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PLANTS-HELLEBORE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) There are over 20 species of hellebores found from Europe to the Mediterranean area. There is one species found in western China (Mitchell & Rook, 1979). Many of these have been brought to the United States and Canada, especially the garden plant Helleborus niger.
    B) Veratum californicum, also called False Hellebore, is not a Helleborus species.

Specific Substances

    A) HELLEBORUS ABRUZZICUS
    1) H. Abruzzicus
    HELLEBORUS ARGUTIFOLIUS
    1) H. Argutifolius
    2) Corsican Hellebore
    HELLEBORUS ATRORUBENS
    1) H. Atrorubens
    HELLEBORUS BOCCONEI
    1) H. Bocconei
    HELLEBORUS CAUCASICUS
    1) H. Caucasicus
    HELLEBORUS CROATICUS
    1) H. Croaticus
    HELLEBORUS CYCLOPHYLLUS
    1) H. Cyclophyllus
    HELLEBORUS DUMETORUM
    1) H. Dumetorum
    HELLEBORUS FOETIDUS
    1) Stinking Hellebore
    2) Bear's Foot
    HELLEBORUS HERCEGOVINUS
    1) H. Hercegovinus
    HELLEBORUS ISTRIACUS
    1) H. Istriacus
    HELLEBORUS LIGURICUS
    1) H. Liguricus
    HELLEBORUS LIVIDUS
    1) H. Lividus
    HELLEBORUS MULTIFIDUS
    1) H. Multifidus
    HELLEBORUS NIGER
    1) Black Hellebore
    2) Christmas Rose
    3) Easter Rose
    4) Helleborus odoris
    HELLEBORUS OCCIDENTALIS
    1) H. Occidentalis
    HELLEBORUS ODORUS
    1) H. Odorus
    HELLEBORUS ORIENTALIS
    1) Lenten Rose
    HELLEBORUS PURPURASCENS
    1) H. Purpurascens
    2) Purple Flower
    HELLEBORUS THIBETANUS
    1) H. Thibetanus
    HELLEBORUS TORQUATUS
    1) H. Torquatus
    HELLEBORUS VESICARIUS
    1) H. Vesicarius
    HELLEBORUS VIRIDIS
    1) Green Hellebore
    2) Bear's Foot

Available Forms Sources

    A) USES
    1) Historically, various preparations of these plants were used (in both animals and man) as purgatives, local anesthetics, or abortifacients. They were also used against various parasitic skin infections.
    2) In Romania, extracts of the helleborus species are used as phytopreparations with immunostimulatory properties (Bussing & Schweizer, 1998). The helleborus niger species is used in Germany in homeopathic medicine and as an adjunctive treatment for tumors in anthroposophical medicine (holistic and human-centered approach to healing).
    3) HELLEBORUS NIGER L. - In homeopathy, this plant has been used for meningitis, encephalitis, nephritis, epilepsy, hydrocephaly, psychosis, melancholy, collapse, cardiac insufficiency, and dementia praecox in homeopathic medicine (Duke, 1985).

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: Twenty species of hellebore grow throughout Europe, the Mediterranean and Asia Minor. A single species grows in western China, and several species have been brought to North America. Historically, various preparations of these plants were used (in both animals and humans) as purgatives, local anesthetics or abortifacients. They were also used against various parasitic skin infections. Several cases have been reported regarding toxicity after exposure to sneezing-powders containing veratrum album.
    B) PHARMACOLOGY: These plants contain a mixture of protoanemonin, saponins, and cardioactive steroids/cardiac glycosides. Cardiac glycosides increase the force of contraction of the heart (positive inotropy) by inhibiting the sodium potassium ATPase and increasing the cytosolic calcium concentration in a cardiac cell.
    C) TOXICOLOGY: Cardiac glycosides decrease the rate of depolarization and conduction through the sinoatrial (SA) and atrioventricular (AV) nodes. This is indirectly achieved via enhancement of the vagally mediated parasympathetic tone, and directly by depression of the nodal tissue. This reflected as PR interval prolongation on the ECG and various degrees of AV nodal blockade. Protoanemonin reacts with sulfhydryl groups. Its subepidermal vesicant activity may depend on its ability to inactivate enzymes containing SH groups, especially those used in glycolysis. The whole plant is poisonous.
    D) EPIDEMIOLOGY: Exposure to hellebore is uncommon. Severe toxicity has been reported but is rare. Death has not been reported to date.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Skin irritation or blisters may occur from contact. Oral irritation, nausea, vomiting, diarrhea, and abdominal pain can occur. Inhalation can cause a burning sensation and pain in the upper abdominal area as well as nausea, vomiting and respiratory irritation.
    2) SEVERE TOXICITY: Signs of toxicity include nausea, vomiting, oral irritation, colic, diarrhea, abdominal pain, visual disturbances, tinnitus, dyspnea, conduction defects, sinus bradycardia, dysrhythmias, premature ventricular contractions, atrioventricular conduction defects or ventricular tachydysrhythmias, increased automaticity either in the atria or the ventricles, including premature ventricular contractions (PVCs). Seizures occur rarely with toxicity. Cardiac glycoside toxicity may lead to hyperkalemia, a marker of poisoning of the sodium-potassium ATPase channel in the cardiac cell. Various ECG abnormalities may occur with cardiac glycoside toxicity including PR interval prolongation, QTC interval shortening, and ST segment and T-wave forces that are opposite in direction to the major QRS forces, resulting in the characteristic scooping of the ST segments.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) May cause irritation to the eyes and mydriasis.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Cardioactive steroids/cardiac glycosides may lead to atrioventricular (AV) conduction delays, including AV nodal blockade, sinus bradycardia, and increased automaticity either in the atria or ventricles, including premature ventricular contractions (PVCs), and atrial and ventricular dysrhythmias.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Dyspnea has been reported following ingestion of helleborus niger.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) No data were available to assess the human neurologic effects following exposure to helleborus plants.
    2) Syncope, seizures, and trembling of the limbs occur in animals.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Cardiac glycoside toxicity may initially manifest with nausea and vomiting. Oral irritation, an acrid taste, colic, diarrhea, and abdominal pain are signs and symptoms of poisoning.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) No data were available to assess the human genitourinary effects following exposure to Helleborus plants.
    2) Genitourinary effects including increased urination and bloody urine occurred in animals.
    0.2.12) FLUID-ELECTROLYTE
    A) Cardiac glycoside toxicity may lead to hyperkalemia, a marker of poisoning of the sodium-potassium ATPase channel in the cardiac cell.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Skin irritation may occur from contact with the protoanemonins.
    0.2.20) REPRODUCTIVE
    A) Ingestion of these plants by pregnant women has produced abortions.
    B) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.

Laboratory Monitoring

    A) Obtain a basic metabolic panel, including a serum potassium concentration on any patient with a history suggesting more than minor exposure.
    B) Monitor fluid and electrolytes in patients with severe vomiting or diarrhea.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Cardiac glycosides/cardioactive steroids may cross-react with a serum digoxin assay due to structural similarities. Depending on the assay used, digoxin serum concentration may or may not be elevated with ingestion of cardiac glycosides. This can be used to confirm exposure, but concentrations will not correlate with toxicity and cannot be used to guide therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. NAUSEA and VOMITING: Administer IV fluids for fluid replacement and antiemetics; monitor electrolytes and renal function. HYPOTENSION: For mild hypotension, administer IV fluids as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Primary treatment for cardiac dysrhythmias is digoxin antibodies. HYPOTENSION: If hypotension is secondary to severe bradycardia or dysrhythmias, treat with digoxin specific antibodies; administer vasopressors if unresponsive to IV fluids. CARDIAC TOXICITY: Administer digoxin-specific antibody fragments (Fab) for cardiac toxicity. The ideal dose is not known and serum digoxin concentrations are not useful for guiding dosing. Administer 10 vials to adult and pediatric patients IV over 30 minutes or as a bolus in a critically ill patient. BRADYCARDIA: For symptomatic bradycardia, administer digoxin specific antibodies. Atropine or pacing may also be useful.
    C) DECONTAMINATION
    1) PREHOSPITAL: ORAL: Consider activated charcoal in a patients with a potentially toxic ingestion who are awake and able to protect their airway. Most effective when administered within one hour of ingestion. Activated charcoal should not be administered in patients who are at risk for the abrupt onset of seizures or mental status depression due to the risk of aspiration in the event of spontaneous emesis. OCULAR EXPOSURE: Remove contact lens and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation or photophobias persist after 15 minutes of irrigation, an ophthalmologic examination should be performed at the hospital. DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area thoroughly with soap and water.
    2) HOSPITAL: Consider activated charcoal in a patients with a potentially toxic ingestion who are awake and able to protect their airway. Most effective when administered within one hour of ingestion. Activated charcoal should not be administered in patients who are at risk for the abrupt onset of seizures or mental status depression due to the risk of aspiration in the event of spontaneous emesis.
    D) ANTIDOTE
    1) Administer digoxin-specific antibody fragment (Fab) for hemodynamically significant dysrhythmias. Administer 10 vials to adult and pediatric patients IV over 30 minutes or as a bolus in a critically ill patient. Note: More than 10 vials may be necessary if cardiac toxicity persists since Fab may not bind the plant cardiac glycoside with the same affinity as digoxin. Repeat dosing if dysrhythmias do not resolve. Serum digoxin concentration cannot be used to guide therapy as it is not known how well the glycosides in hellebore cross-react with the assay. As hyperkalemia is an accepted marker of severe toxicity in cardiac glycoside poisoning, all patients with a serum potassium greater than 5 mEq/L following hellebore exposure should be treated with Fab.
    E) AIRWAY MANAGEMENT
    1) Endotracheal intubation should be performed with excessive drowsiness and the inability to protect their own airway.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Children with exploratory ingestions who do not have symptoms beyond mild GI upset can be managed at home.
    2) OBSERVATION CRITERIA: Symptomatic children and adults with symptoms or deliberate overdose should be sent to a medical facility. Patients should be observed in a medical facility until free of symptoms or if asymptomatic for at least 6 hours after exposure.
    3) ADMISSION CRITERIA: All patients who are symptomatic should be admitted for observation until clinical symptoms have resolved.
    4) CONSULT CRITERIA: Consult a medial toxicologist for symptomatic patients.
    G) TOXICOKINETICS
    1) Oral absorption occurs quickly and most reports show that patients that become symptomatic have clinical effects within the first 48 hours.
    H) DIFFERENTIAL DIAGNOSIS
    1) Should include digoxin toxicity, ingestion of other cardiac glycosides, toxicity from poisons or toxins that cause conduction disturbances, primary GI or cardiac etiologies, myocardial infarction and primary conduction disturbances.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: 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, the patient should be seen in a healthcare facility.
    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: Only a few leaves are necessary to cause toxicity in cattle. Similarly small amounts would be expected to produce toxicity in humans. Minimum lethal human exposure is unknown.

Clinical Effects

Summary Of Exposure

    A) USES: Twenty species of hellebore grow throughout Europe, the Mediterranean and Asia Minor. A single species grows in western China, and several species have been brought to North America. Historically, various preparations of these plants were used (in both animals and humans) as purgatives, local anesthetics or abortifacients. They were also used against various parasitic skin infections. Several cases have been reported regarding toxicity after exposure to sneezing-powders containing veratrum album.
    B) PHARMACOLOGY: These plants contain a mixture of protoanemonin, saponins, and cardioactive steroids/cardiac glycosides. Cardiac glycosides increase the force of contraction of the heart (positive inotropy) by inhibiting the sodium potassium ATPase and increasing the cytosolic calcium concentration in a cardiac cell.
    C) TOXICOLOGY: Cardiac glycosides decrease the rate of depolarization and conduction through the sinoatrial (SA) and atrioventricular (AV) nodes. This is indirectly achieved via enhancement of the vagally mediated parasympathetic tone, and directly by depression of the nodal tissue. This reflected as PR interval prolongation on the ECG and various degrees of AV nodal blockade. Protoanemonin reacts with sulfhydryl groups. Its subepidermal vesicant activity may depend on its ability to inactivate enzymes containing SH groups, especially those used in glycolysis. The whole plant is poisonous.
    D) EPIDEMIOLOGY: Exposure to hellebore is uncommon. Severe toxicity has been reported but is rare. Death has not been reported to date.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Skin irritation or blisters may occur from contact. Oral irritation, nausea, vomiting, diarrhea, and abdominal pain can occur. Inhalation can cause a burning sensation and pain in the upper abdominal area as well as nausea, vomiting and respiratory irritation.
    2) SEVERE TOXICITY: Signs of toxicity include nausea, vomiting, oral irritation, colic, diarrhea, abdominal pain, visual disturbances, tinnitus, dyspnea, conduction defects, sinus bradycardia, dysrhythmias, premature ventricular contractions, atrioventricular conduction defects or ventricular tachydysrhythmias, increased automaticity either in the atria or the ventricles, including premature ventricular contractions (PVCs). Seizures occur rarely with toxicity. Cardiac glycoside toxicity may lead to hyperkalemia, a marker of poisoning of the sodium-potassium ATPase channel in the cardiac cell. Various ECG abnormalities may occur with cardiac glycoside toxicity including PR interval prolongation, QTC interval shortening, and ST segment and T-wave forces that are opposite in direction to the major QRS forces, resulting in the characteristic scooping of the ST segments.

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) May cause irritation to the eyes and mydriasis.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS may occur after Hellebore ingestion (Frohne & Pfander, 1984; Duke, 1985).
    2) VISUAL DISTURBANCES were seen in a woman who used the material to kill lice (Cooper & Johnson, 1984).
    3) EYE IRRITATION occurred with topical application of the powdered root of Helleborus odoris (Duke-Elder & MacFaul, 1972). Other authors also noted eye irritation from contact with the bruised root stocks and leaves (Muenscher, 1957)(Cornevin, 1887; Piffard, 1881).
    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) Tinnitus has been reported following ingestion of helleborus niger (Duke, 1985).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) SNEEZING may be attributed to the protoanemonin content (Lampe & Fagerstrom, 1968).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Dry or scratchy throat can occur following ingestion of the seeds or medicinal overdoses (Duke, 1985).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Cardioactive steroids/cardiac glycosides may lead to atrioventricular (AV) conduction delays, including AV nodal blockade, sinus bradycardia, and increased automaticity either in the atria or ventricles, including premature ventricular contractions (PVCs), and atrial and ventricular dysrhythmias.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH POISONING/EXPOSURE
    a) Cardiac toxicity may occur with some species, but is unlikely in Helleborus niger, since the bufadienolides have yet to be identified in this species (Wisser & Kating, 1971).
    b) Cardiac glycosides may lead to atria-ventricular conduction delays and various degrees of atria-ventricular (AV) nodal blockade (Hack & Lewin, 2006).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Conduction defects and sinus bradycardia may be seen in some cases. Usually the only arrhythmias seen are escape beats (Lampe & McCann, 1985; Duke, 1985).
    b) Hellebore toxicity may result in a variety of dysrhythmias, including sinus bradycardia, premature ventricular contractions, atrioventricular conduction defects, or ventricular tachydysrhythmias (Nelson et al, 2007).
    c) The AV nodal blockade prevents the conduction of the electrical impulse from the atria to the ventricle through the AV node (Hack & Lewin, 2006).
    C) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Various ECG abnormalities may occur with cardiac glycoside toxicity including PR interval prolongation, QTC interval shortening, and ST segment and T-wave forces that are opposite in direction to the major QRS forces, resulting in the characteristic scooping of the ST segments (Hack & Lewin, 2006).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Dyspnea has been reported following ingestion of helleborus niger.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Symptoms of dyspnea have occurred following ingestion of the seeds or accidental exposure of helleborus niger (Duke, 1985).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) No data were available to assess the human neurologic effects following exposure to helleborus plants.
    2) Syncope, seizures, and trembling of the limbs occur in animals.
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SYNCOPE
    a) Syncope has been seen after ingestion of other protoanemonin containing plants (Lampe & Fagerstrom, 1968).
    2) SEIZURE
    a) Seizures and trembling have been reported in animal cases (Cooper & Johnson, 1984; Holliman & Milton, 1990).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Cardiac glycoside toxicity may initially manifest with nausea and vomiting. Oral irritation, an acrid taste, colic, diarrhea, and abdominal pain are signs and symptoms of poisoning.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting and colic may occur after ingestion of the Helleborus plant (Frohne & Pfander, 1984; Duke, 1985).
    B) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) A tingling sensation of the mouth and throat may be followed by increased salivation (Frohne & Pfander, 1984).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may occur after ingestion of these plants (Frohne & Pfander, 1984; Duke, 1985).
    D) TASTE SENSE ALTERED
    1) WITH POISONING/EXPOSURE
    a) Plants containing protoanemonin generally have an acrid taste and cause a burning sensation in the mouth and throat (Lampe & McCann, 1985; Cooper & Johnson, 1984).
    E) GASTROINTESTINAL IRRITATION
    1) WITH POISONING/EXPOSURE
    a) The mouth may become irritated, or ulcers may develop (Lampe & McCann, 1985; Duke, 1985).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) No data were available to assess the human genitourinary effects following exposure to Helleborus plants.
    2) Genitourinary effects including increased urination and bloody urine occurred in animals.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMATURIA
    a) Animals have experienced increased urination, and the urine may be bloody (Cooper & Johnson, 1984).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Skin irritation may occur from contact with the protoanemonins.
    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Skin irritation or blisters may occur (Lampe & McCann, 1985; Duke, 1985).

Reproductive

    3.20.1) SUMMARY
    A) Ingestion of these plants by pregnant women has produced abortions.
    B) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) ABORTION
    1) An abortion occurred in a woman who used a decoction of hellebore for the treatment of lice (Cooper & Johnson, 1984).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain a basic metabolic panel, including a serum potassium concentration on any patient with a history suggesting more than minor exposure.
    B) Monitor fluid and electrolytes in patients with severe vomiting or diarrhea.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Cardiac glycosides/cardioactive steroids may cross-react with a serum digoxin assay due to structural similarities. Depending on the assay used, digoxin serum concentration may or may not be elevated with ingestion of cardiac glycosides. This can be used to confirm exposure, but concentrations will not correlate with toxicity and cannot be used to guide therapy.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Obtain a basic metabolic panel, including a serum potassium concentration. Serum potassium should be monitored for hyperkalemia (Lampe & McCann, 1985).
    2) If vomiting and diarrhea are extensive, monitor the patient for fluid and electrolyte loss (Lampe & Fagerstrom, 1968).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring (Lampe & McCann, 1985).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Routine laboratory analysis will not detect protoanemonin. Several methods exist to quantitate this compound, including paper and thin layer chromatography, colorimetry, and spectrophotometry. The most sensitive methods are by normal and reverse phase HPLC (Bonora et al, 1985; Bruni et al, 1986).
    2) Cardiac glycosides/cardioactive steroids may cross-react with a serum digoxin assay due to structural similarities. The best assay for hellebore-specific cardiac glycosides has not been determined. In oleander, which also contains cardiac glycosides similar to Helleborus species, detection may be sensitive via fluorescence polarization immunoassay (FPIA) (Dasgupta & Datta, 2004).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All patients who are symptomatic should be admitted for observation until clinical symptoms have resolved.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children with exploratory ingestions who do not have symptoms beyond mild GI upset can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medial toxicologist for symptomatic patients.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic children and adults with symptoms or deliberate overdose should be sent to a medical facility. Patients should be observed in a medical facility until free of symptoms or if asymptomatic for at least 6 hours after exposure.

Monitoring

    A) Obtain a basic metabolic panel, including a serum potassium concentration on any patient with a history suggesting more than minor exposure.
    B) Monitor fluid and electrolytes in patients with severe vomiting or diarrhea.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Cardiac glycosides/cardioactive steroids may cross-react with a serum digoxin assay due to structural similarities. Depending on the assay used, digoxin serum concentration may or may not be elevated with ingestion of cardiac glycosides. This can be used to confirm exposure, but concentrations will not correlate with toxicity and cannot be used to guide therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) 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) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive (Cooper & Johnson, 1984).
    2) Spasmolytics may be considered for colic (Duke, 1985).
    3) Monitor electrolytes and ECG (Lampe & McCann, 1985).
    B) MONITORING OF PATIENT
    1) Obtain a basic metabolic panel, including a serum potassium concentration on any patient with a history suggesting more than minor exposure.
    2) Monitor fluid and electrolytes in patients with severe vomiting or diarrhea.
    3) Obtain an ECG and institute continuous cardiac monitoring. Cardiac glycosides/cardioactive steroids may cross-react with a serum digoxin assay due to structural similarities. Depending on the assay used, digoxin serum concentration may or may not be elevated with ingestion of cardiac glycosides. This can be used to confirm exposure, but concentrations will not correlate with toxicity and cannot be used to guide therapy.
    C) DIGOXIN IMMUNE FAB (OVINE)
    1) SUMMARY
    a) Digoxin-specific antibody fragments (FAB) are designed to have high affinity to digoxin and digitoxin. All cardioactive steroids share structural similarities. Digoxin-specific antibody fragments are available as Digibind(R), using human albumin as the large carrier protein, or as Digifab(R), using keyhole-limpet hemocyanin as the large carrier protein. Each vial of Digibind(R) and Digifab(R) contains 38 mg and 40 mg, respectively, of digoxin-immune ovine immunoglobulin fragments in the form of purified lyophilized powder (Prod Info DIGIFAB(R) injection, 2005; Prod Info DIGIBIND(R) IV injection, 2003).
    2) INDICATIONS
    a) Manifestations of toxicity including conduction disturbance, bradycardia, tachydysrhythmia, or hyperkalemia with or without detectable serum cardiac glycoside concentration.
    3) DOSE
    a) Start with 10 vials for an adult or a child.
    b) Given that digoxin-specific antibody fragment may not bind to the plant cardiac glycoside with the same affinity as digoxin, dosing depends on the continued presence of cardiac toxicity. Although not reported with Hellebore, various cardioactive steroids respond to digoxin-specific antibody fragments, with one case necessitating 37 vials (Rich et al, 1993).
    4) ADMINISTRATION
    a) Reconstitute each vial in 4 mL of sterile water. Administer intravenously over 30 minutes, infused through a 0.22 micron filter. Intraosseous administration is not recommended. A bolus may be given to a critically ill patient.
    5) PRECAUTIONS
    a) SERUM DIGOXIN CONCENTRATION: Depending on the assay used, digoxin serum concentration may or may not be elevated with ingestion of cardiac glycosides.
    b) ALLERGIC REACTION: Risk of an allergic reaction in patients with allergy to papain, chymopapain, or other papaya extracts.
    D) WIDE QRS COMPLEX
    1) Atropine or pacing may be helpful (Lampe & McCann, 1985).
    a) When sinus bradycardia is producing or complicated by frequent PVCs, or when the patient is hypotensive with signs of decreased perfusion, atropine should be used (B Honigman , 1991).
    b) ATROPINE/DOSE
    1) 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).
    2) 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.
    a) There is no minimum dose (de Caen et al, 2015).
    b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

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).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) Dermal application of the fresh root of the helleborus niger L. can cause severe irritation (Duke, 1985).
    2) 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) EXTRACORPOREAL ELIMINATION
    1) At the time of this review, there are no effective methods of enhanced elimination for this agent.

Range Of Toxicity

Summary

    A) TOXICITY: Only a few leaves are necessary to cause toxicity in cattle. Similarly small amounts would be expected to produce toxicity in humans. Minimum lethal human exposure is unknown.

Minimum Lethal Exposure

    A) SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.

Pharmacology Toxicology

Toxicologic Mechanism

    A) PROTOANEMONIN - Reacts with sulfhydryl (SH) groups. Its sub-epidermal vesicant activity may depend on its ability to inactivate enzymes containing SH groups, especially those used in glycolysis (Frohne & Pfander, 1983).
    B) CARDIAC GLYCOSIDES/CARDIOACTIVE STEROIDS
    1) Cardiac glycosides increase the force of contraction of the heart (positive inotropy) by inhibiting the sodium-potassium ATPase and increasing the cytosolic calcium concentration in a cardiac cell (Hack & Lewin, 2006).
    2) Cardiac glycosides decrease the rate of depolarization and conduction through the sinoatrial (SA) and atrioventricular (AV) nodes. This is indirectly achieved via enhancement of the vagally mediated parasympathetic tone, and directly by depression of the nodal tissue. This is reflected as PR interval prolongation on the ECG and various degrees of AV nodal blockade (Hack & Lewin, 2006).
    3) Cardiac glycosides increase automaticity by shortening the repolarization intervals of the atria and ventricles. This is reflected as QTc interval shortening on the ECG. In addition, ST segment and T-wave forces are opposite in direction to the major QRS forces, resulting in the characteristic scooping of the ST segments (Hack & Lewin, 2006).
    C) SAPONINS - Toxicologic mechanism has not been fully delineated.

Physicochemical

Physical Characteristics

    A) Plants containing protoanemonin generally have an acrid taste and cause a burning sensation in the mouth and throat (Lampe & Fagerstrom, 1968).

Molecular Weight

    A) Varies

Animal Toxicology

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) Seventeen Friesian-cross yearling cattle obtained access to some discarded H. foetidus (Holliman & Milton, 1990).
    1) Within 15 hours, one animal was seen recumbent with violent leg movements. Within another 6 hours, 3 animals were dead, and another 3 were sick, showing slight abdominal distension, inflamed conjunctiva, increased heartbeat, unsteady gait, subnormal temperature, and depression. One had foul smelling diarrhea.
    2) Despite symptomatic treatment, all of these animals died within an additional 6 to 18 hours, showing signs of abdominal pain, deeply sunken eyes, blood around the mouth, scouring and blood around the anus.
    3) The other animals developed no overt symptoms other than increased thirst.
    4) Postmortem examination showed evidence of hellebore in the rumen, intense congestion of the abomasal and small intestinal muscosa, and excessive fluid in the large bowel. No other abnormalities were seen except for slight lung congestion/cellular filtration, which was probably due to congestion and stasis.
    B) Application of green hellebore to the neck resulted in a swollen neck, anorexia, poor coat condition, muscular tremors, dyspnea, and prostration. It is unknown if all these symptoms occured after skin absorption, or whether the area was licked and oral absorption occurred (Berselli, 1936).
    C) Ingested hellebore produced abdominal pain, ataxia, and diarrhea. Deaths occured in some animals within 2 to 3 days, others took 10 to 11 days to die (Johnson & Routledge, 1971).
    D) Bradycardia, an irregular pulse, coma, and seizures have been seen prior to death in some animals (Chomel et al, 1981).
    E) Diarrhea fluids may contain blood or mucus; urination may be frequent (Forsyth AA, 1968).
    F) Postmortem examinations in some of these cases showed inflammation and ulceration of the digestive tract, and occasionally hemorrhages in the intestine and surrounding the heart (Cooper & Johnson, 1984).
    G) Cattle will eat the plants even when better forage is available (Humphreys, 1988).

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    5) Due to lack of reports of small animal intoxication with this substance, the following sections address large animals (horses, ruminants, and swine) only. In the case of a poisoning involving small animals, consult a veterinary poison control center.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) RUMINANTS/HORSES/SWINE
    a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
    b) ACTIVATED CHARCOAL - Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube.
    c) CATHARTIC - Administer an oral cathartic: mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon); magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 gram/kilogram); or milk of magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os). Give these solutions via stomach tube and monitor for aspiration.
    d) REMOVE animals from source of forage.
    11.2.5) TREATMENT
    A) HORSES/CATTLE/SWINE
    1) Maintain vital functions: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    2) Decontaminate as specified above.
    3) Treat symptomatically and maintain supportive care.

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) CATTLE
    1) In the fatal cases reported by Holliman & Milton (1990), only a small quantity (exact amount not stated) of leaves were found in the rumen. Five bullocks that consumed only 100 grams of leaves among them died within 11 days of consumption (Humphreys, 1988).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    5) Due to lack of reports of small animal intoxication with this substance, the following sections address large animals (horses, ruminants, and swine) only. In the case of a poisoning involving small animals, consult a veterinary poison control center.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) RUMINANTS/HORSES/SWINE
    a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
    b) ACTIVATED CHARCOAL - Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube.
    c) CATHARTIC - Administer an oral cathartic: mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon); magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 gram/kilogram); or milk of magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os). Give these solutions via stomach tube and monitor for aspiration.
    d) REMOVE animals from source of forage.
    11.4.3) TREATMENT
    11.4.3.5) SUPPORTIVE CARE
    A) GENERAL
    1) Ongoing treatment is symptomatic and supportive.
    11.4.3.6) OTHER
    A) OTHER
    1) GENERAL
    a) POSTMORTEM FINDINGS were non-specific, including congestion of the lungs and of the pyloric area of the abomasum, intestines, and heart. The kidneys were pale (Humphreys, 1988).

Pharmacology Toxicology

    A) GENERAL
    1) TOXIC EFFECTS are due to the plants' purgative and glycosidic properties (Beasley et al, 1989).

References

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