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PLANTS-MISTLETOE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The term mistletoe is used for a number of parasitic plants of the family Loranthaceae. In the United States and Canada the mistletoe of Christmas decorations is Phoradendron serotinum.
    B) European literature about mistletoe refers primarily to Viscum album, which is found in the US in only Sonoma county California. It is not imported.

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Phoradendron flavescens
    2) Phoradendron serotinum
    3) American Mistletoe
    4) Phoradendron macrophyllum
    5) Phoradendron tomentosum
    6) Viscum album
    7) Viscum abietis
    8) Viscum austriacum
    9) Miseltoe (misspelling of mistletoe)
    10) Misiltoe (misspelling of mistletoe)
    11) Missletoe (misspelling of mistletoe)

Available Forms Sources

    A) FORMS
    1) Brand names of some Viscum preparations include Iscador(TM), Helixor(TM), and Plenosol(TM). Iscador(TM) and Helixor(TM) are intended for subcutaneous use, Phenosol(TM) for intracutaneous or IV use (Wagner et al, 1986).
    2) Iscador(TM) has been shown to contain the lectins ML II/III but not ML I (Wagner et al, 1986).
    3) In 1982, there were over 150 mistletoe containing products on the market in Great Britain (Anon, 1982).
    B) USES
    1) CHRISTMAS DECORATIONS: Phoradendron is used in the United States (Becker, 1986).
    2) Both genera have been used in herbal treatments. Phoradendron was specifically recommended by herbalists as an abortifacient. Other alleged uses of both include recommendations as a antihypertensive, antispasmodic and sedative (Spoerke, 1980).
    3) Viscum has also been researched for its antineoplastic activity (Bradley & Clover, 1989; Anon, 1982).
    4) The main areas where some preparations (eg; Iscador(TM), Helixor(TM), and Plenosol(TM)) are still occasionally used for cardiovascular illnesses (hypertension, arteriosclerosis), cancer, and arthrosis.
    5) FDA: The FDA has classified mistletoe as food additives, thus they can not be marketed unless proven safe (Anon, 1981).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Actual human overdose experience is limited. Most data are from animal parenteral experimentation that may not be applicable to the responses following oral ingestion. The toxicity of mistletoe is further confused because of the number of different types of toxins associated with the plants. The common name, mistletoe, applies to Phoradendron species and to Viscum species. Check plant descriptions for the correct species.
    B) Ingestions of Phoradendron species usually results in acute (less than 6 hours) symptoms. Lectins, which cause the delayed gastroenteritis, have been reported in both Viscum and Phoradendron exposures.
    C) Ingesting a few of the relatively nontoxic berries would, at most, produce mild gastroenteritis. Ingesting concentrated extracts of the plant, including the berries, may produce serious poisonings.
    0.2.4) HEENT
    A) Fixed and dilated pupils, diplopia, and irritated conjunctiva were reported.
    0.2.5) CARDIOVASCULAR
    A) Phoradendron poisoning reports show increased blood pressure. Viscum species may cause a decrease in blood pressure, possibly due to a cholinomimetic effect.
    0.2.7) NEUROLOGIC
    A) Seizures, mental confusion, drowsiness, and hallucinations have been reported in human cases.
    0.2.8) GASTROINTESTINAL
    A) Gastroenteritis was reported in both humans and animals. In one human case, vomiting, diarrhea, and abdominal cramps persisted 8 to 12 hours after ingestion of a mistletoe-containing tea.
    0.2.9) HEPATIC
    A) Although hepatitis has been reported after the ingestion of a mistletoe- containing tea, its relationship to mistletoe, other herbs in the product, or possible contaminants is unclear.
    0.2.13) HEMATOLOGIC
    A) Transient eosinophilia occurred following administration of Viscum extract and Viscumin was shown to hemoagglutinate all groups of human erythrocytes.
    0.2.20) REPRODUCTIVE
    A) Phoradendron species have been shown to produce increased tonus of dog and cat uteri.
    0.2.21) CARCINOGENICITY
    A) Viscumin is a cytotoxic compound. Actual cancer cases were not found.

Laboratory Monitoring

    A) Monitor liver enzymes and electrolytes in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Most patients do not require gastrointestinal decontamination. Activated charcoal should be considered after an ingestion equal to or greater than 6 berries or 4 leaves.
    B) 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.
    C) GASTROENTERITIS: Gastroenteritis may be especially prominent. Monitor and replace fluid and electrolytes. Use of a cathartic is generally NOT indicated due to concurrent diarrhea.
    D) 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.
    E) HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses.
    F) 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.
    G) PREGNANCY: Pregnant patients should be monitored carefully for increased uterine muscle tone.

Range Of Toxicity

    A) TOXICITY: Toxic doses have not been established for human exposures, but the ingestion of 3 berries or 2 leaves or less are NOT thought to produce significant clinical effects. Ingestion of American mistletoe (Phoradendron) is unlikely to cause significant toxicity.

Clinical Effects

Summary Of Exposure

    A) Actual human overdose experience is limited. Most data are from animal parenteral experimentation that may not be applicable to the responses following oral ingestion. The toxicity of mistletoe is further confused because of the number of different types of toxins associated with the plants. The common name, mistletoe, applies to Phoradendron species and to Viscum species. Check plant descriptions for the correct species.
    B) Ingestions of Phoradendron species usually results in acute (less than 6 hours) symptoms. Lectins, which cause the delayed gastroenteritis, have been reported in both Viscum and Phoradendron exposures.
    C) Ingesting a few of the relatively nontoxic berries would, at most, produce mild gastroenteritis. Ingesting concentrated extracts of the plant, including the berries, may produce serious poisonings.

Heent

    3.4.1) SUMMARY
    A) Fixed and dilated pupils, diplopia, and irritated conjunctiva were reported.
    3.4.3) EYES
    A) CASE REPORT: DIPLOPIA was noted in a 23-year-old who ingested over 100 grams of bee pollen containing 83% Phoradendron pollen. Strabismus and estropia were also noted (Rhoads et al, 1986).
    B) CASE REPORT: MIOSIS was reported in one case from around the turn of the century (Osol & Farrar, 1955).
    C) MYDRIASIS: Viscum album caused fixed and dilated pupils as well as irritated conjunctiva and "livid lips" (Dixon, 1874).
    D) IRRITATION: One case of eye irritation after ocular exposure has been reported (Spiller et al, 1996).

Cardiovascular

    3.5.1) SUMMARY
    A) Phoradendron poisoning reports show increased blood pressure. Viscum species may cause a decrease in blood pressure, possibly due to a cholinomimetic effect.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Human case reports show cardiovascular collapse caused by Phoradendron (Moore, 1963). It is unclear if this is direct toxicity or secondary to hypovolemic shock following protracted vomiting and diarrhea.
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Viscum species may cause a decrease in blood pressure, possibly due to a cholinomimetic mechanism (Petkov, 1979).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CARDIAC ARREST
    a) DIGITALIS EFFECT (PARENTERAL DOSING): Although early literature (Buster, 1871 to 1888) discussed mistletoe as having a digitalis-like action, the specific pharmacologic activity is unclear. Death in animals was caused by asystole (Samuelsson, 1958).
    2) HYPOTENSION
    a) Experiments using viscotoxin or phoratoxin have shown an initial fall in blood pressure followed by a sustained rise (Crawford, 1981), bradycardia, hypotension, and increased cardiac contractility.
    3) PERIPHERAL ISCHEMIA
    a) VASOCONSTRICTION: Higher doses produced decreased peripheral vasoconstriction in skin and skeletal muscles (Rosell & Samuelsson, 1966).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Increased and stertorious respirations were reported with Viscum and Phoradendron exposures (Moore, 1963).

Neurologic

    3.7.1) SUMMARY
    A) Seizures, mental confusion, drowsiness, and hallucinations have been reported in human cases.
    3.7.2) CLINICAL EFFECTS
    A) HALLUCINATIONS
    1) WITH POISONING/EXPOSURE
    a) Hallucinations and mental confusion were reported following exposures to Viscum and Phoradendron species (Osol & Farrar, 1955) (Moore, 1965).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures were reported in humans (Osal & Farrar, 1955).
    b) In a retrospective study of 92 patients with mistletoe ingestion, one case of seizures was reported in an infant after an unwitnessed exposure. A sprig of Phoradendron with both leaves and berries intact was found in the crib (Spiller et al, 1996).
    C) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of 92 patients with mistletoe ingestion, ataxia was reported in a 21-month-old child (number of berries ingested was not stated) (Spiller et al, 1996).
    D) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Spiller et al (1996) reported one case of mild drowsiness in 92 exposures. The amount ingested was not stated (Spiller et al, 1996)
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IN-VITRO STUDIES
    a) Viscotoxin produced depolarization of skeletal muscle fibers (Samulsson & Ekblad, 1967). Alcoholic or aqueous extracts produce a direct stimulatory action on smooth muscle, arteries, intestines, bladder and uterus. These actions are similar to pressor amines (Hanzlik & French, 1924).

Gastrointestinal

    3.8.1) SUMMARY
    A) Gastroenteritis was reported in both humans and animals. In one human case, vomiting, diarrhea, and abdominal cramps persisted 8 to 12 hours after ingestion of a mistletoe-containing tea.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Mild gastroenteritis can develop following the ingestion of several berries from the Phoradendrom serotinum (mistletoe) plant (Courtemanche & Peterson, 2006).
    b) Vomiting, diarrhea, and abdominal cramps persisted for 8 to 12 hours after ingestion of a mistletoe-containing tea (Moore, 1963). The patient became ill 1 to 2 hours after ingestion, and died within 12 hours. The genus (Viscum or Phoradendron) was not identified.
    c) In a case review of 92 cases of ingestion, six patients developed gastrointestinal irritation (Spiller et al, 1996).
    d) Nausea and diarrhea were reported after the administration of Viscum extract (Quercus Frischsaft). Nine healthy and 32 HIV-positive patients were given escalating doses from 0.01 to 10 mg over 2 to 17 weeks. The extract was standardized for lectin and viscotoxin concentrations and given subcutaneously. The rate of adverse effects was higher in HIV-positive patients than in healthy patients (Gorter et al, 1999).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GASTROENTERITIS
    a) Animals poisoned with viscumin developed ascites, gastroenteritis, edematous intestines, and pancreatic hemorrhages (Stirpe et al, 1980).

Hepatic

    3.9.1) SUMMARY
    A) Although hepatitis has been reported after the ingestion of a mistletoe- containing tea, its relationship to mistletoe, other herbs in the product, or possible contaminants is unclear.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hepatitis was reported in one case of chronic herbal tea ingestion. The product was a combination of various herbs, and mistletoe itself was never tested alone (Harvey & Colin-Jones, 1981). Hepatitis has been seen in test animals.
    B) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) HERBAL EXTRACTS: A 55-year-old healthy man was admitted to a hospital with a 10 day history of fever and dark urine and complaining of epigastric and right upper quadrant pain. He reported taking mistletoe extract for 1 month and kudzu root extract for 10 days to promote general wellness. He was not taking any routine medications. Initial laboratory studies resulted in significantly elevated liver enzymes (aspartate aminotransferase (AST) 958 International Units/L and alanine aminotransferase (ALT) 1000 International Units/L). A serologic viral hepatitis study was negative. The Roussel Ulcaf Causality Assessment Method (RU-CAM) yielded a score of 9 which was consistent with a diagnosis of drug-induced liver injury with acute hepatitis and the probable causative agent was the herbal extracts. Liver enzymes gradually improved following discontinuation of the extracts. By day 8, he was discharged to home and one week later his liver function was normal (Kim et al, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD UREA ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Transient increases in blood urea nitrogen and creatinine were reported after the use of Viscum extract (Quercus Frischsaft). Nine healthy and 32 HIV-positive patients were given escalating doses from 0.01 to 10 mg over 2 to 17 weeks. The extract was standardized for lectin and viscotoxin concentrations and given subcutaneously. The rate of adverse effects was higher in the HIV-positive patients than in the healthy patients (Gorter et al, 1999).

Hematologic

    3.13.1) SUMMARY
    A) Transient eosinophilia occurred following administration of Viscum extract and Viscumin was shown to hemoagglutinate all groups of human erythrocytes.
    3.13.2) CLINICAL EFFECTS
    A) EOSINOPHIL COUNT RAISED
    1) Transient eosinophilia was reported after the administration of Viscum extract (Quercus Frischsaft). Nine healthy and 32 HIV-positive patients were given escalating doses from 0.01 to 10 mg over 2 to 17 weeks. The extract was standardized for lectin and viscotoxin concentrations and given subcutaneously. The rate of adverse effects was higher in the HIV-positive patients than in the healthy patients (Gorter et al, 1999).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) COAGULATION TIME DECREASED
    a) Viscumin (isolated from Viscum species) has been shown to hemagglutinate all groups of human erythrocytes in vitro.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Dermatitis from handling a plant was observed, but is not common (O'Farrel, 1943).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) WITH THERAPEUTIC USE
    a) Cytotoxic and immunomodulatory effects of Viscum album preparations have been reported (Gorter et al, 1999; Kovacs et al, 1991; Hajto, 1986; Khwaja et al, 1986; Franz, 1986) (Riberean-Gayon et al, 1986).
    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IMMUNE SYSTEM DISORDER
    a) A Viscum album preparation (Isorel(R)) enhanced skin graft rejection of mice when administered 2 to 5 days after foreign skin graft, and increased the immunoreactivity of mice which had tumors (Jurin et al, 1993). Tumor necrosis factor expression has been induced in human peripheral monocytes and murine macrophages in vitro by a Viscum album lectin (Mannel et al, 1991).

Reproductive

    3.20.1) SUMMARY
    A) Phoradendron species have been shown to produce increased tonus of dog and cat uteri.
    3.20.3) EFFECTS IN PREGNANCY
    A) ABORTION
    1) DOG/CAT - Phoradendron species have been shown to produce increased tonus of dog and cat uteri (Hanzlik & French, 1924).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Viscumin is a cytotoxic compound. Actual cancer cases were not found.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) ANTINEOPLASTIC ACTIVITY - Viscumin a cytotoxic compound, has been tested with other toxalbumins for its antineoplastic activity. Results of anti-tumor testing has shown limited promise (Salzer, 1986; Anon, 1982).
    2) IN VITRO STUDY - Aqueous Viscum album extracts and purified mistletoe lectins caused a dose-dependent inhibition in the growth of cultured human and murine tumor cell lines (Janssen et al, 1993). Tumor cell growth inhibition was considered to be due to apoptosis.
    3) Iscador(R), a Viscum album preparation, has shown considerable cytotoxic and immunomodulatory effects in recent European studies (Kovacs et al, 1991; Hajto, 1986; Khwaja et al, 1986; Franz, 1986) Riberean-Gayon et al, 1986).
    4) IN VITRO/ANIMAL STUDY - A Viscum album extract (Isorel(R)) enhanced the immune reactivity of tumor-bearing mice, was cytotoxic to cultured tumor cells, but increased the growth of normal hamster cells in vitro. Isorel alone was not therapeutically effective in tumor-bearing mice, but Isorel prior to and after local irradiation resulted in a cure rate (120 day survival) of >65% (Jurin et al, 1993).
    5) The utility of Viscum album preparations for the treatment of cancer remains controversial (Gabius et al, 1994). The results of many clinical studies have been questioned (Hauser, 1991) and not all studies have been positive. Kjaer (1989) tested Iscador(R) on 14 patients with verified renal adenocarcinoma stage IV with lung metastases. All patients died with no clinical response demonstrated by the Iscador.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor liver enzymes and electrolytes in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor liver enzymes after significant ingestion of Viscum species.
    2) Monitor serum electrolytes and assess hydration if vomiting and diarrhea have been extensive.

Methods

    A) CHROMATOGRAPHY
    1) The lectin content of mistletoe (Viscum species) and drug preparations like Iscador(R) can be determined by single radial immunodiffusion using high performance liquid chromatography (HPLC) (Wagner et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.2) HOME CRITERIA/ORAL
    A) Based on data from a retrospective study of mistletoe ingestion, it is suggested that no treatment is necessary and observation alone is appropriate in cases of accidental Phoradendron flavescens (American Mistletoe) ingestion of 5 berries or less or 3 leaves or less (Spiller et al, 1996). Patients should be observed for 4 to 6 hours at home, with telephone support, for the development of CNS symptoms. Patients with larger ingestions should be referred to a healthcare facility.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Based on data from a retrospective study of mistletoe ingestion, it is suggested that no treatment is necessary and observation alone is appropriate in cases of accidental Phoradendron flavescens (American Mistletoe) ingestion of 5 berries or less or 3 leaves or less (Spiller et al, 1996).

Monitoring

    A) Monitor liver enzymes and electrolytes in symptomatic patients.

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) SUMMARY
    1) Most patients do not require gastrointestinal decontamination. Activated charcoal should be considered after an ingestion equal to or greater than 6 berries or 4 leaves.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Gastroenteritis may be especially prominent. Inflammatory changes may be produced in the intestinal wall. Monitor fluid and electrolytes. Consider appropriate fluid replacement based on electrolyte results.
    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).
    C) MONITORING OF PATIENT
    1) Hepatitis has been reported in one human case of questionable etiology and in animals. Monitor for elevated liver enzymes.
    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, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    F) MALIGNANT HYPERTENSION
    1) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    2) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    3) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    4) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    5) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    G) EXPERIMENTAL THERAPY
    1) IN VITRO, increased calcium extracellularly has reversed or prevented the effects of viscotoxin. This has not been tried clinically in human poisonings (Andersson & Johannsson, 1973).
    H) PATIENT CURRENTLY PREGNANT
    1) Phoradendron species are known to increase uterine muscle tonus in animals. Pregnant patients may need to be monitored carefully.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) Although dermatitis has been reported by handling this plant, this is an unusual response. Washing the exposed area with soap and water may be indicated as a preventive measure.

Range Of Toxicity

Summary

    A) TOXICITY: Toxic doses have not been established for human exposures, but the ingestion of 3 berries or 2 leaves or less are NOT thought to produce significant clinical effects. Ingestion of American mistletoe (Phoradendron) is unlikely to cause significant toxicity.

Maximum Tolerated Exposure

    A) SUMMARY
    1) Literature review would indicate that 1 to 3 berries does not represent a significant hazard, but no detailed human studies substantiate this. Current recommendations of emesis with 3 or more berries may be over aggressive but until more data are available this extra caution may be required.
    2) Toxic doses have not been determined for human oral exposures. Hall et al (1986) concluded that ingestion of 1 to 3 berries or 1 or 2 leaves is unlikely to produce serious toxicity (Hall et al, 1986).
    3) Clinical factors useful in evaluating reports on mistletoe toxicity include:
    1) Species involved
    2) Host tree
    3) Onset of action
    4) Combination with other herbal preparations
    B) CASE REPORTS
    1) CASE SERIES: A retrospective study of American mistletoe exposures reported to the American Association of Poison Control Centers (AAPCC) were examined during the period of 1985 to 1992. Of the 1754 American mistletoe (Phoradendron leucarpum) exposures, no fatalities were reported and 90.3% of those exposed remained asymptomatic. Children accounted for 92.1% of the cases (accidental exposures); 4.1% of all cases were intentional (Krenzelok et al, 1997).
    a) Gastrointestinal decontamination did not influence patient outcome in this study (96.2% who were decontaminated remained asymptomatic vs. 96.3% who received no therapy). One limitation of the data was the inability to determine the morphologic part of the plant involved nor the quantity ingested. The authors, however, concluded that American mistletoe unlike European mistletoe (Viscum album (with known reports of fatalities)) was not associated with significant toxicity (Krenzelok et al, 1997).
    2) CASE SERIES: Evaluation of 92 pediatric cases ranging from ingestion of 5 to 20 berries and 1 to 5 leaves did not result in life-threatening toxicity. Severity of illness did not correlate well with the history of amount ingested (Spiller et al, 1996).
    3) BEE POLLEN: A case involving persistent diplopia, dizziness, and weakness was seen in a 23-year-old who ingested approximately a quarter pound of bee pollen consisting of 83% pollen from Phoradendron (Rhoads et al, 1986).
    4) HERBAL EXTRACTS: A 55-year-old healthy man was admitted to a hospital with a 10 day history of fever and dark urine and complaining of epigastric and right upper quadrant pain. He reported taking mistletoe extract for 1 month and kudzu root extract for 10 days to promote general wellness. He was not taking any routine medications. Initial laboratory studies resulted in significantly elevated liver enzymes (aspartate aminotransferase (AST) 958 International Units/L and alanine aminotransferase (ALT) 1000 International Units/L). A serologic viral hepatitis study was negative. The Roussel Ulcaf Causality Assessment Method (RU-CAM) yielded a score of 9 which was consistent with a diagnosis of drug-induced liver injury with acute hepatitis and the probable causative agent was the herbal extracts. Liver enzymes gradually improved following discontinuation of the extracts. By day 8, he was discharged to home and one week later his liver function was normal (Kim et al, 2015).
    C) ANIMAL DATA
    1) PARENTERAL DOSING: The information below is based on toxicity seen in experiments done on animals given doses parenterally. It SHOULD NOT BE USED FOR ORAL DOSING.
    a) VISCUMIN: The amount obtained from Viscum leaves ranges from 7 to 40 mg/100 g (Stirpe, 1983). In a study by Olsnes et al (1982), 1,300 mg of protein toxin was derived from 115 g of Viscum album. After further filtration, 65% to 70% of the cytotoxic and hemoagglutinating activity of the lectins remained, approximating a 0.8% yield of toxic lectins (Olsnes et al, 1982).
    b) VISCOTOXINS: In an effort to differentiate the toxicity of viscumin from viscotoxins, mice were treated with mistletoe extracts that had been treated with antiviscumin. These animals died rapidly of cardiovascular collapse. Mice treated with an extract containing excess antiviscumin either died in the first hour (from the viscotoxins) or did not die at all. It is assumed that the viscumin was no longer present to cause delayed toxicity. When untreated extract was used, it took nearly 30 times the dose to kill mice immediately then would have been necessary if the animals had been allowed to absorb the viscumin and died days later (Olsnes et al, 1982).
    D) CONCENTRATION LEVEL
    1) PHORATOXINS: Approximately, 217 mg of phoratoxin resulted from extracting 2,000 g of leaves and stems. The yield was approximately 0.01% to 0.03% depending on the purity (Samuelsson & Ekblad, 1967). The amino acid sequence of Phoratoxin was determined to have 46 amino acids (Mellstrand & Samuelsson, 1974).
    2) ALKALOIDS: Khwaja et al (1980) isolated several toxic alkaloids of viscumin in Viscumin album coloratum, and found these highly cytotoxic substances to be effective anti-tumor agents in mice. The alkaloid yield was 0.38% (Khwaja et al, 1980).
    3) VARIATIONS DUE TO THE HOST TREE: The toxicity of various species may be related to the type of tree on which it is parasitic. Those grown on a poplar are said to be more toxic than those grown on apple or pear (Crawford, 1911). Mistletoe may incorporate toxic compounds from the tree on which it is a parasite. Identification of the host tree may be important (Tyler et al, 1981), although this has not been documented clinically.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) VISCUMIN
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 2.7-80 mcg/kg (Stirpe, 1983)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 10 mcg/100 g body weight -- died 3-4D later
    b) 100 mcg/100 g body weight -- died in 22-24H (Stirpe et al, 1980)

Pharmacology Toxicology

Toxicologic Mechanism

    A) LECTINS -
    1) Viscum species contain a number of bioactive components (polysaccharides, alkaloids, and lectins (viscotoxins)). The most potent of these, in cytogenicity and immunomodulatory action are the lectins (Park et al, 1999). These actions are used as justification for its herbal uses for cancer, ataralgesia, lumbago, and hypertension.
    2) VISCUM LECTINS - Are cytotoxic by inhibiting protein synthesis on the ribosomal level. Both the A & B chains, as well as the lectin itself, activates macrophages and releases lymphokines from lymphocytes. They also inhibit allergen-induced histamine release from leukocytes and collagen-induced serotonin from platelets (Franz, 1986).
    3) VISCUMIN (LECTIN I) -
    a) This substance is a protein of approximately 110,000 molecular weight. It is related to toxalbumins like ricin and abrin and will hemagglutinate all human red cells in vitro. Unlike abrin and ricin, there is no differentiation between toxins and hemagglutinins (Franz et al, 1981).
    b) Viscum also inhibits protein synthesis in a cell free system (Olsnes et al, 1982), and reacts with immunoglobins (Franz et al, 1981). The effects of viscumin are often delayed.
    c) Viscumin is a dual chain molecule. Chain A performs the toxic action which is to catalytically activate the 60 S ribosomal subunit. One A-chain molecule is estimated to inactivate 50 ribosomal sub-units within 10 minutes (Olsnes et al, 1982).
    B) PHORATOXIN AND VISCOTOXIN -
    1) EFFECTS - The effects of these two compounds are similar, with viscotoxin being approximately 10 times as potent a cardiac toxin and 5 times as potent a vasoconstrictor. Both produced reflex bradycardia, negative inotropic effects, and, in high doses, vasoconstriction of skin and skeletal muscle vessels (Rosell & Samuelsson, 1966).
    2) VISCOTOXIN -
    a) Viscotoxin is a 46 amino acid peptide derived from Viscum species.
    b) Several types of viscotoxins have been derived. The main ones being A2, A3, and B (Andersson & Johannsson, 1973).
    c) A possible mechanism of action for viscotoxin is that they bind to cell membranes and displace bound calcium from the membrane site causing muscle depolarization.
    3) PHORATOXIN -
    a) Phoratoxin is a polypeptide (about twice the weight of viscotoxin) derived from Phoradendron (Samuelsson & Ekblad, 1967; Andersson & Johannsson, 1973).
    b) Initial studies would indicate that phoratoxin comprises approximately 0.01% to 0.23% of Phoradendron leaves and stems.
    c) PHORATOXIN B - which was isolated from Phoradendron tomentosum macrophyllum, has properties similar to the cardiotoxins or membrane toxins from elapid snakes (Thunberg, 1983) and has been shown to depolarize the membrane in frog heart and skeletal muscles (Pater et al, 1984) rat papillary heart muscle (Sauviat et al, 1985) and frog skeletal muscles (Sauviat, 1990).
    C) POLYSACCHARIDES/VISCUM SPECIES - Various polysaccharides are thought to be involved in pharmacological effects of Viscum album when used in cancer therapy. The green parts contain primarily highly esterified galacturonian, the berries primarily arabinogalactan (Jordan & Wagner, 1986).

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