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PLANTS-VERATRUM ALKALOIDS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This management contains information on 3 similar types of toxins: zigadenus alkaloids, veratrum alkaloids and sabadilla (a veratrum type alkaloid). Sabadilla seeds (from a Zigadenes species) do contain veratrine.

Specific Substances

    A) Zigadenus Common Names
    1) Poison Sego
    2) Death Camus
    3) Sand Corn
    4) Black Snakeroot
    Zigadenus species
    1) Z. venenosus
    2) Z. peniculatus
    3) Z. nuttollii
    4) Z. graminius
    5) Z. elegans
    6) Z. densus
    7) Z. fremontii
    8) Z. glaucus
    Zigadenus Alkaloids
    1) Zygadenine
    2) Zygacine
    3) Veratroylzygadenine
    4) Vanilloylzygadenine
    5) Neogermitrine
    6) Germidine
    7) Neogermidine
    8) Protoveratridine germine
    9) References: Kupchan et al, 1955
    Veratrum Common Names
    1) False Hellebore
    2) American White Hellebone
    3) Corn Lily
    4) Earth Gall
    5) Green Hellebore
    6) Indian Poke
    7) Itch Weed
    8) Pepper-Root
    9) Rattlesnake Weed
    10) Skunk Cabbage
    11) Swamp Hellebore
    12) Tickle Weed
    13) White Hellebore
    14) References: Lampe & McCann, 1985
    Veratrum Alkaloids
    1) Cervadine
    2) Plants-Sabadilla veratrum
    3) Protoveratirine A and B
    4) Sabadilla veratrum
    5) Veratramine
    6) Veratridine
    7) Veratrine

Available Forms Sources

    A) SOURCES
    1) Cevadilla ceradine and Sabadilla extract are from Schoenocaulon officinale (Liliaceae). Alkavervir is a mixture of alkaloids obtained from green veratrum, and cryptenomine acetate or tannate salts of alkaloids derived from an extract of green veratrum.
    B) USES
    1) VERATRUM ALBUM has been used for the treatment of digestive problems, including diarrhea accompanied by vomiting. Veratrum album is most commonly used for heat exhaustion.
    2) VERATRUM VIRIDE has traditionally been used as an analgesic and a cardiac sedative, due to its hypotensive properties. Powdered rhizomes or some of its alkaloids have been used in insecticidal agents. Tinctures have been used for cancers; the powdered rhizome has also been used for respiratory ailments, seizures, mania, neuralgia, and headaches; infusions have been gargled for sore throat and tonsillitis (Duke, 1985).
    3) VERATRINE has been used externally as an analgesic and parasiticide, as well as internally for arteriosclerosis and interstitial nephritis (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) INGESTION: The principle effects are severe nausea and vomiting followed by bradycardia, syncope, paresthesias, weakness, diaphoresis, salivation. Cardiovascular events can include hypotension and ECG changes (sinus bradycardia, short PR interval, short QTc interval, bundle-branch block, nodal rhythm, depressed ST segment). Rare events include visual disturbances, unconsciousness, and headaches. Young plants or their bulbs can be mistaken for other plants including wild onions or sego lilies. ONSET; 30 minutes to 4 hours. DURATION: In most patients about 24 to 48 hours, if left untreated some can experience symptoms for up to 5 to 10 days.
    0.2.5) CARDIOVASCULAR
    A) Bradycardia, AV block, and hypotension may occur in both humans and animals.
    0.2.6) RESPIRATORY
    A) Dyspnea may occur.
    0.2.7) NEUROLOGIC
    A) Salivation, muscular weakness, and syncope may occur.
    B) Coma may occur in severe cases.
    C) Headache, aphasia, and seizures are uncommon effects of intoxication.
    0.2.8) GASTROINTESTINAL
    A) Severe nausea and vomiting with epigastric and substernal pain may occur.
    0.2.14) DERMATOLOGIC
    A) Sweating has been reported.
    0.2.20) REPRODUCTIVE
    A) Veratrine alkaloids are known to produce teratogenic effects in rats, mice, cattle sheep, goats, and hamsters.

Laboratory Monitoring

    A) Monitor vital signs and blood pressure closely.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    C) Monitor serum electrolytes in patients with severe vomiting and diarrhea or dysrhythmias.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) ATROPINE: ADULT DOSE: BRADYCARDIA: BOLUS: 0.5 mg IV may repeat every 3 to 5 min. Maximum: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kg ET). Repeat once, if needed. Minimum dose: 0.1 mg. Maximum single dose: Child: 0.5 mg; Adolescent: 1 mg. Maximum total dose: Child: 1 mg; Adolescent: 2 mg.
    C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    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) Acute toxic oral doses in humans has been estimated at 1 to 2 Zigadenus bulbs. Four to five bulbs may be fatal in a child and about 40 to 50 may be fatal in an adult (extrapolated from animal data.)
    B) The whole plant is toxic; most often the bulb and flowers are involved. Seeds and leaves also produce poisonings, but this is unusual in humans.
    C) 100 grams of veratrum has produced hypotension and bradycardia in an adult.

Clinical Effects

Summary Of Exposure

    A) INGESTION: The principle effects are severe nausea and vomiting followed by bradycardia, syncope, paresthesias, weakness, diaphoresis, salivation. Cardiovascular events can include hypotension and ECG changes (sinus bradycardia, short PR interval, short QTc interval, bundle-branch block, nodal rhythm, depressed ST segment). Rare events include visual disturbances, unconsciousness, and headaches. Young plants or their bulbs can be mistaken for other plants including wild onions or sego lilies. ONSET; 30 minutes to 4 hours. DURATION: In most patients about 24 to 48 hours, if left untreated some can experience symptoms for up to 5 to 10 days.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA - Subnormal temperatures have been reported (Hardin & Arena, 1974).

Heent

    3.4.3) EYES
    A) CONJUNCTIVITIS may occur (Jaffe et al, 1990). The Natural Medicines database notes blindness as a possible, but rare effect of poisoning.
    B) VISUAL DISTURBANCES have been described rarely (Schep et al, 2006).
    3.4.5) NOSE
    A) Chronic exposure can produce irritation to nasal mucous membranes (Spoerke & Spoerke, 1979). Sneezing and rhinorrhea are common after acute inhalation of powdered root extracts.
    3.4.6) THROAT
    A) An immediate numbness and tingling in the mouth has been reported after ingestion (Prince & Stork, 2000). Salivation, dysphagia, and throat irritation are possible effects following exposures.

Cardiovascular

    3.5.1) SUMMARY
    A) Bradycardia, AV block, and hypotension may occur in both humans and animals.
    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) Bradycardia has been reported and may be typical in large ingestions (Schep et al, 2006; Zagler et al, 2005; Quatrehomme et al, 1993; Courtemanche et al, 1989; Jaffe et al, 1990; Heilpern, 1995).
    2) INCIDENCE - In one study, 6 out of 8 (75%) patients developed bradycardia (defined as heart rate equal to or less than 40 beats per minute) after ingestion of Veratrum species (Jaspersen-Schib et al, 1996).
    a) In another case series, 3 of 8 patients developed bradycardia (range 46 to 56 beats per minute) following the ingestion of Zigadenus bulbs ("foothill camas bulbs" found in the western United States). These patients also required hospitalization for supportive care; recovery was uneventful (Peterson & Rasmussen, 2003).
    3) CASE REPORT - Bradycardia (pulse 48 beats per minute) and a prolonged QTc (0.455 seconds) developed in a 4-year-old boy following inadvertent ingestion of a Zigadenus bulb (thought to be a wild onion). The patient's cardiovascular status stabilized within 14 hours of admission, and his vital signs were normal within 24 hours (Dunnigan et al, 2002).
    4) CASE REPORT - Bradyarrhythmias and A-V node dissociation developed in an adult after ingestion of an infusion of Veratrum album (Festa et al, 1996).
    5) CASE REPORT - Sinus bradycardia (heart rate = 40's), shown on initial ECG, was reported in a 52-year-old woman following ingestion of a Hellebore plant. Her pulse rate increased to 100 beats/min after atropine 0.5 mg was administered. The patient was discharged in 2 days with full recovery (Schuetz & Adams, 1998).
    6) CASE REPORT - Approximately 45 minutes following the ingestion of a soup made from Veratrum viride a 51-year-old male presented to the ED with heart rate of 30 bpm (fluctuating between second and third degree AV block on continuous cardiac monitor) and blood pressure of 40 mmHg. Emergency care consisted of fluid hydration, atropine and dopamine. The patient was discharged 3 days later (Prince & Stork, 2000).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) Characteristically these patients will develop P-R and Q-T shortening, S-T depression, bundle branch block, AV blocks, and T wave changes (Jaffe et al, 1990; Marinov et al, 1987; Festa et al, 1996).
    2) CASE REPORT - Following the ingestion of a soup made from Veratrum viride, a 51-year-old male developed bradycardia and hypotension. A 12-lead ECG revealed sinus rhythm, second degree AV block, junctional escape complexes and nonspecific ST abnormalities. About one hour, later the ECG showed persistent ST segment depressions in V2 through V6, which continued and evolved into a right bundle branch block. The patient was treated with intensive supportive care, and 3 days later ECG showed resolution of the right bundle branch block (Prince & Stork, 2000).
    C) HYPOTENSIVE EPISODE
    1) Moderate to extreme hypotension, requiring fluid and vasopressor therapy, may occur (Dunnigan et al, 2002; Nelson, 1954; Courtemanche et al, 1989; Jaffe et al, 1990; Schuetz & Adams, 1998; Festa et al, 1996; Prince & Stork, 2000).
    a) Patients may become hypotensive, become normotensive or even hypertensive (Jaffe et al, 1990).
    2) INCIDENCE - Five of eight patients (62.5%) reported in one Swiss study developed shock after ingestion of Veratrum species (Jaspersen-Schib et al, 1996).
    a) In another case series, 3 of 8 patients developed hypotension (range 81/54 to 94/57) following the ingestion of Zigadenus bulbs ("foothill camas bulbs" found in the western United States). These patients also required hospitalization for supportive care; recovery was uneventful (Peterson & Rasmussen, 2003).
    3) Repeated ingestions of small doses may produce tolerance to hypotensive effect but not hypertensive effect (Cameron, 1952).
    4) CASE REPORT - Hypotension (systolic blood pressure of 62 mmHg) and bradycardia developed in a 4-year-old boy following inadvertent ingestion of a Zigadenus bulb (thought to be a wild onion). A dopamine infusion was required and was gradually weaned within 14 hours of admission. The patient's vital signs were normal within 24 hours (Dunnigan et al, 2002).
    D) HYPERTENSIVE EPISODE
    1) CASE SERIES - One of six patients reported by Jaffe et al (1990) became hypertensive after receiving atropine to treat bradycardia and hypotension. The more common response is hypotension.
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPERTENSION
    a) Blood pressures fall, except with a large ingestion which may cause rise to 200 mm of mercury or higher accompanied by a rapid, thready pulse.

Respiratory

    3.6.1) SUMMARY
    A) Dyspnea may occur.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) Dyspnea has been reported in patients following ingestions (Jaffe et al, 1990).

Neurologic

    3.7.1) SUMMARY
    A) Salivation, muscular weakness, and syncope may occur.
    B) Coma may occur in severe cases.
    C) Headache, aphasia, and seizures are uncommon effects of intoxication.
    3.7.2) CLINICAL EFFECTS
    A) APHASIA
    1) Aphasia and hemiparesis was seen in an adult with veratrum induced hypotension (Garnier et al, 1985).
    B) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) In a case series, 3 of 8 patients developed dizziness following the ingestion of Zigadenus bulbs ("foothill camas bulbs" found in the western United States) (Peterson & Rasmussen, 2003).
    C) COMA
    1) Coma has been reported in children who ingested Zigadenus flowers and bulbs (Cameron, 1952).
    2) CASE REPORT - Decreased level of consciousness was reported in a 4-year-old boy after inadvertently ingesting a Zigadenus bulb (thought to be a wild onion). Six hours after ingestion he remained sleepy and responsive only to painful stimuli. The patient's mental status cleared within 8 hours of admission and within 36 hours his neuro status was normal. No permanent sequelae occurred (Dunnigan et al, 2002).
    D) HEADACHE
    1) Headache has been reported after veratrum ingestion (Schep et al, 2006; Zagler et al, 2005; Jaffe et al, 1990).
    E) SYNCOPE
    1) Syncope was reported after exposure to veratrum alkaloids in a sneezing powder (Carlier et al, 1983) and after ingestion of a hellebore plant (Schuetz & Adams, 1998). Lightheadedness may be reported after veratrum ingestion (Jaffe et al, 1990).
    F) SEIZURE
    1) Seizures are an uncommon effect of intoxication (Schep et al, 2006; Quatrehomme et al, 1993).
    G) DELIRIUM
    1) Delirium is an uncommon reported sign of poisoning (Quatrehomme et al, 1993).
    H) CLOUDED CONSCIOUSNESS
    1) Confusion and loss of short-term memory may occasionally occur following a poisoning. Slurred speech has been reported (Quatrehomme et al, 1993; Prince & Stork, 2000).
    I) PARESTHESIA
    1) Paresthesias and "spasms" have been reported in patients who ingested veratrum (Schep et al, 2006; Jaffe et al, 1990; Schuetz & Adams, 1998). Increased muscle tone and paresthesia are characteristic of veratrum poisonings.
    J) MUSCLE FASCICULATION
    1) Transient abdominal wall fasciculations developed in an adult male after ingestion of one Zigadenus bulb (Heilpern, 1995).

Gastrointestinal

    3.8.1) SUMMARY
    A) Severe nausea and vomiting with epigastric and substernal pain may occur.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) Acute exposure to Zigadenus and Veratrum species may result in severe nausea and vomiting which may occur within 30 minutes of ingestion (Schep et al, 2006; Zagler et al, 2005; Coville, 1897; Jaffe et al, 1990; Schuetz & Adams, 1998; Heilpern, 1995; Prince & Stork, 2000).
    2) INCIDENCE - In a case series of 8 patients every individual developed nausea, with most patients developing vomiting following the ingestion of Zigadenus bulbs ("foothill camas bulbs" found in the western United States). Three of 8 patients required hospitalization for supportive care; recovery was uneventful (Peterson & Rasmussen, 2003).
    B) DIARRHEA
    1) Severe diarrhea may occur (Zagler et al, 2005; Cameron, 1952; Schuetz & Adams, 1998).
    C) ABDOMINAL PAIN
    1) Epigastric pain and substernal pain may also develop, often within 30 minutes of ingestion (Quatrehomme et al, 1993; Festa et al, 1996; Schep et al, 2006).
    D) EXCESSIVE SALIVATION
    1) Profuse salivation may occur (Hardin & Arena, 1974; Prince & Stork, 2000; Schep et al, 2006).
    E) TASTE SENSE ALTERED
    1) An unpleasant, bitter taste may occur (Spoerke & Spoerke, 1979; Prince & Stork, 2000).

Dermatologic

    3.14.1) SUMMARY
    A) Sweating has been reported.
    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) DIAPHORESIS, which can be profound, may occur after veratrum ingestion (Jaffe et al, 1990; Prince & Stork, 2000).
    2) CASE REPORT - Sweating occurred within 30 minutes in 2 adults who ingested wine made from Veratrum (Quatrehomme et al, 1993). Severe sweating occurred in a woman following ingestion of a hellebore plant (Veratrum viride) (Schuetz & Adams, 1998).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) Muscular weakness may occur.

Reproductive

    3.20.1) SUMMARY
    A) Veratrine alkaloids are known to produce teratogenic effects in rats, mice, cattle sheep, goats, and hamsters.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Veratrine alkaloids are known to produce teratogenic effects in rats, mice, cattle sheep, goats, and hamsters (Keeler, 1969; Keeler, 1975; Binns et al, 1972; Keeler & Binns, 1966; Keeler & Binns, 1968).
    2) HAMSTERS - Gaffield & Keeler (1993) demonstrated teratogenicity in hamsters from jerveratrum alkaloids resulting in craniofacial malformation in 50% of the litters of treated dams.
    3) SHEEP - Early embryonic death was noted in sheep (laboratory and field observations) which ingested Veratrum californicum. Doses of the plant were given to 16 ewes. Six of the 8 in the experimental group were barren, compared to none in the control group (Keeler, 1990). When ewes were given Veratrum californica by gavage (started at day 29) the fetal metacarpal, metatarsal, and tibial bones were shortened. There was also arthrogryposis, fused metacarpi, and joint articular surface defects (Keeler & Stuart, 1987).
    4) MICE - Swiss Webster mice and Sprague Dawley mice are relatively insensitive to the effect of Veratrum teratogens. Species differences are known for these teratogens, but strain differences were also noted. The 3 strains used were C57BL/6J, A/J, and N:GP(S); all were given jervine (a Veratrum steroid alkaloid) in doses of 70, 150, or 300 mg/kg. No abnormalities were seen in the N:GP(S) mandibular micrognathia or agnathia (Omnell et al, 1990).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and blood pressure closely.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    C) Monitor serum electrolytes in patients with severe vomiting and diarrhea or dysrhythmias.

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Electron mass spectrometry has been used to identify Zigadenus alkaloids in animal poisonings. Different Zigadenus species have different spectra (Smith & Lewis, 1991).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor vital signs and blood pressure closely.
    B) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    C) Monitor serum electrolytes in patients with severe vomiting and diarrhea or dysrhythmias.

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) BRADYCARDIA
    1) ATROPINE
    a) Because there are multiple sites of action (medulla carotid, sinus, and nodose ganglion) atropine is only partially effective in reversing the hypotensive effects (Spoerke & Spoerke, 1979; Carlier et al, 1983).
    b) Clinical response to atropine varies, and in one study, only 1 of 6 cases reported ECG changes reversed by atropine (Courtemanche et al, 1989).
    c) 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).
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) PHENYLEPHRINE
    a) MILD OR MODERATE HYPOTENSION
    1) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).
    b) CONTINUOUS INFUSION
    1) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
    2) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    3) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).
    c) ADVERSE EFFECTS
    1) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    5) CASE SERIES - In 3 of 6 cases in the Courtemanche et al (1989) study, vasopressors were required to maintain blood pressure.
    6) CASE SERIES: Jaffe et al (1990) reported that metaraminol was required in 3 of 6 patients who ingested veratrum. Dopamine and metaraminol have been used (Garnier et al, 1985).
    C) ANTIEMETIC
    1) The nausea and vomiting of veratrum alkaloids are not well controlled by anti-emetic agents (Carlier et al, 1983).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

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) 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).

Abstracts

Case Reports

    A) ADULT
    1) A 40-year-old ingested an approximate 100 grams of veratrum. Five hours later he developed diaphoresis, light headedness, leg "spasms", and bilateral retrobulbar headache. He was seen in the emergency department where he was vomiting, with a pulse of 38 and a blood pressure of 70/45 mmHg. Rapid improvement was seen after a 0.5 mg I.V. dose of atropine. The nausea was unchanged. Further atropine doses (0.5 mg) were given 7.5, 11, 13 and 15.5 hours post-ingestion (Jaffe et al, 1990).

Range Of Toxicity

Summary

    A) Acute toxic oral doses in humans has been estimated at 1 to 2 Zigadenus bulbs. Four to five bulbs may be fatal in a child and about 40 to 50 may be fatal in an adult (extrapolated from animal data.)
    B) The whole plant is toxic; most often the bulb and flowers are involved. Seeds and leaves also produce poisonings, but this is unusual in humans.
    C) 100 grams of veratrum has produced hypotension and bradycardia in an adult.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Extrapolated from animal data, a fatal dose for a child was estimated to be 4 to 5 bulbs (0.1 pound) and for an adult about 1 pound of bulbs (Wagstaff & Case, 1987).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) VERATRUM - Approximately, 100 grams of plant material produced vomiting, headache, hypotension, and bradycardia (Jaffe et al, 1990).
    2) ZIGADENUS - One to two bulbs of Zigadenus species has produced severe symptoms in a 2-year-old (Cameron, 1952). Each bulb is 10 to 15 grams (Wagstaff & Case, 1987).
    3) Exposures to Veratrum and Zigadenus often occur when the bulbs are mistaken for wild edibles such as wild onion and wild parsnips. An infusion of Veratrum album (early growth stages) was made by a person trying to make an herbal Gentiana lutea herbal product and gathered the wrong plant (Festa et al, 1996).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) VERATRUM ALKALOID
    1) LD50- (ORAL)MOUSE:
    a) 4500 mcg/kg (RTECS , 2001)
    2) LD50- (ORAL)RAT:
    a) 12 mg/kg (RTECS , 2001)
    B) ZIGADENUS PANICULATUS ALKALOID EXTRACT

Pharmacology Toxicology

Toxicologic Mechanism

    A) EMETIC ACTION is produced by stimulation of the nodose ganglion rather than the medulla (Osol & Farrar, 1975; (Borison & Fairbanks, 1952).
    B) CARDIAC EFFECTS are thought to be a result of a neural reflex called the Bezold-Jarisch reflex. The veratrum alkaloids purportedly produces bradycardia and hypotension by interacting with cardiac receptors in the left ventricle posterior wall as well as the baroreceptor area of the coronary sinus. Multiple depolarizations in the vagal nerve evokes a reflex that induces bradycardia, systemic hypotension, and dyspnea (Schep et al, 2006). In the past, veratrum extracts were investigated clinically to treat hypertension, but adverse events (eg, nausea, vomiting, muscle weakness) resulted in a lack of clinical utility (Schep et al, 2006).
    C) NERVE EFFECTS
    1) Veratrum alkaloids act on the membranes of excitable cells, resulting in repetitive firing after a single stimulus. They depolarize the membranes of those excitable cells. Veratrine maintains the sodium channel in the open position (Nanasi et al, 1994).
    a) Veratrum alkaloids interact at the sodium channel which is modulated by the kinetic state of the channel. While the channel is in an open state, binding is greatly enhanced. A negative stimulation threshold then occurs which enables a repetitive response to a single stimulus, and thus toxic signs and symptoms develop (Prince & Stork, 2000).
    2) Sensitivity varies considerably. The nerve endings of the afferent vagal fibers in coronary sinus and left ventricles have some of the lowest thresholds, thus a decrease in heart rate and blood pressure occurs (Carlier et al, 1983). The activity on these receptors produces a reflex hypotension by a lowering of peripheral alpha-adrenergic tone (Hintze, 1987).
    3) These alkaloids increase muscle tone. Germine diacetate (a veratrum alkaloid) has been evaluated as treatment for myasthenia gravis (Anon, 1967).
    4) Veratramine is a serotonin agonist, causing classic serotonin syndrome in mice, reversible with cyproheptadine and methysergide (Nagata & Izumi, 1991).

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) Fowl poisoned with Zigadenus developed diarrhea, incoordination, prostration, and often coma. Within 24 to 48 hours of developing symptoms, most of the birds were dead (Niemann, 1928).
    11.1.2) BOVINE/CATTLE
    A) Cattle have similar symptoms to sheep, but the nausea may be slightly greater and the salivation less (Kingsbury, 1964).
    11.1.5) EQUINE/HORSE
    A) Symptoms are similar to those of sheep (Kingsbury, 1964).
    11.1.9) OVINE/SHEEP
    A) Symptoms include excessive salivation, nausea, vomiting, muscle weakness, ataxia, trembling, and eventual prostration.
    B) The pulse is fast and weak, dyspnea occurs, and cyanosis may appear.
    C) Coma may occur in serious cases, before death. The period between coma and death may be a few hours or a few days (Kingsbury, 1964; Chestnut & Wilcox, 1901).
    D) When an extract of Z. gramineus was injected, respiratory inhibition was the primary symptom seen. Both increased and decreased blood pressure were seen (McLaughlin, 1931).
    E) TERATOGENIC EFFECTS - Fetal facial abnormalities and signs of wastage have been seen in as many as 25% of live births (Kingsbury, 1964).
    11.1.10) PORCINE/SWINE
    A) Although swine are thought to be highly susceptible to the zigadenus alkaloids, they vomit so readily that serious poisonings are uncommon (Marsh CD & Clawson AB, 1924).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) SWINE
    1) Pigs vomit after ingestion of just 1 or 2 bulbs (Marsh CD & Clawson AB, 1924).
    B) SHEEP
    1) Sheep may be killed by ingestion of one-half pound of Zigadenus bulbs per 100 pounds of body weight (Marsh CD & Clawson AB, 1924).
    2) There is considerable variation in toxicity from one Zigadenus species to another. It takes 7 times as much Z. elegans as Z. paniculatus to produce the same toxic effect in sheep (Marsh CD & Clawson AB, 1922).
    3) Time of onset may be as soon as 1.5 hours, or as much as 7.75 hours.

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