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ECHINACEA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Echinacea angustifolia and related species (E. purpurea and E. pallida) are native American plants that have been used in traditional herbal medicine for more than a century.

Specific Substances

    A) COMMON NAMES -
    1) Echinacea
    2) American coneflower
    3) purple coneflower
    4) snakeroot
    5) Kansas snakeroot
    6) black sampson
    7) narrow-leaved purple coneflower
    8) survy root
    9) Indian head
    10) comb flower
    11) black susans
    12) hedgehog
    PRODUCTS -
    1) Echinacea Capsules (Irwin Naturals)
    2) EchniaCare Liquid (Phyto Pharmica)
    Echinacea may be combined with other drugs in many proprietary
    1) preparations (Weiss, 1988).

Available Forms Sources

    A) FORMS
    1) Echinacea products can be produced in many different forms from crude plant products (ground or powdered), freeze-dried, alcohol-based tincture (hydroalcohol), or liquid extracts (Murray, 1995), and are also available alone or in combination in capsule form. Different products use different parts of the plant (mostly roots); therefore, products can vary widely (Ernst, 2002).
    2) Despite a lack of consensus, many experts consider the fresh-pressed juice of E. purpurea the best preparation because it provides the greatest range of active compounds and shows clinical efficacy (Murray, 1995).
    3) Parenteral preparations are available in Germany; injectable preparations are not obtainable in the United States (Tyler, 1993).
    4) Hydroalcoholic extract is the most readily available form in the United States (Tyler, 1993).
    5) Based on several clinical trials, there is currently insufficient evidence to recommend a specific Echinacea product (Ernst, 2002).
    B) USES
    1) SUMMARY - Echinacea has no direct bactericidal or bacteriostatic properties, rather its benefits are brought about by its ability to act as an immunostimulant (Tyler, 1994). Its use as an immunostimulant in the treatment of viral upper respiratory infections is common in the United States and Europe (Pepping, 1999). To date, it appears that the best researched indications of Echinacea are for the treatment and prevention of upper respiratory tract infections (Ernst, 2002).
    a) Echinacea and its plant extract have been used topically for wound-healing, eczema, psoriasis and herpes simplex. It is also ingested to stimulate the immune system and often used to treat the common cold, influenza, snakebites, and arthritis. Echinacea is stated to have antiseptic, antiviral, and peripheral vasodilator properties (Tyler, 1993; Murray, 1995; pp 134-135). Echinacea has also been used as an adjunct to conventional microbial treatment and more severe infections (Pepping, 1999).
    b) Echinacea may have anticancer activity by its immuno-enhancing effects (Murray, 1995).
    c) At the time of this review, the role of Echinacea in the treatment of AIDS and other conditions including yeast infections, side effects of radiation therapy, rheumatoid arthritis, and cancer remains unproven (Tyler, 1994).

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: Echinacea and its plant extract have been used topically for wound-healing, eczema, psoriasis and herpes simplex. It is also ingested to stimulate the immune system and often used to treat the common cold, influenza, snakebites, and arthritis. Echinacea is stated to have antiseptic, antiviral, and peripheral vasodilator properties.
    B) PHARMACOLOGY: Echinacea has been shown to have immune stimulating properties as well as anti-inflammatory effects. It has been shown to stimulate phagocytosis, macrophages, T-lymphocytes, natural killer cells, and increases circulating fibroblasts. Echinacea also stimulates the production of interferon which includes Tumor Necrosis Factor (important to the body's response against cancerous cells). High concentrations of Echinacea can also inhibit the action of hyaluronidase, an enzyme secreted by bacteria.
    C) EPIDEMIOLOGY: Echinacea is widely available over-the-counter. Use is common, but severe toxicity with Echinacea ingestion is unlikely.
    D) WITH THERAPEUTIC USE
    1) Adverse effects are usually mild; serious adverse events are not usually associated with Echinacea. Adverse effects include: hypotension, dizziness, dyspnea, fever, nausea, and dermatologic effects. Most effects are reported infrequently and appear related to an allergic or hypersensitivity response.
    2) RARE: Hepatitis is rarely reported.
    E) WITH POISONING/EXPOSURE
    1) Overdose is rare. One patient ingested approximately twice the recommended dose of an Echinacea extract (5 mL of a 40% alcohol solution) and experienced immediate oral and pharyngeal irritation, followed by a hypersensitivity reaction (chest tightness, urticaria, diarrhea) approximately 15 minutes later. She had also been taking multiple vitamin and herbal dietary supplements. In general, overdose events are anticipated to be similar to adverse events reported with Echinacea therapy.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported following Echinacea use.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) No carcinogenic or mutagenic effects have been reported with Echinacea use (Pepping, 1999).

Laboratory Monitoring

    A) Monitor vital signs in symptomatic patients.
    B) Routine laboratory studies are not necessary unless otherwise clinically indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after overdose.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is generally not necessary; consider activated charcoal after large or symptomatic ingestion or in those with significant co-ingestants.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Enhanced elimination, including hemodialysis, is not anticipated to be necessary.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult or child with an inadvertent minor exposure (eg, a single tablet ingested by a young child) may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored for symptoms. Patients may be discharged to home if no symptoms develop.
    3) ADMISSION CRITERIA: Patients with persistent symptoms should be admitted for further treatment.
    4) CONSULT CRITERIA: Contact a medical toxicologist or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    H) PITFALLS
    1) When managing a suspected Echinacea overdose, the possibility of multidrug involvement should be considered. Lack of adequate history to determine other co-ingestants.

Range Of Toxicity

    A) TOXICITY: Minimum toxic dose has not been established. Anaphylaxis was reported in an adult following ingestion of 5 mL of a 40% alcohol in water solution of Echinacea.
    B) THERAPEUTIC DOSE: Echinacea in the form of an extract (1:1 in 45% alcohol) 0.25 to 1 mL 3 times/day; or given by the dropperful (approximately 10 to 25 drops) taken at the first signs of a cold and can be repeated up to 2 or 3 times daily.

Clinical Effects

Summary Of Exposure

    A) USES: Echinacea and its plant extract have been used topically for wound-healing, eczema, psoriasis and herpes simplex. It is also ingested to stimulate the immune system and often used to treat the common cold, influenza, snakebites, and arthritis. Echinacea is stated to have antiseptic, antiviral, and peripheral vasodilator properties.
    B) PHARMACOLOGY: Echinacea has been shown to have immune stimulating properties as well as anti-inflammatory effects. It has been shown to stimulate phagocytosis, macrophages, T-lymphocytes, natural killer cells, and increases circulating fibroblasts. Echinacea also stimulates the production of interferon which includes Tumor Necrosis Factor (important to the body's response against cancerous cells). High concentrations of Echinacea can also inhibit the action of hyaluronidase, an enzyme secreted by bacteria.
    C) EPIDEMIOLOGY: Echinacea is widely available over-the-counter. Use is common, but severe toxicity with Echinacea ingestion is unlikely.
    D) WITH THERAPEUTIC USE
    1) Adverse effects are usually mild; serious adverse events are not usually associated with Echinacea. Adverse effects include: hypotension, dizziness, dyspnea, fever, nausea, and dermatologic effects. Most effects are reported infrequently and appear related to an allergic or hypersensitivity response.
    2) RARE: Hepatitis is rarely reported.
    E) WITH POISONING/EXPOSURE
    1) Overdose is rare. One patient ingested approximately twice the recommended dose of an Echinacea extract (5 mL of a 40% alcohol solution) and experienced immediate oral and pharyngeal irritation, followed by a hypersensitivity reaction (chest tightness, urticaria, diarrhea) approximately 15 minutes later. She had also been taking multiple vitamin and herbal dietary supplements. In general, overdose events are anticipated to be similar to adverse events reported with Echinacea therapy.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported following Echinacea use.
    3.3.3) TEMPERATURE
    A) Fever has been reported following Echinacea use (Murray, 1995). The fresh-pressed juice of E. purpurea has resulted in temperature elevations of 1 degree or less and presumably caused by a secretion of interferon and interleukin 1 by activated macrophages.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Infrequent reports of hypotension have been observed following preparations of E. purpurea which were presumed to be related to a hypersensitivity reaction (Fachinformation, 1996).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported infrequently following E. purpurea preparations and appears related to a hypersensitivity reaction (Fachinformation, 1996).
    B) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Asthma has been reported in 3 cases of Echinacea use. Symptoms appear related to a hypersensitivity response (Ernst, 2002).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has occurred in some individuals following E. purpurea preparations and appears to be a hypersensitivity response (Fachinformation, 1996; Giles et al, 2000; Ernst, 2002).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) In a randomized controlled trial to determine the efficacy of Echinacea purpurea on cold symptoms, 7% of patients (n=54) reported tiredness, somnolence, dizziness, headache, and a tendency to aggressiveness with treatment; these effects were not reported in the control group (Grimm & Muller, 1999; Giles et al, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Nausea, mild epigastric pain and constipation have been reported during therapeutic use of Echinacea (Giles et al, 2000).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) There have been three reports of hepatitis with Echinacea therapy (Ernst, 2002).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 60-year-old healthy woman was undergoing a lumpectomy under general anesthesia, and unusual bleeding was reported. Coagulation studies were normal except for a slightly elevated thrombin time. The authors suspected that the excessive bleeding was due to chronic Echinacea (3 weeks of daily intake) use (Ananthanarayan & Urbach, 2000).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Exanthema and erythema have been reported with oral and topical preparations of Echinacea and associated with a hypersensitivity reaction (Fachinformation, 1996; Ernst, 2002).
    b) CASE REPORTS
    1) Recurrent erythema nodosum occurred in a 41-year-old man after taking Echinacea routinely for intermittent episodes (4 occurrences in 18 months) of influenza-like symptoms. Episodes were successfully treated with prednisone (Soon & Crawford, 2001).
    B) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions have resulted in pruritus after oral and topical exposure to Echinacea (Fachinformation, 1996).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Severe allergic reactions following the use of Echinacea appear rare. Patients with a history of hypersensitivity to the daisy family (e.g., sunflower seeds, ragweed) are advised to use caution when taking Echinacea (Giles et al, 2000).
    B) CELLULAR IMMUNE DEFECT
    1) WITH THERAPEUTIC USE
    a) It has been suggested that Echinacea is contraindicated in individuals with autoimmune illness, and other progressive systemic diseases (e.g., tuberculosis, multiple sclerosis, and HIV-infection) due to Echinacea's tendency to raise tumor necrosis factor levels in the body which could have a negative impact in this population (Tyler, 1994; pp 134-135).
    C) CASE REPORT
    1) WITH THERAPEUTIC USE
    a) ORAL EXPOSURE: A 37-year-old woman who took dietary supplements prophylactically ingested multiple herbal and vitamin preparations (vitamins B12 and E, an herbal iron preparation, folate, vitamin B complex, a multivitamin, zinc, antioxidants, and evening primrose oil) and approximately 15 minutes later ingested nearly double the manufacturer's recommended amount (5 mL or equivalent to 3825 mg whole plant extract of E. angustifolia and 150 mg dry root of E. purpurea) of a commercially prepared 40% alcohol solution of Echinacea (Mullins, 1998). Immediately after ingesting the Echinacea the patient developed burning of the mouth and throat and within 15 minutes had developed tightness in the chest, generalized urticaria, and diarrhea.
    1) The patient had self administered promethazine 75 mg orally prior to hospital admission and required no further treatment. The author concluded that although other dietary supplements could not be totally excluded as the source, the symptoms were probably Echinacea-induced based on a positive skin test and radioallergosorbent (RAST) testing which confirmed Echinacea-binding IgE in the serum (Mullins, 1998).
    b) Myers & Wohlmuth (1998) have suggested that the immediate pharyngeal irritation that was reported with Echinacea was likely due to isobutyl amide constituent, echinacein, which can cause notable pharyngeal tingling and increased salivation. In addition, the authors raise the concern of a food item or one of the many dietary supplements as a factor in the anaphylactoid symptoms reported (Myers & Wohlmuth, 1998).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF EFFECT
    1) In a comparative study, 206 pregnant women were prospectively followed for pregnancy outcome after the gestational use of Echinacea (54% had used Echinacea in the first trimester, 8% were exposed in all three trimesters), and were compared with a matched control group. Rates of malformations or alterations in pregnancy outcome (i.e., delivery methods, birth weight, fetal distress, maternal weight gain) were not statistically significant between the two groups (Gallo et al, 2000).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF EFFECT
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) No carcinogenic or mutagenic effects have been reported with Echinacea use (Pepping, 1999).

Genotoxicity

    A) No mutagenic activity was noted in tests with fresh-pressed juice of E. purpurea (Murray, 1995).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs in symptomatic patients.
    B) Routine laboratory studies are not necessary unless otherwise clinically indicated.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent symptoms should be admitted for further treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic adult or child with an inadvertent minor exposure (eg, a single tablet ingested by a young child) may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored for symptoms. Patients may be discharged to home if no symptoms develop.

Monitoring

    A) Monitor vital signs in symptomatic patients.
    B) Routine laboratory studies are not necessary unless otherwise clinically indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) It is not known whether activated charcoal is useful in treating Echinacea ingestions. Most cases will probably not require gastric decontamination.
    2) 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).
    3) 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) Gastrointestinal decontamination is generally NOT necessary. Consider activated charcoal after a large or symptomatic ingestion or in those with significant co-ingestants.
    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) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Significant toxicity is not expected after overdose.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) Monitor vital signs in symptomatic patients.
    2) Routine laboratory studies are not necessary unless otherwise clinically indicated.
    C) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Enhanced elimination, including hemodialysis, is not anticipated to be necessary.

Range Of Toxicity

Summary

    A) TOXICITY: Minimum toxic dose has not been established. Anaphylaxis was reported in an adult following ingestion of 5 mL of a 40% alcohol in water solution of Echinacea.
    B) THERAPEUTIC DOSE: Echinacea in the form of an extract (1:1 in 45% alcohol) 0.25 to 1 mL 3 times/day; or given by the dropperful (approximately 10 to 25 drops) taken at the first signs of a cold and can be repeated up to 2 or 3 times daily.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) ONGOING THERAPY - Some data suggests that continuous dosing is NOT beneficial and recommend an alternating schedule of three days on and three days off. This dosing regimen allegedly allows the individual's immune response to return to a normal state before further immunostimulation (Murray, 1995).
    B) ROUTE OF ADMINISTRATION
    1) ORAL -
    a) SUMMARY - The usual recommended dose is between 900 to 1000 milligrams three times daily, equivalent to 6 to 9 milliliters of pressed juice or 0.75 to 1.5 milliliters of tincture daily (Ernst, 2002).
    b) INITIAL DOSE - Echinacea in the form of an extract (1:1 in 45% alcohol) 0.25 to 1.0 milliliter 3 times/day; or given by the dropperful (approximately 10-25 drops) taken at the first signs of a cold and can be repeated up to 2 or 3 times daily (Grimm & Muller, 1999). Echinacea can also come in the form of capsules or tablets with 1-2 taken per day.
    c) ACUTE INFECTIONS - Doses of up to 40-60 drops every 2 hours, for up to 10 days have been recommended with a 2 to 3 day rest period, followed by another 10-day course. Dosing is repeated depending on symptoms present (Grimm & Muller, 1999). The immuno-stimulating effects may diminish with prolonged use (Pepping, 1999).
    d) IMMUNE FUNCTION - Echinacea's immunostimulating properties may decline following extended periods of use, and preparations are generally not recommended for longer than 8 consecutive weeks (Giles et al, 2000).
    e) The following are suggested doses for various forms of Echinacea (E. purpurea) with scheduled dosing three times daily:
    1) DRIED ROOT (or as a tea) - 1 to 2 grams NOTE: The active components cannot be standardized in teas (Pepping, 1999).
    2) FREEZE DRIED PLANT - 325 to 650 milligrams
    3) JUICE OR AERIAL PORTION - of E. purpurea in 22% ethanol - 2 to 3 milliliters
    4) TINCTURE - (1:5 ratio; 45% ethanol) - 1 to 5 milliliters - 3 times per day is recommended by the British Herbal Pharmacopoeia
    5) FLUID EXTRACT - (1:1 ratio) - 1 to 2 milliliters taken 3 to 4 times per day in juice or water or sublingually
    6) SOLID (dry powdered) extract (6.5:1 or 3.5% echinacoside) - 150 to 300 milligrams of a dry powdered can be taken in a solid oral dosage form 3 times per day if the juice or fluid extract cannot be tolerated
    7) (REFERENCES - Murray, 1995; (Pepping, 1999; Giles et al, 2000)
    2) TOPICAL -
    a) EXTERNAL APPLICATION - Apply liquid extract to a cotton pad and fix in place, or make a tea of the root or leaves and apply. If area is infected, change dressing frequently and apply more Echinacea (Grimm & Muller, 1999).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) At the time of this review, Echinacea preparations have NOT been evaluated in children or infants, and are not recommended (Giles et al, 2000).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Numerous studies have indicated no acute or chronic toxicity with Echinacea when used at suggested therapeutic levels (Murray, 1995). Extracts and components of Echinacea have been injected at high doses without toxic effects (Anon, 1996).
    B) CASE REPORTS
    1) Anaphylaxis was reported in one patient following oral administration of 5 mL (3825 mg whole plant extract of E. angustifolia and 150 mg dry root of E. purpurea) of a 40% alcohol in water solution of Echinacea along with numerous other dietary supplements that were taken 15 minutes prior to onset; recovery was uneventful (Mullins, 1998).
    C) ANIMAL DATA
    1) ACUTE
    a) LACK OF EFFECT: In studies with mice and rats NO abnormalities were reported following oral or parenteral administration (Mengs et al, 1991).
    2) CHRONIC
    a) Male and female rats given oral doses via a gastric tube in doses of 0, 800, 2400 or 8000 mg/kg/day (the highest dose given was estimated to be 60 times the daily dose in humans) for 4 weeks showed NO toxicity (Mengs et al, 1991).
    1) Male rats experienced a decrease in plasma alkaline phosphatase at the two highest doses (2400 and 8000 mg/kg/day) and females showed a rise in prothrombin time. Despite these laboratory changes they remained within the normal physiological range and NO other necropsy findings of toxicity were observed (Mengs et al, 1991).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 1,000 to 2,500 mg/kg (aerial portion polysaccharides of E. purpurea)(Murray, 1995)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Echinacea has been shown to have immune stimulating properties as well as anti-inflammatory effects. It has been shown to stimulate phagocytosis, macrophages, T-lymphocytes, natural killer cells, and increases circulating fibroblasts. Echinacea also stimulates the production of interferon which includes Tumor Necrosis Factor (important to the body's response against cancerous cells). High concentrations of Echinacea can also inhibit the action of hyaluronidase, an enzyme secreted by bacteria (Murray, 1995; Anon, 1996; Peng, 1997; Pepping, 1999).
    B) As an external agent, Echinacea has fungicidal, and bacteriostatic properties and an anti-inflammatory effect that has an ongoing role in wound treatment (Murray, 1995; Anon, 1996; Peng, 1997).

Toxicologic Mechanism

    A) There is minimal data regarding the toxicity of this plant. Its use has been documented in traditional American medicine for over a century with minimal acute or chronic toxicity reported (Weiss, 1988; (Anon, 1996).

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