAN BUFO SPECIES
    1) Bufo arenarum
    2) Bufo asper
    3) Bufo blombergi
    4) Bufo bufo
    5) Bufo bufo gargarizans
    6) Bufo formosus
    7) Bufo melanophryniscus
    8) Bufo melanostictus
    9) Bufo peltocephalus
    10) Bufo regularis
    11) Bufo viridis
    AMERICAN BUFO SPECIES
    1) For a list of the American Bufo species of toads, please refer to the description section below.

Available Forms Sources

    A) SOURCES
    1) BUFOTOXINS: Is the name of a collection of compounds found in the toad venom which may be secreted into toad skin or found in 2 glands behind the eyes, called parotid glands (Tyler, 1976). Bufotoxins may also be specifically applied to the conjugates of a bufagin with suberylargine.
    2) Bufox(R) (Laboratories Hardy, France), a pharmaceutical product derived from toad toxins and marketed as a "hemostatic and stimulant of the adrenal glands," was available in France in 1960 (Lescure, 1985).
    B) USES
    1) FOLK USES: Before digitalis was extracted from Digitalis purpura, dried and powdered toad skins were used as a cardiac medication (Ch'an Su and Senso) (Burton, 1977; Chern et al, 1991).
    a) Other "folk" uses include expectorant, diuretic, and remedy for toothaches, sinusitis, and hemorrhage of the gums.
    2) Several Chinese traditional non-prescription medications, (e.g., Chan Su, Yixan Wan, Lu-Shen Wan, Kyushin) contain bufalin, cinobufaginal or other bufadienolides, which may interfere with therapeutic drug monitoring (Fushimi et al, 1989; Kwan et al, 1992; CDC, 1995).
    3) A bufotine-containing product marketed as an aphrodisiac under the names Stone, LoveStone, Black Stone and Rock Hard has been available in grocery stores, smoke shops and by street vendors (CDC, 1995).
    4) HALLUCINOGENS: Toad skins have also been used for their hallucinogenic effect (Emboden, 1979). In Taiwan, toad soup is considered a blood detoxifying agent (Chern et al, 1991).

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: Toads are found throughout most of the world, except Madagascar, New Zealand, New Guinea and Polynesia. Toxicity can develop after ingesting or licking the toad or its skin secretions. Toad toxins have been used in folk medicine, traditional Chinese medicine, and have been found in substances marketed as aphrodisiacs in the western world. Toad toxins have also been used for hallucinogenic effects.
    B) TOXICOLOGY: There are several types of toxic substances found in toads, including cardioactive agents, catecholamines, indolealkylamines and noncardiac sterols. These toxins are located in the skin and parotid glands and eggs and may be transferred by handling or ingesting a toad's skin and secretions and or by ingesting products (eg, aphrodisiacs) which contain the toad toxins. Ingestion or dermal absorption of the venom from Bufo species can cause typical digitalis poisoning, with dysrhythmias, heart block, hypotension, and vomiting. Ingestion of the eggs has produced severe digoxin-like toxicity resulting in death in some cases.
    C) EPIDEMIOLOGY: While the incidence of exposure to poisonous frogs is unknown, in the United States serious toxicity and fatalities are rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Secretions of the toad parotid glands will cause pain and severe irritation when placed in eyes, nose and throat. Ocular exposure can cause pain, severe irritation, transient edema, corneal clouding, conjunctival hyperemia, decreased intraocular pressure and transient blindness. Salivation and vomiting may occur. Many bufagins have local anesthetic actions, especially on the oral mucosa.
    2) SEVERE TOXICITY: CARDIOVASCULAR: Ingestion or dermal absorption of the venom form Bufo species can cause typical digitalis poisoning, with dysrhythmias, heart block, hypotension and vomiting. Ingestion of the eggs has produced severe digoxin-like toxicity resulting in death in some cases. Cardiac arrest, atrial fibrillation, right bundle branch block, bradycardia, ventricular fibrillation and severe hypotension have been reported. OTHER: Dyspnea, hyperpnea and weakened respirations may be present. Respiratory failure has occurred. Seizures have been reported. Dizziness and general weakness, followed by unconsciousness occurred within 4 hours of toad soup ingestion. Toad skin has been used for its hallucinogenic properties throughout the world, but Bufo alvarins is the only Bufo species known to contain a hallucinogenic tryptamine. Hyperkalemia has been reported in 3 fatal cases and is similar to that which occurs in digitalis poisoning. Contact may lead to a condition of temporary blindness that usually resolves within 48 hours after exposure.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Secretions of the toad parotid glands will cause pain and severe irritation when placed in eyes, nose and throat.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Cardiac arrest, atrial fibrillation, right bundle branch block, bradycardia, ventricular fibrillation, hypotension and measurable digoxin levels have been reported in humans. Ventricular fibrillation and symptoms resembling digitalis toxicity have been reported in dogs. Vasoconstriction may occur.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Dyspnea, hyperpnea and weakened respirations may be present. Respiratory failure has occurred.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Paralysis has been reported in animals. Seizures have been reported in humans and animals. Many bufagins have local anesthetic actions, especially on the oral mucosa.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Salivation and vomiting may occur. These toxins may cause numbness of the oral mucosa if ingested.

Laboratory Monitoring

    A) Monitor vital signs. Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor serum electrolytes, particularly potassium.
    C) Polyclonal digoxin immunoassays cross react with the cardiac genins contained in toad venoms, allowing confirmation of exposure, although the digoxin concentrations obtained do not correlate well with clinical effects.
    D) Monoclonal digoxin assays do not appear to cross react with the cardiac genins in toad venoms, and may not be useful to confirm exposure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Mild to moderate toxicity can be managed with basic symptomatic and supportive care. Administer IV fluids and antiemetics for severe nausea and vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) DIGOXIN IMMUNE FAB (ovine): Use of digitalis Fab fragments should be considered in any patient with hyperkalemia or hemodynamically significant dysrhythmias. Serum digoxin levels cannot be used to calculate the dose of digoxin immune Fab after bufotoxin poisoning. Empiric use of large amounts (eg, 10 vials) of Digibind(R) has been suggested for symptomatic patients.
    2) HYPERKALEMIA: Hyperkalemia following acute overdose may be life-threatening. Administration of digitalis Fab fragments should be considered in any patient with hyperkalemia. If digoxin immune Fab is not available, the emergency management of life-threatening hyperkalemia (potassium levels greater than 6.5 mEq/L) includes the IV administration of bicarbonate, glucose and insulin. Administer 0.2 unit/kg of regular insulin with 200 to 400 mg/kg glucose (IV dextrose 25% in water). Concurrent administration of IV sodium bicarbonate (approximately 1 mEq/kg up to 44 mEq/dose in an adult) may be of additive value in rapidly lowering serum potassium levels. Monitor the ECG while administering glucose, insulin and sodium bicarbonate. This therapy should lower the serum potassium level for up to 12 hours.
    3) ATROPINE: If digoxin immune Fab is not available, atropine may be useful in the management of bradycardia, varying degrees of heart block and other cardiac irregularities due to the digitalis-like induced effects of enhanced vagal tone on the SA node rhythm and on conduction through the AV node. Dosing should be based on standard ACLS guidelines.
    4) TRANSVENOUS PACING: Should be considered in patients with severe bradycardia and/or slow ventricular rate.
    C) DECONTAMINATION
    1) PREHOSPITAL: Immediately flush the oral mucous membranes to decrease absorption. Do not swallow the rinse water. Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Consider prehospital administration of activated charcoal in patients with recent ingestions who are alert and can protect their airway. OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes.
    2) HOSPITAL: Immediately flush the oral mucosa membranes to decrease absorption. Do not swallow the rinse water. Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Administer activated charcoal for recent ingestions in patients who are alert and can protect their airway. OCULAR: Remove contact lenses and irrigate exposed eyes with copious amount of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed.
    D) BRADYCARDIA
    1) EMERGENCY CARDIAC PACEMAKER: Insertion of a transvenous pacemaker should be considered in patients with severe bradycardia and/or slow ventricular rate due to second degree AV block who fail to respond to digoxin immune Fab and/or atropine.
    E) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be required but may be necessary in the management of seizures, significant sedation, or severe cardiac toxicity.
    F) ANTIDOTE
    1) DIGOXIN IMMUNE FAB (ovine): Use of digitalis Fab fragments should be considered in any patient with hyperkalemia or hemodynamically significant dysrhythmias. Serum digoxin concentrations cannot be used to calculate the dose of digoxin Fab after bufotoxin poisoning. Empiric use of large amounts (eg, 10 to 20 vials) of Digibind(R) has been suggested for symptomatic patients. Beyond a low risk of allergic reaction, no adverse reaction to digitalis Fab fragments should be expected.
    G) ENHANCED ELIMINATION
    1) Cardiac glycosides and bufandienolides are adsorbed to activated charcoal and enterohepatic circulation may be decreased by multiple-dose activated charcoal. Multiple dose activated charcoal has not been shown to affect outcome after exposure to toad toxins and routine use is NOT recommended. Consider a second dose of activated charcoal in patients with severe toxicity or when digitalis Fab fragments are not available. Hemodialysis has been ineffective in removing cardiac glycosides but may assist in restoring potassium to normal levels. It has yet to be tried on bufagins.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Only asymptomatic patients with minimal skin exposure may be observed at home.
    2) OBSERVATION CRITERIA: All patients with a significant skin exposure or ingestion should be observed for 6 hours. At the end of 6 hours, if there is no evidence of cardiac or neurologic toxicity, the patient may be discharged.
    3) ADMISSION CRITERIA: All patients with a clinically significant neurologic or cardiac signs/symptoms or ECG/laboratory evidence of cardiac toxicity should be admitted to a monitored setting until the patient is clearly improving.
    4) CONSULT CRITERIA: A toxicologist should be consulted in any patients with evidence of neurologic or cardiac toxicity. An ophthalmologist should be consulted in patients with evidence of ocular injury on slit-lamp and visual acuity exams.
    I) PITFALLS
    1) Failure to monitor ECGs and potassium for evidence of cardiac glycoside toxicity.
    J) TOXICOKINETICS
    1) The toxicokinetics of toad toxins are unknown.
    K) DIFFERENTIAL DIAGNOSIS
    1) Digitalis poisoning, overdose with beta blockers, calcium channel blockers or other antidysrhythmias.

Range Of Toxicity

    A) TOXIC DOSE: The skin of one toad is sufficient to cause significant symptoms and even death in both animals and humans, however, most fatalities occur following ingestion. No toxic serum or blood levels have yet been established. Two children became severely ill after ingesting the skin and eggs of a Bufo melanostictus Schneider; one died within 12 hours of exposure, and the other developed digoxin-like toxicity (ie, bradycardia, hypotension) but recovered. A fatality occurred following an ingestion of approximately 100 mL of a Chinese herbal tea containing Ch'an su. Fatalities have been reported in men ingesting topical aphrodisiacs containing toad toxins.

Clinical Effects

Summary Of Exposure

    A) USES: Toads are found throughout most of the world, except Madagascar, New Zealand, New Guinea and Polynesia. Toxicity can develop after ingesting or licking the toad or its skin secretions. Toad toxins have been used in folk medicine, traditional Chinese medicine, and have been found in substances marketed as aphrodisiacs in the western world. Toad toxins have also been used for hallucinogenic effects.
    B) TOXICOLOGY: There are several types of toxic substances found in toads, including cardioactive agents, catecholamines, indolealkylamines and noncardiac sterols. These toxins are located in the skin and parotid glands and eggs and may be transferred by handling or ingesting a toad's skin and secretions and or by ingesting products (eg, aphrodisiacs) which contain the toad toxins. Ingestion or dermal absorption of the venom from Bufo species can cause typical digitalis poisoning, with dysrhythmias, heart block, hypotension, and vomiting. Ingestion of the eggs has produced severe digoxin-like toxicity resulting in death in some cases.
    C) EPIDEMIOLOGY: While the incidence of exposure to poisonous frogs is unknown, in the United States serious toxicity and fatalities are rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Secretions of the toad parotid glands will cause pain and severe irritation when placed in eyes, nose and throat. Ocular exposure can cause pain, severe irritation, transient edema, corneal clouding, conjunctival hyperemia, decreased intraocular pressure and transient blindness. Salivation and vomiting may occur. Many bufagins have local anesthetic actions, especially on the oral mucosa.
    2) SEVERE TOXICITY: CARDIOVASCULAR: Ingestion or dermal absorption of the venom form Bufo species can cause typical digitalis poisoning, with dysrhythmias, heart block, hypotension and vomiting. Ingestion of the eggs has produced severe digoxin-like toxicity resulting in death in some cases. Cardiac arrest, atrial fibrillation, right bundle branch block, bradycardia, ventricular fibrillation and severe hypotension have been reported. OTHER: Dyspnea, hyperpnea and weakened respirations may be present. Respiratory failure has occurred. Seizures have been reported. Dizziness and general weakness, followed by unconsciousness occurred within 4 hours of toad soup ingestion. Toad skin has been used for its hallucinogenic properties throughout the world, but Bufo alvarins is the only Bufo species known to contain a hallucinogenic tryptamine. Hyperkalemia has been reported in 3 fatal cases and is similar to that which occurs in digitalis poisoning. Contact may lead to a condition of temporary blindness that usually resolves within 48 hours after exposure.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) CASE SERIES: HYPOTHERMIA occurred in 2 fatal cases involving ingestion of a topical aphrodisiac which contained bufadienolides (CDC, 1995).
    2) FEVER has been reported in humans who ingested Bufo marinus eggs (Licht, 1968). It is also common in cats and dogs who have eaten toads (Perry & Bracegirdle, 1973).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Secretions of the toad parotid glands will cause pain and severe irritation when placed in eyes, nose and throat.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Toad secretory fluids, whether squirted or otherwise brought into contact with the eyes, have varied local toxic effects including transient edema, corneal clouding, conjunctival hyperemia, decreased intraocular pressure and transient blindness.
    2) Contact may lead to a condition of temporary blindness that usually resolves within 48 hours after exposure (Grant, 1978) (Peyresblanques, 1964; Van Tittelboom et al, 1987).
    3) If the secretions of the toad parotid glands come in contact with human eyes, pain and severe irritation may result (Tyler, 1976; Smith, 1982).
    4) BLURRED VISION has developed within 30 minutes of ingesting a toad soup (Chern et al, 1991).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) Exposure of the nasal mucous membranes to the toad toxins may produce severe irritation (Chen & Kovarikova, 1967; Ko et al, 1996).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) The mouth and throat may become anesthetized if bufotoxins have been ingested (Chen & Kovarikova, 1967; Ko et al, 1996).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Cardiac arrest, atrial fibrillation, right bundle branch block, bradycardia, ventricular fibrillation, hypotension and measurable digoxin levels have been reported in humans. Ventricular fibrillation and symptoms resembling digitalis toxicity have been reported in dogs. Vasoconstriction may occur.
    3.5.2) CLINICAL EFFECTS
    A) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Fatal cardiac arrest occurred in a 31-year-old who ingested toad soup (Chern et al, 1991), in 4 adults who ingested a topical aphrodisiac, which contained bufadienolides (CDC, 1995), and in a 25-year-old who ingested a Chinese herbal tea contaminated with Ch'an su (Ko et al, 1996).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Conduction disturbances similar to digoxin toxicity have been reported following the ingestion of toad soup, the eggs of a Bufo melanostictus toad, and by topical exposure of the toad toxin used as an aphrodisiac (Brubacher et al, 1995; Chi et al, 1998; Kwan et al, 1992)
    b) CASE SERIES: Dysrhythmias (e.g., atrial fibrillation, ventricular fibrillation, right bundle branch block) and/or bradycardia developed in 4 fatal cases and 1 nonfatal case, following ingestion of a toad toxin-containing topical aphrodisiac (Brubacher et al, 1995; CDC, 1995). All patients received medical treatment.
    c) CASE REPORTS
    1) TOAD VENOM INGESTION
    a) TOAD VENOM: A patient with atrial fibrillation taking toad venom developed syncope and multiple pauses in beats, the longest being 13.5 seconds. The patient was thought to have an underlying AV node conduction disease (Kwan et al, 1992).
    b) TOAD EGGS: Cardiac dysrhythmias and death have been reported following the ingestion of Bufo marinus eggs (Licht, 1968).
    1) A 6-year-old boy from Laos developed significant bradycardia (40 beats/min), hypotension (70/40 mmHg) and extrasystoles following the ingestion of a grilled toad dish containing the skin, eggs and meat of a Bufo melanostictus Schneider. The patient improved with supportive care and was discharge to home on day 10 (Keomany et al, 2007).
    c) TOAD EGGS: A 19-year-old woman ate cooked toad eggs and developed nausea and vomiting and general weakness about an hour after eating the meal. Her initial ECG showed first-degree AV block, a serum potassium of 7.1 mmol/L and a serum digoxin concentration of 2.42 nmol/L. Her condition started to deteriorate with lethargy and disorientation. A transvenous pacemaker was inserted and the patient was treated with Digoxin Fab fragments about 4 hours after admission. She clinically improved with a gradual decrease in digoxin and potassium levels. The patient was discharged to home on day 5 (Kuo et al, 2007).
    d) TOAD SOUP: Sinus arrest with high grade AV block but normal QRS and a heart rate of 46 beats/min were reported in an adult who had been resuscitated from a cardiac arrest following ingestion of toad soup (Chern et al, 1991).
    e) TOAD SOUP: Two children presented to the ED with dysrhythmias 4 hours after ingesting toad soup. An ECG of the 15-month-old boy showed ventricular escape rhythm followed by ventricular fibrillation. Despite atropine and lidocaine administration and attempted cardioversion, the child died due to refractory bradydysrhythmia. An ECG of the 20-month-old girl showed varying degrees of AV block and ventricular tachycardia, and fibrillation developed following admission into the pediatric ICU. The patient's dysrhythmias gradually subsided with cardioversion, intravenous bolus of lidocaine and installation of a pacemaker (Chi et al, 1998).
    1) The children's uncle (a 16-year-old boy) also ingested the toad soup, and subsequently developed sinus bradycardia. The patient recovered with supportive care.
    2) Elevated serum digoxin levels were observed in the 20-month-old child and in the 16-year-old, thereby indicating that the dysrhythmias may be a manifestation of digitalis intoxication due to the ingestion of the toad soup.
    2) HERBAL PREPARATIONS
    a) HERBAL APHRODISIAC: Six previously heathy young men intentionally ingested a topical aprhodisiac (ie, Chan Su, Chinese herbal medicine produced from toad venom) and developed early symptoms of persistent nausea and vomiting. The presence of a substance that cross reacted with the digoxin assay was confirmed in each patient (range: 0.9 ng/mL to 3.08 ng/mL). Four patients died due to conduction disturbances that included ventricular fibrillation and asystole that were unresponsive to resuscitation. Of these patients, 3 died rapidly following admission (within 3 hours). The 2 patients that survived were treated with Digoxin Fab fragments (initial dose: 10 vials) with complete resolution in one case, the other patient required a second course (10 vials) of Digibind(R). Serum digoxin concentrations prior to Digibind(R) therapy were 3.9 ng/mL and 1.8 ng/mL, respectively (Brubacher et al, 1996a).
    b) HERBAL APHRODISIAC: A 40-year-old previously healthy man ingested 3 pills of an unknown aphrodisiac approximately 7 hours prior to admission with complaints of nausea, vomiting and diaphoresis. An ECG showed sinus bradycardia with first-degree atrioventricular block. The patient had a serum digoxin concentration of 0.9 nmol/L. Digoxin Fab fragment was ordered but the patient rapidly deteriorated with respiratory insufficiency requiring intubation and ventilation. Likewise, his rhythm deteriorated into ventricular tachycardia followed by ventricular fibrillation. Cardiac resuscitation was unsuccessful. It was suspected the patient had ingested Chan su, a Chinese herbal medicine, containing Chinese toad venom (bufadienolide) (Gowda et al, 2003).
    c) HERBAL TEA: A 25-year-old pregnant woman ingested approximately 100 mL of a Chinese herbal tea containing Ch'an su (made of dried Bufo melanostictus Schneider) and developed bradycardia and progressive hypotension 30 minutes later. After administration of atropine, she developed sinus tachycardia followed by cardiopulmonary arrest. During resuscitative efforts, ventricular tachycardia followed by intractable fibrillation was noted. She subsequently died 2.5 hours after initial ingestion of the tea. Postmortem testing of the patient's serum revealed lethal amounts of cardiac glycosides (Ko et al, 1996).
    d) HERBAL MEDICINE: A 90-year-old man presented with syncope, bradycardia, atrial fibrillation with a slow ventricular response and multiple pauses after taking Yixin Wan, a Chinese medicine containing bufotoxin (Kwan et al, 1992).
    3) OTHER
    a) DERMAL EXPOSURE: A 16-year-old boy developed vomiting, fatigue, bradycardia, hypotension, and third degree AV block after removing and eating 15 toad livers. Eating the livers is usually not associated with toxicity, so it was believed that his exposure was cutaneous (Du & Due, 2001).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Significant hypotension (systolic was 40 mmHg in one case) has been reported in an adult and children who ingested toad soup and required cardiopulmonary resuscitation (Chern et al, 1991; Chi et al, 1998), and in at least 2 adults who ingested a toad toxin-containing topical aphrodisiac (CDC, 1995). Significant hypotension has also been reported following the ingestion of Bufo melanostictus Schneider toad eggs, thought to contain toxins resembling cardiac glycosides (Keomany et al, 2007).
    b) CASE REPORT: A 26-year-old man developed bradycardia and hypotension after eating 5 to 6 toads as an aphrodisiac. Symptoms occurred within several hours of ingestion. Inotropic support was started. An echocardiogram revealed LV dysfunction with an ejection fraction of 48% along with mild hypokinesia. The patient was empirically treated for myocarditis. Following supportive care the patient gradually recovered; repeat echocardiogram on day 4 had improved (Ashok et al, 2011).
    c) CASE REPORT: A 25-year-old pregnant woman became progressively hypotensive approximately 30 minutes after ingesting a Chinese herbal tea containing Ch'an su (Bufo melanostictus Schneider) (Ko et al, 1996).
    d) CASE REPORT: A 16-year-old boy developed vomiting, fatigue, bradycardia, hypotension (less than 80 mmHg systolic), and third degree AV block after removing and eating 15 toad livers. Eating the livers is usually not associated with toxicity, so it was believed that his exposure was cutaneous (Du & Due, 2001).
    D) VASOSPASM
    1) WITH POISONING/EXPOSURE
    a) Bufagins constrict arterial blood vessels (Chen & Kovarikova, 1967). Bufotenine acts as a pressor agent (Kantor et al, 1980).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VENTRICULAR FIBRILLATION
    a) DOGS intentionally poisoned orally with bufagins develop ventricular fibrillation and die if untreated (Palumbo et al, 1975). The symptoms resemble digitalis poisoning.

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Dyspnea, hyperpnea and weakened respirations may be present. Respiratory failure has occurred.
    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Respiratory distress progressing to respiratory failure occurred in an adult who ingested a toad toxin-containing topical aphrodisiac (CDC, 1995).
    B) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Dyspnea, rapid and/or weakened respirations may occur following the ingestion of toad toxins (Keomany et al, 2007; Smith, 1982; Licht, 1968; CDC, 1995; Chi et al, 1998; Ko et al, 1996).
    C) PULMONARY EDEMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 26-year-old man developed bradycardia, hypotension, myocarditis and pulmonary edema after eating 5 to 6 toads as an aphrodisiac. Symptoms occurred within several hours of ingestion. Inotropic support was started. A chest x-ray showed evidence of pulmonary edema (ie, bilateral midzone infiltrates). The patient was intubated and ventilated. He gradually improved with supportive care and was discharge to home on day 7 with no residual effects (Ashok et al, 2011).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Paralysis has been reported in animals. Seizures have been reported in humans and animals. Many bufagins have local anesthetic actions, especially on the oral mucosa.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Status epilepticus developed in a 5-year-old boy within 5 minutes of mouthing a Bufo Alvarius (Colorado River Toad). The seizures continued for 60 minutes, but were successfully treated with diazepam and phenobarbital (Hitt & Ettinger, 1986).
    b) CASE REPORT: A 25-year-old pregnant woman developed cardiac arrest, following ingestion of a Chinese herbal tea that contained Ch'an su, and during the resuscitative effort, experienced a grand-mal-type seizure (Ko et al, 1996).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) Dizziness and general weakness, followed by unconsciousness, occurred within 4 hours of toad soup ingestion (Chern et al, 1991; Chi et al, 1998).
    C) ABSENCE OF SENSATION
    1) WITH POISONING/EXPOSURE
    a) Many bufagins have local anesthetic actions, especially on the oral mucosa (Chen & Kovarikova, 1967; Ko et al, 1996). Onset was within 30 minutes of ingesting a toad soup (Chern et al, 1991).
    D) HALLUCINATIONS
    1) WITH POISONING/EXPOSURE
    a) In 1971, drug users in Queensland were smoking the chopped skins of Bufo marinus for its hallucinogenic effect (Tyler, 1976). Others have ingested the secretions or skin of toads for their possible hallucinogenic effect (Lyttle, 1993). Toad skin has been used for its hallucinogenic properties throughout the world (Emboden, 1979), but Bufo alvarins is the only Bufo species known to contain a hallucinogenic tryptamine (McKenna & Towers, 1984).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PARALYSIS
    a) Paraplegia has been noted in toad poisonings of dogs and cats. Early symptoms may include incoordination and progressive paralysis (Perry & Bracegirdle, 1973; Smith, 1982).
    2) SEIZURES
    a) Seizures have occurred in poisoned dogs and cats (Palumbo et al, 1975; Chen & Kovarikova, 1967).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Salivation and vomiting may occur. These toxins may cause numbness of the oral mucosa if ingested.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Protracted vomiting has been reported in humans (Du & Due, 2001; Chern et al, 1991; CDC, 1995) and animals (Perry & Bracegirdle, 1973) following ingestion of toad toxins. The onset in several cases was 30 min to several hours after ingestion of a toad-toxin (Keomany et al, 2007; CDC, 1995).
    b) CASE REPORT: Vomiting (severe in some cases) was reported in children who ingested the eggs of a Bufo melanostictus Schneider toad. However, family members that ate only the meat of the toad did not become ill (Keomany et al, 2007).
    c) CASE REPORTS: Nausea and vomiting occurred in 2 children and 4 adults one hour after ingesting toad soup (Chi et al, 1998).
    d) Nausea, vomiting, and abdominal pain occurred in a 25-year-old pregnant woman immediately following ingestion of approximately 100 mL of a Chinese herbal tea containing Ch'an su (Ko et al, 1996).
    B) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Intense salivation has been reported in a child (Hitt & Ettinger, 1986) and occurs in poisoned cats and dogs (Perry & Bracegirdle, 1973).
    C) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) The toxins cause numbness of the oral mucosa following ingestion (Smith, 1982; Chen & Kovarikova, 1967; Chi et al, 1998; Ko et al, 1996).
    D) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea, sometimes watery, has occurred in two children and four adults one hour after ingesting toad soup (Chi et al, 1998) and has also been reported following the ingestion of toad eggs (Bufo melanosticuts Schneider) in a child (Keomany et al, 2007).

Hematologic

    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CYANOSIS
    a) DOGS: Cyanosis has been reported in dogs (Hitt & Ettinger, 1986).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ANHIDROSIS
    1) WITH POISONING/EXPOSURE
    a) Although handling toads is rarely seriously injurious to humans, it is thought to dramatically reduce perspiration (Smith, 1982).
    B) SKIN ABSORPTION
    1) WITH POISONING/EXPOSURE
    a) Bufotoxin is secreted by the skin of bufo toads, poisoning can occur by dermal exposure as well as ingestion.
    b) CASE REPORT: A 16-year-old boy developed vomiting, fatigue, bradycardia, hypotension, and third-degree AV block after removing and eating 15 toad livers. Eating the livers is usually not associated with toxicity, so it was believed that his exposure was cutaneous (Du & Due, 2001).
    C) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Contact with the "African Red Banded Rubber Frog" (Phrynamantis bifasciatus) can cause skin irritation with an erythematous rash and temporary inflammation. Prolonged contact may cause local pain (Pantanowitz et al, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs. Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor serum electrolytes, particularly potassium.
    C) Polyclonal digoxin immunoassays cross react with the cardiac genins contained in toad venoms, allowing confirmation of exposure, although the digoxin concentrations obtained do not correlate well with clinical effects.
    D) Monoclonal digoxin assays do not appear to cross react with the cardiac genins in toad venoms, and may not be useful to confirm exposure.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) A serum potassium level should be drawn to test for hyperkalemia (Chen & Kovarikova, 1967). An elevated serum potassium has been observed in numerous cases following exposure to toad toxins.
    2) DIGOXIN LEVEL
    a) Polyclonal digoxin immunoassays cross react with the cardiac genins contained in toad venoms, allowing confirmation of exposure, although the digoxin concentrations obtained do not correlate well with clinical effects. Monoclonal digoxin assays do not appear to cross react with the cardiac genins in toad venoms, and may not be useful to confirm exposure (Brubacher et al, 1996).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Patients who have had significant exposures should have a baseline ECG to observe for abnormalities and continuous cardiac monitoring should be instituted. Symptomatic patients should have serial ECGs performed.

Methods

    A) IMMUNOASSAY
    1) The Abbott TDx analyzer, used with Digoxin II reagents, has been used to detect glycosides other than digoxin, including bufadienolides. There is cross-reactivity, allowing for detecting the presence of these compounds, but the concentrations found are not linearly related (Cheung et al, 1989; Panesar, 1992).
    a) When one tablet of Kyushin (a nonprescription Chinese medication containing bufalin and cinobufaginal) was tested, it had digoxin-like immunoreactivity that differed depending on the methods used.
    b) The Abbott TDx showed an equivalency of 1.9 mcg; the DuPont 'Aca V' showed 1.5 mcg; and the 'Enzymum-Test' by Boehringer Mannheim showed 72 mcg (Fushimi et al, 1989).
    2) A fluorescence polarization immunoassay method, normally used for the detection of digitoxin, was described for the identification of bufalin toxicity, a cardioactive compound in Bufo toads, in human serum (Dasgupta & Datta, 1998).
    a) Bufalin caused positive interference in serum digoxin or digitoxin measurements when the digoxin or digitoxin concentrations were measured by this immunoassay method.
    3) Monoclonal digoxin immunoassays (CIBA Corning ACS(R)) do not appear to cross react with the cardiac genins in toad venoms, and may not be useful to confirm exposure (Brubacher et al, 1996).
    B) CHROMATOGRAPHY
    1) A gas chromatographic-mass spectrometric method was used to identify the components of a Chinese herbal tea consumed by a 25-year-old woman who subsequently died. Ch'an su, a bufadienolide, was identified as the toxic ingredient of the herbal tea (Ko et al, 1996).

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) All patients with clinically significant neurologic or cardiac signs/symptoms or ECG/laboratory evidence of cardiac toxicity should be admitted to a monitored setting until the patient is clearly improving.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Only asymptomatic patients with minimal skin exposure may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) A toxicologist should be consulted in any patients with evidence of neurologic or cardiac toxicity. An ophthalmologist should be consulted in patients with evidence of ocular injury on slit-lamp and visual acuity exams.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with significant skin exposure or ingestion should be observed for 6 hours. At the end of 6 hours, if there is no evidence of cardiac or neurologic toxicity, the patient may be discharged.

Monitoring

    A) Monitor vital signs. Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor serum electrolytes, particularly potassium.
    C) Polyclonal digoxin immunoassays cross react with the cardiac genins contained in toad venoms, allowing confirmation of exposure, although the digoxin concentrations obtained do not correlate well with clinical effects.
    D) Monoclonal digoxin assays do not appear to cross react with the cardiac genins in toad venoms, and may not be useful to confirm exposure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) INGESTION: Immediately flush the oral mucous membranes to decrease absorption. Do not swallow the rinse water. Consider prehospital administration of activated charcoal in patients with recent ingestions who are alert and can protect the airway.
    2) DERMAL: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water.
    3) OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes.
    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) ACTIVATED CHARCOAL
    1) Administer activated charcoal for recent ingestions. Cardiac glycosides and bufandienolides are adsorbed to activated charcoal and enterohepatic circulation may be decreased by multiple-dose activated charcoal (Balz & Bader, 1974).
    2) MULTIPLE DOSE CHARCOAL
    a) LACK OF EFFICACY: Multiple dose activated charcoal has not been shown to affect outcome after exposure to toad toxins and routine use is NOT recommended. Consider a second dose of activated charcoal in patients with severe toxicity or when digitalis Fab fragments are not available.
    3) 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.
    4) 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).
    B) IRRIGATION
    1) One of the best first-aid measures to prevent toxicity in animals is to immediately flush the oral mucous membranes of dogs, cats, and even people who have had mucous membrane exposure to decrease absorption. Do not swallow the rinse water.
    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) MONITORING OF PATIENT
    1) MONITOR ECG CONTINUOUSLY: For abnormal cardiac rates and rhythms. In patients with previously healthy hearts, the most common manifestation is bradycardia with or without varying degrees of AV block. Ventricular fibrillation has occurred. Peaked T waves, depressed ST segments, widened QRS and prolonged PR interval may also be present. Monitor serum potassium.
    B) DIGOXIN IMMUNE FAB (OVINE)
    1) SUMMARY: Use of digitalis Fab fragments should be considered in any patient with hyperkalemia or hemodynamically significant dysrhythmias.
    2) Digibind(R) has been used in 2 adults who had high digoxin levels after ingesting toad toxin-containing topical aphrodisiacs (CDC, 1995).
    a) Digibind(R) was administered approximately 15 hours after the ingestion in 1 fatal case which was complicated by ventricular fibrillation and respiratory failure; the digoxin level prior to cardiac arrest was 0.9 ng/mL.
    b) A nonfatal case was principally bradycardic (no ventricular fibrillation or respiratory failure) and received Digibind(R) 36 hours after the ingestion; the digoxin level decreased from 3.1 ng/mL at 6 hours post Digibind(R) to 0.9 ng/mL 30 hours after Digibind(R).
    3) Serum digoxin levels cannot be used to calculate the dose of digoxin immune FAB after bufotoxin poisoning. Empiric use of large amounts (e.g. 10 vials) of Digibind(R) has been suggested for symptomatic patients (CDC, 1995).
    4) STUDY: In a mouse model pretreatment with digoxin specific Fab fragments reduced the incidence of seizures and death from Chan Su, a Chinese medication derived from the venom of bufo toads (Brubacher et al, 1999).
    C) HYPERKALEMIA
    1) Hyperkalemia following acute overdose may be life-threatening. Administration of digitalis Fab fragments should be considered in any patient with hyperkalemia.
    a) If digoxin immune FAB is not available, the emergency management of life-threatening hyperkalemia (potassium levels greater than 6.5 mEq/L) includes the IV administration of bicarbonate, glucose and insulin.
    2) DOSE: Administer 0.2 unit/kg of regular insulin with 200 to 400 mg/kg glucose (intravenous dextrose 25% in water).
    3) Concurrent administration of intravenous sodium bicarbonate (approximately 1 mEq/kg up to 44 mEq/dose in an adult) may be of additive value in rapidly lowering serum potassium levels.
    4) Monitor the ECG while administering the glucose, insulin and sodium bicarbonate. This therapy should lower the serum potassium level for up to 12 hours.
    D) ATROPINE
    1) Atropine is useful in the management of bradycardia, varying degrees of heart block, and other cardiac irregularities due to the digitalis-like induced effects of enhanced vagal tone on the SA node rhythm and on conduction through the AV node (Chern et al, 1991).
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    E) PHENYTOIN
    1) Phenytoin is useful in the management of digitalis-like induced ventricular dysrhythmias and improves conduction through the AV node.
    2) LOW DOSE PHENYTOIN (Adult: 25 mg/dose IV at 1 to 2 hour intervals; Child: 0.5 to 1 mg/kg/dose IV at 1 to 2 hour intervals) appears to improve AV conduction. Larger doses are needed for the management of ventricular dysrhythmias.
    3) LOADING DOSE FOR ADULTS AND CHILDREN
    a) Administer 15 mg/kg up to 1 g IV not to exceed a rate of 0.5 mg/kg/min.
    4) MAINTENANCE DOSE
    a) ADULT: Administer 2 mg/kg IV every 12 hours as needed; CHILD: Administer 2 mg/kg every 8 hours as needed.
    5) Monitor serum phenytoin levels just prior to initiating and during maintenance therapy to assure therapeutic levels of 10 to 20 mcg/mL (39.64 to 79.28 nanomoles/liter). Monitor ECG carefully.
    F) MAGNESIUM
    1) Magnesium has been reported to reverse digoxin induced dysrhythmias. It should be used extremely cautiously if at all in the presence of renal failure.
    2) DOSE: ADULT: 20 mL of 20% solution over 20 minutes by slow infusion. Infusion should be stopped if patient vomits, becomes hypotensive, develops worsening heart block or loses deep tendon reflexes. Magnesium levels in serum should be followed.
    G) LIDOCAINE
    1) SUMMARY: Lidocaine is useful in the management of ventricular tachyarrhythmias, PVCs, and bigeminy. Lidocaine does not improve conduction through the AV node.
    2) LIDOCAINE/DOSE
    a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    3) LIDOCAINE/MAJOR ADVERSE REACTIONS
    a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    4) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    H) EMERGENCY CARDIAC PACEMAKER
    1) Insertion of a transvenous pacemaker should be considered in those patients with severe bradycardia and/or slow ventricular rate due to second degree AV block who fail to respond to atropine and/or phenytoin drug therapy.
    I) CHOLESTYRAMINE
    1) Digitoxin (and theoretically bufagin) elimination appears to be enhanced by the serial administration of cholestyramine, 4 g orally every 6 hours. Cholestyramine appears to have minimal effect on absorption and excretion of cardiac glycosides in humans.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Severe irritation and possible temporary loss of vision may result from ocular contact with toad secretory fluids.
    2) Prolonged irrigation and early ophthalmic consultation may be required.
    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).

Enhanced Elimination

    A) SUMMARY
    1) Cardiac glycosides and bufandienolides are adsorbed to activated charcoal and enterohepatic circulation may be decreased by multiple-dose activated charcoal. Multiple dose activated charcoal has not been shown to affect outcome after exposure to toad toxins and routine use is NOT recommended. Consider a second dose of activated charcoal in patients with severe toxicity or when digitalis Fab fragments are not available. Hemodialysis has been ineffective in removing cardiac glycosides but may assist in restoring potassium to normal levels. It has yet to be tried on bufagins.
    B) MULTIPLE DOSE ACTIVATED CHARCOAL
    1) LACK OF EFFICACY: Cardiac glycosides and bufandienolides are adsorbed to activated charcoal and enterohepatic circulation may be decreased by multiple-dose activated charcoal (Balz & Bader, 1974). However, multiple dose activated charcoal has not been shown to affect outcome after exposure to toad toxins and routine use is NOT recommended. Consider a second dose of activated charcoal in patients with severe toxicity or when digitalis Fab fragments are not available.
    C) HEMODIALYSIS
    1) Hemodialysis has been ineffective in removing cardiac glycosides but may assist in restoring potassium to normal levels. It has yet to be tried on bufagins.

Abstracts

Case Reports

    A) BUFO MARINUS: Licht (1968) reported the case of a family (mother and two children) from a small village on the Rio Ampiyacu in the Peruvian Amazon who were intoxicated after eating Bufo marinus eggs. The patients developed symptoms of hyperpyrexia, hyperpnea, dehydration and cardiac arrhythmias. The 34-year-old mother and 4-year-old daughter died as a result of the poisoning. The 9-year-old son survived (Licht, 1968).
    B) PEDIATRIC
    1) BUFO MELANOSTICTUS: Within a community in Laos, a 9-year-old boy developed severe vomiting shortly after ingesting a large amount of a grilled toad dish containing the skin, meat and eggs; he died within 12 hours without receiving medical care. A younger sibling ate the meat and some of the eggs of the toad and developed vomiting and diarrhea, but recovered. The patient's mother and sister ate only the meat and developed no symptoms. In another family, a 7-year-old boy developed vomiting within 2 hours of ingesting the meat and some eggs, but recovered without medical care. A younger sister (3 years) and brother (2 years) ate only the meat of the toad and were asymptomatic (Keomany et al, 2007).
    2) BUFO ALVARIUS: A 5-year-old who had mouthed a Bufo alvarius (Colorado River Toad) developed status epilepticus successfully treated with diazepam and phenobarbital (Hitt & Ettinger, 1986).

Range Of Toxicity

Summary

    A) TOXIC DOSE: The skin of one toad is sufficient to cause significant symptoms and even death in both animals and humans, however, most fatalities occur following ingestion. No toxic serum or blood levels have yet been established. Two children became severely ill after ingesting the skin and eggs of a Bufo melanostictus Schneider; one died within 12 hours of exposure, and the other developed digoxin-like toxicity (ie, bradycardia, hypotension) but recovered. A fatality occurred following an ingestion of approximately 100 mL of a Chinese herbal tea containing Ch'an su. Fatalities have been reported in men ingesting topical aphrodisiacs containing toad toxins.

Minimum Lethal Exposure

    A) SUMMARY
    1) The skin of one toad (especially the parotid glands) is sufficient to cause significant symptoms and even death in both animals and humans. The toxins are also present in the eggs.
    B) PEDIATRIC
    1) BUFO MELANOSTICTUS: Within a community in Laos, a 9-year-old boy developed severe vomiting shortly after ingesting a large amount of a grilled toad dish containing the skin, meat and eggs; he died within 12 hours without receiving medical care. A younger sibling ate the meat and some of the eggs of the toad and developed vomiting and diarrhea but recovered. The patient's mother and sister ate only the meat and developed no symptoms (Keomany et al, 2007).
    C) ADULT
    1) BUFO MELANOSTICTUS: A 25-year-old woman developed ventricular tachycardia and intractable ventricular fibrillation, and subsequently died 2.5 hours after ingesting approximately 100 mL of a Chinese herbal tea containing Ch'an su (Ko et al, 1996).
    2) HERBAL APHRODISIA: A 40-year-old previously healthy man ingested 3 pills of an unknown aphrodisiac approximately 7 hours prior to admission with complaints of nausea, vomiting and diaphoresis. An ECG showed sinus bradycardia with first-degree atrioventricular block. The patient had a serum digoxin concentration of 0.9 nmol/L. Digoxin Fab fragment was ordered but the patient rapidly deteriorated with respiratory insufficiency requiring intubation and ventilation. Likewise, his rhythm deteriorated into ventricular tachycardia followed by ventricular fibrillation. Cardiac resuscitation was unsuccessful. It was suspected the patient had ingested Chan su, a Chinese herbal medicine, containing Chinese toad venom (bufadienolide) (Gowda et al, 2003).
    3) HERBAL APHRODISIAC: Six previously heathy young men intentionally ingested a topical aprhodisiac (ie, Chan Su, Chinese herbal medicine produced from toad venom) and developed early symptoms of persistent nausea and vomiting. Serum digoxin was confirmed in each patient (range: 0.9 ng/mL to 3.08 ng/mL). Four patients died due to conduction disturbances that included ventricular fibrillation and asystole that were unresponsive to resuscitation. Of these patients, 3 died rapidly following admission (within 3 hours). The 2 patients that survived were treated with Digoxin Fab fragments (initial dose: 10 vials) with complete resolution in one case, the other patient required a second course (10 vials) of Digibind(R). Serum digoxin concentrations prior to Digibind(R) therapy were 3.9 ng/mL and 1.8 ng/mL, respectively (Brubacher et al, 1996a).

Maximum Tolerated Exposure

    A) BUFO MENOSTATICS: Two children became severely ill after ingesting the skin and eggs of a Bufo melanostictus Schneider; one died within 12 hours of exposure, and the other developed digoxin-like toxicity (i.e., bradycardia, extrasystoles, hypotension) but recovered following supportive care (Keomany et al, 2007).
    B) TOAD EGGS: A 19-year-old woman ate cooked toad eggs and developed nausea and vomiting and general weakness about an hour after eating the meal. Her initial ECG showed first-degree AV block, a serum potassium of 7.1 mmol/L and a serum digoxin concentration of 2.42 nmol/L. Her condition started to deteriorate with lethargy and disorientation. A transvenous pacemaker was inserted and the patient was treated with Digoxin Fab fragments about 4 hours after admission. She clinically improved with a gradual decrease in digoxin and potassium levels. The patient was discharged to home on day 5 (Kuo et al, 2007).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) No toxic serum or blood levels have yet been established.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) 12BETA-HYDROXYMARINOBUFAGIN
    B) 12BETA-HYDROXYRESIBUFOGENIN
    C) ACETYLBUFOTALIDIN
    D) ACETYLCINOBUFAGIN
    E) ACETYLCINOBUFOTALIN
    F) ACETYLMARINOBUFAGIN
    G) ALVAROBUFOTOXIN
    H) ARENOBUFAGIN
    I) ARENOBUFOTOXIN
    J) BUFALIN
    K) BUFOTALIDIN (HELLEBRIGENIN)
    L) BUFOTALIN
    M) BUFOTALININ
    N) CINOBUFAGIN
    O) CINOBUFOTALIN
    P) CINOBUFOTOXIN
    Q) DESACETYLBUFOTALIN
    R) FOWLEROBUFAGIN
    S) FOWLEROBUFOTOXIN
    T) GAMABUFOTALIN
    U) GAMABUFOTOXIN
    V) MARINOBUFAGIN
    W) MARINOBUFOTOXIN
    X) QUERCICOBUFAGIN
    Y) REGULAROBUFAGIN
    Z) REGULAROBUFOTOXIN
    AA) TELOCINOBUFAGIN
    AB) VALLICEPOBUFAGIN
    AC) VIRIDOBUFAGIN
    AD) VIRIDOBUFOTOXIN
    AE) VULGAROBUFOTOXIN

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Most bufandienolides are cardiotonic sterols synthesized by toads from cholesterol (Siperstein et al, 1957). The lactone ring is 6-membered of an alpha pyrone type attached to C17.
    1) They have a secondary hydroxy group at C3 and are called bufagins - which corresponds to the aglycones found in the cardiac glycosides in plants.
    2) None of these bufandienolides conjugates with a carbohydrate (as do the plants) to form glycosides, but some do form bufotoxins by combining with suberylargine (Chen & Kovarikova, 1967).
    B) In the toad, some of these compounds (eg, resibufogenin) are ouabain-like and increase the force of contraction of heart muscle (Lichtstein et al, 1986).
    C) The pharmacology of the catecholamines found in toad venom is well known and need not be discussed here.
    D) INDOLEALKYLAMINES - Pharmacology is also known. Besides having some hallucinogenic effects, these compounds may stimulate uterine and intestinal muscle (Chen & Kovarikova, 1961). Garraffo et al (1993) have profiled the alkaloids extracted from the skin of bufonid toads (genus Melanophryniscus).

Toxicologic Mechanism

    A) Bufagins and bufotoxins have been shown to inhibit sodium, potassium and ATPase activity (Lichtstein et al, 1986). Their action is almost the same as that of the digitalis glycosides (Palumbo et al, 1975).

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) SIGNS - Distress and excessive salivation, neurologic abnormalities (including seizures, stupor, ataxia, nystagmus, extensor rigidity, opisthotonus, and status epilepticus), hyperemic mucous membranes, ptyalism, recumbency or collapse, tachypnea, and vomiting are common (Roberts et al, 2000). Some toads produce prostration, seizures and death within 15 minutes. May produce cardiac arrhythmias.
    B) A typical animal case report involves a dog that finds a slow hopping toad and mouths the animal playfully. The animal usually experiences immediate salivation, and irritation of the mucus membranes of the mouth and throat.
    1) If the dog eats the toad, vomiting and paralysis may lead to seizures and death. Animals who recover usually do not have significant sequelae (Chern et al, 1991).

Treatment

    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.5) TREATMENT
    A) GENERAL TREATMENT
    1) ANIMALS (ESPECIALLY DOGS) may respond to the following treatment (Palumbo et al, 1975):
    a) FLUSH MUCOUS MEMBRANES - One of the best first aid measures to prevent toxicity in animals is to immediately flush the oral mucous membranes of dogs or cats who have had mucous membrane exposure to decrease absorption.
    b) ATROPINE may be used to decrease secretions and block vagal effects. It is not a specific antidote.
    c) ANTIHISTAMINES OR CORTICOSTEROIDS may reduce the effects of bufotoxins on the mucous membranes of the mouth and other organs, but have little direct action.
    d) PENTOBARBITAL-INDUCED ANESTHESIA does increase canine tolerance to toad venom intoxication.
    e) PROPRANOLOL has been tried on canines, with some success. The dose used was high: 5 milligrams/kilogram.

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) SPECIFIC TOXIN
    1) The toxins are located in the skin and parotid glands and may be transferred by handling a toad. A toad that sits in a dog's watering dish for some time may leave enough toxin to make the pet ill (Smith, 1982).
    2) The toxicity varies considerably by the toad species and its geographic location. The death rate for untreated animals exposed to Bufo marinus is nearly 100% in Florida, is low in Texas, and only about 5% in Hawaii (Palumbo et al, 1975).

References

General Bibliography

    1) 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.
    2) Ashok G, Ramkumar, Sakunthala SR, et al: An interesting case of cardiotoxicity due to bufotoxin (toad toxin). J Assoc Physicians India 2011; 59:737-738.
    3) Belz GG & Bader H: Effect of oral charcoal on plasma levels of intravenous methyl proscillaridin. Klin Wochenschr 1974; 52:1134-1135.
    4) Brubacher JR, Hoffman RS, & Kile T: Toad venom poisoning: failure of a monoclonal digoxin immunoassay to cross-react with the cardioactive steroids. Clin Toxicol 1996; 34:529-530.
    5) Brubacher JR, Lachmanen D, & Ravikumar PR: Efficacy of digoxin specific Fab fragments (Digibind(R)) in the treatment of toad venom poisoning. Toxicon 1999; 37:931-942.
    6) Brubacher JR, Ravikumar PR, & Hoffman RS: Analysis of fatal aphrodisiac known as love stone or rock hard (abstract 139). J Tox Clin Tox 1995; 33:539.
    7) Brubacher JR, Ravikumar PR, Bania T, et al: Treatment of toad venom poisoning with digoxin-specific fab fragments. Chest 1996a; 110(5):1282-1288.
    8) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    9) Burton R: Venomous Animals, Colour Library International Ltd, London, England, 1977.
    10) CDC: Deaths associated with a purported aphrodisiac-- City, February 1993-May 1995. CDC: MMWR 1995; 44:853-861.
    11) Caravati EM, Knight HH, & Linscott MS: Esophageal laceration and charcoal mediastinum complicating gastric lavage. J Emerg Med 2001; 20:273-276.
    12) Chen KK & Kovarikova A: Pharmacology and toxicology of toad venom. J Pharm Sci 1967; 56:1535-1541.
    13) Chern MS, Ray CY, & Wu D: Biologic intoxication due to digitalis-like substance after ingestion of cooked toad soup. Am J Cardiol 1991; 67:443-444.
    14) Cheung K, Hinds JA, & Duffy P: Detection of poisoning by plant-origin cardiac glycoside with the Abbott TDx analyzer. Clin Chem 1989; 35:295-297.
    15) Chi HT, Hung DZ, & Hu WH: Prognostic implications of hyperkalemia in toad toxin intoxication. Hum Exp Toxicol 1998; 17:343-346.
    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) Daly JW & Witkop B: Chemistry and pharmacology of frog venoms. In: Bucherl W & Buckly EE (eds). Venomous Animals and Their Venoms, vol 2, Academic Press, New York, NY, 1971.
    19) Dasgupta A & Datta P: Rapid detection of cardioactive bufalin toxicity using fluorescence polarization immunoassay for digitoxin. Ther Drug Monitor 1998; 20:104-108.
    20) Du NT & Due P: Severe toad venom poisoning by dermal absorption (abstract). J Toxicol Clin Toxicol 2001; 39:563.
    21) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    22) Emboden W: Narcotic Plants, MacMillan Publishing Company, Inc, New York, NY, 1979.
    23) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    24) Fushimi R, Tachi J, & Amino N: Chinese medicine interfering with digoxin immunoassays. Lancet 1989; 1:339.
    25) Gilman AG, Goodman LS, & Rall TW: The Pharmacological Basis of Therapeutics, 7th ed, MacMillan Publishing Company, New York, NY, 1985.
    26) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    27) Gowda RM, Cohen RA, & Khan IA: Toad venom poisoning: resemblance to digoxin toxicity and therapeutic implications. Heart 2003; 89:e14.
    28) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    29) 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.
    30) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    31) Hitt M & Ettinger DD: Toad toxicity. N Engl J Med 1986; 314:1517.
    32) Kantor RE, Dudlettes SD, & Shulgin AT: 5-Methoxy-a-methyl-tryptamine (a, O-dimethylserotonin), a hallucinogenic homolog of serotonin. Biological Psychiatry 1980; 15:349-352.
    33) Keomany S, Mayxay M, Souvannasing P, et al: Toad poisoning in Laos. Am J Trop Med Hyg 2007; 77(5):850-853.
    34) Kibmer B & Wichtl M: Bufadienolide aus samen von helleborus odorus. Planta Med 1986; 2:77-162.
    35) 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.
    36) Ko RJ, Greenwald MS, & Loscutoff SM: Lethal ingestion of Chinese herbal tea containing Ch'an su. West J Med 1996; 164:71-75.
    37) Kuo HY, Hsu CW, Chen JH, et al: Life-threatening episode after ingestion of toad eggs: a case report with literature review. Emerg Med J 2007; 24(3):215-216.
    38) Kwan T, Paiusco AD, & Kohl L: Digitalis toxicity caused by toad venom. Chest 1992; 102:949-950.
    39) Lescure J: Notes du Cours "Animaux et Toxiques, Laboratoire de Zoologie - Reptiles et Amphibians - Museum National d'Histoire Naturelle, Paris, France, 1985.
    40) Licht LE: Unpalatibility and toxicity of toad eggs. Herpetologica 1968; 24:93-98.
    41) Lichtstein P, Kachalsky S, & Deutsch J: Identification of a ouabain-like compound in toad skin and plasma as a bufodienolide derivative. Life Sci 1986; 38:1261-1270.
    42) Lincoff G & Mitchel DH: Toxic and Hallucinogenic Mushroom Poisoning, Van Nostrand Reinhold Company, Dallas, TX, 1977.
    43) Lyttle T: Misuse and legend in the "toad licking" phenomenon. Int J Addict 1993; 28:521-538.
    44) McKenna DJ & Towers GH: Biochemistry and pharmacology of tryptamines and beta-carbolines, a minireview. J Psychoactive Drugs 1984; 16:347-358.
    45) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    46) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    47) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    48) Palumbo NE, Perri S, & Read G: Experimental induction and treatment of toad poisoning in the dog. J Am Vet Med Assoc 1975; 167:1000-1005.
    49) Panesar NS: Bufalin and unidentified substances(s) in traditional chinese medicine cross-react in commercial digoxin assay (letter). Clin Chem 1992; 38:2155-2156.
    50) Pantanowitz L, Naude TW, & Leisewitz A: Noxious toads and frogs of South Africa. SAMJ 1998; 88:1408-1414.
    51) Pantanowitz L: Drug-induced hyperkalemia (letter). Am J Med 2002; 112:334.
    52) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    53) Perry BD & Bracegirdle JR: Toad poisoning in small animals. Vet Rec 1973; 92:589-590.
    54) Peyresblanques J: Atteinte oculaire par venin de crapaud. Bulletin des Scoietes d'Ophtalmologie de France 1964; 64:493-502.
    55) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    56) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    57) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    58) Roberts BK, Aronsohn MG, & Moses BL: Bufo marinus intoxication in dogs: 94 cases (1997-1998). J Am Vet Med Assoc 2000; 216:1941-1944.
    59) Siperstein MD, Murray AW, & Titus E: Biosynthesis of cardiotonic sterols from cholesterol in the toad Bufo marinus. Arch Biochem Biophys 1957; 67:154-160.
    60) Smith RL: Venomous Animals of Arizona, Cooperative Extension Service, College of Agriculture, University of Arizona, Tucson, AZ, 1982.
    61) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    62) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    63) Tyler MJ: Frogs, William Collins Ltd, Sydney, Austrailia, 1976.
    64) Vale JA, Kulig K, American Academy of Clinical Toxicology, et al: Position paper: Gastric lavage. J Toxicol Clin Toxicol 2004; 42:933-943.
    65) 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.
    66) Van Tittelboom T, Strauven A, & Kuhn D: A propos d'un cas d'atteinte oculaire par venin de crapaud (Abstract), Presented at the XXV ieme Congres de Centres Anti-Poisons, Paris, France, 1987.
    67) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.