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PLANTS-GRAYANOTOXINS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Grayanotoxins are resinoid substances (diterpenes) which occur in nectar, flowers, leaves, and stems of the plant family Ericaceae.
    B) Specific genera in which grayanotoxins are found in either native or cultivated form in the United States include Kalmia, Leucothoe, Lyonia, Pernettya, Pieris, and Rhododendron (Lampe & McCann, 1985).
    1) Many of these plants may also be found in other parts of the world, particularly Europe, Near Eastern countries, and Asia.

Specific Substances

    A) SPECIES ASSOCIATED WITH GRAYANOTOXIN POISONING
    1) Agauria spp
    2) Andromeda spp.
    3) Kalmia spp. (Mountain laurel, lambkill, calico bush)
    4) Leucothoe spp. (Dog hobble, dog laurel, fetter bush, sweet bells)
    5) Lyonia spp. (Fetter bush, male berry, stagger bush)
    6) Pernettya spp. (no trivial names in U.S.)
    7) Pieris spp (Fetterbush, lily-of-the-valley bush)
    8) Rhododendron spp. (Rhododendron, azalea, rosebay)
    9) Rhodendron flavum
    10) Rhododendron groenlandicum
    11) Rhododendron mucronulatum
    12) Rhododendron ponticum
    13) Rhododendron luteum
    TERMS RELATED TO THE RHODODENDRON SPECIES: PONTICUM AND LUTEUM
    1) Mad honey poisoning
    2) Mad honey
    RELATED COMPOUNDS-TOXINS
    1) Grayanotoxins
    2) Andromedotoxin
    3) Acetylandromedol
    4) Rhodotoxin
    5) Lyoniol A

Available Forms Sources

    A) SOURCES
    1) Grayanotoxins occur in the nectar, flowers, and leaves of certain members of the Ericaceae family of plants. Intoxication may occur from ingesting plant nectar (especially children sucking nectar from flowers), from eating plant parts, from consuming contaminated honey, or from smoking plant parts for medicinal purposes.
    2) It is important to recognize that tremendous variability exists in the Ericaceae family to produce grayanotoxins. This is most evident in the Rhododendron genus, where frequent hybridization of rhododendrons and azaleas creates an unpredictable toxic status for many plants of this group.
    3) The species that have been found to be sources of grayanotoxin and cause human toxicity in the Ericaceae family are (Gunduz et al, 2008):
    1) Agauria spp.
    2) Andromeda spp.
    3) Kalmia spp.
    4) Rhododendron flavum (Rhododendron luteum)
    5) Rhododendron ponticum
    6) Kalmia latifolia
    4) It has been suggested that grayanotoxin is heat labile and can be destroyed by commercial honey processing. However, the exact amount known to destroy the toxin is not known (Gunduz et al, 2008).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) BACKGROUND: Grayanotoxins are resinoid substances (dipertenes) which occur in nectar, flowers, leaves and stem of the plant family Ericaceae.
    B) USES: Specific genera in which grayanotoxins are found in either native or cultivated form in the USA include Kalmia, Leucothoe, Lyonia, Pernettya, Pieris and Rhododendron. These plants are used for decorative purposes in landscaping. Honey produced by the nectar of these species (primarily in Turkey) is sold as an alternative health product.
    C) TOXICOLOGY: Grayanotoxins bind to sodium channels in cell membrane and prevents inactivation of these sodium channels. Excitable nerve and muscle cells are thus maintained in a state of depolarization.
    D) EPIDEMIOLOGY: Toxicity from ingestion of plant parts containing grayanotoxins is extremely rare. Most poisonings are secondary to ingestion of honey made from nectar from these plants. In modern medical literature, the majority of mad honey poisonings are from honey produced in Turkey. However, cases of mad honey toxicity have occurred in Nepal with a similar clinical course and outcome.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting and bradycardia are common. Mouth burning, perioral numbness and tingling, diarrhea, diaphoresis, excessive salivation and paresthesias may occur.
    2) SEVERE TOXICITY: In severe cases, hypotension, bradydysrhythmias, AV conduction disturbances, complete AV block, and even asystole may develop. Altered mental status, seizures, coma, transient blindness, blurred vision, generalized muscle weakness, circumoral and extremity paresthesias, confusion, and ataxia have been reported. In most reported cases of mad honey intoxication, significant hypotension and bradycardia are present (over 90%), diaphoresis, dizziness and altered mental status occur in about 70% of patients, and syncope in 30%. Non ST-segment elevation myocardial infarction has rarely been reported after ingestion of mad honey.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Monitor blood pressure and cardiac rate/rhythm.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Transient blindness and blurred vision have been reported.

Laboratory Monitoring

    A) Monitor vital sign and mental status.
    B) Institute continuous cardiac monitoring and obtain serial ECGs in patients with bradycardia and hypotension.
    C) Other laboratory or radiologic studies may be guided by symptoms such as electrolytes for patients with paresthesias or serial troponin levels in patients with cardiovascular symptoms.
    D) No readily available testing of blood or urine exists for grayanotoxins. However, contaminated honey may possibly be submitted to health departments for analysis as chromatographic techniques do exist to determine the presence of grayanotoxins in honey.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) For mild to moderate toxicity, treatment is symptomatic and supportive care. Treat nausea and vomiting with antiemetics and treat symptomatic bradycardia with atropine.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) For patients with severe toxicity, treatment is still symptomatic and supportive care. Treat symptomatic bradycardia with atropine, a pacemaker should be used if there is no response to atropine. Hypotension not responsive to atropine and/or a pacemaker should be treated with intravenous fluids and vasopressors, if necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is rarely indicated, toxicity is very unusual after ingestion of plant parts, and patients ingesting mad honey generally present after symptoms have developed. Consider activated charcoal in the rare patient who presents shortly after a potentially toxic ingestion and is awake, alert and not vomiting. No significant toxicity would be expected from dermal or ocular exposures, but simple washing or eye irrigation would be reasonable.
    2) HOSPITAL: GI decontamination is rarely indicated, toxicity is very unusual after ingestion of plant parts and patients ingesting mad honey generally present after symptoms have developed. Consider activated charcoal in the rare patient who presents shortly after a potentially toxic ingestion and is awake, alert and not vomiting. No significant toxicity would be expected from dermal or ocular exposures, but simple washing or eye irrigation would be reasonable.
    D) ANTIDOTE
    1) There is no specific antidote for grayanotoxin poisoning.
    E) ENHANCED ELIMINATION
    1) No data exists to suggest hemodialysis, hemoperfusion, or multiple doses of activated charcoal would be helpful in grayanotoxin poisoning.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent exposures to plant parts can be managed at home. Asymptomatic adults without underlying cardiac disease can be managed at home after inadvertent exposure to mad honey. Patients with minimal symptoms that are improving or asymptomatic may potentially remain at home after exposure to grayanotoxins.
    2) OBSERVATION CRITERIA: The following patients should be referred to a healthcare facility for evaluation and treatment: Any symptomatic patient, any patient with a self harm ingestion, any child ingesting mad honey, adults with underlying cardiac disease ingesting mad honey, any patient ingesting a decoction or infusion of grayanotoxin containing plants. Patients may be sent home or cleared for psychiatric evaluation if they are clearly improving or asymptomatic for a period of observation of 4 to 6 hours.
    3) ADMISSION CRITERIA: All patients with persistent symptoms should be admitted to a monitored setting until symptoms resolve. Patients with bradycardia, AV conduction disturbances, or hypotension should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for symptomatic patients and those for whom the diagnosis is unclear. For intentional self-harm exposures, psychiatry consultation is necessary. Depending on the severity of the illness, critical care specialists might be needed
    G) PITFALLS
    1) One potential pitfall in the management of grayanotoxin poisoning includes not recognizing exposure to grayanotoxins in a symptomatic patient as it is a rare diagnosis. Exposure to plant parts rarely results in toxicity, do not over treat.
    H) TOXICOKINETICS
    1) Absorption of grayanotoxin following ingestion of contaminated honey is rapid; symptoms usually occur within 30 to 120 minutes. Duration of symptoms averages about 24 hours.
    I) PREDISPOSING CONDITIONS
    1) Patients at the extremes of age, those with underlying cardiac disease, and those taking medications that cause bradycardia or interfere with AV conduction may be more sensitive to the toxic effects of grayanotoxin.
    J) DIFFERENTIAL DIAGNOSIS
    1) Grayanotoxins poisonings may mimic other toxic exposures that can cause bradycardia and hypotension such as calcium channel blockers, beta blockers, clonidine, and cardiac glycosides.

Range Of Toxicity

    A) In historical literature, deaths have been recorded but not in modern medical literature.
    B) Approximately, 50 to 75 mL of contaminated honey (bees utilizing nectar from selected plants of the Ericaceae family) have caused toxicity.
    C) Honey poisonings occurred in 66 adults following ingestion of 5 to 30 g (mean 13.45 +/- 5.39 g) of honey, produced from nectar of the Rhododendron ponticum.
    D) Eight adults ingested 20 to 150 g of "mad honey" and became intoxicated.
    E) Ingestion of 10 azalea blossoms (Rhododendron mucronulatum) caused toxicity in a 76-year-old man.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: Grayanotoxins are resinoid substances (dipertenes) which occur in nectar, flowers, leaves and stem of the plant family Ericaceae.
    B) USES: Specific genera in which grayanotoxins are found in either native or cultivated form in the USA include Kalmia, Leucothoe, Lyonia, Pernettya, Pieris and Rhododendron. These plants are used for decorative purposes in landscaping. Honey produced by the nectar of these species (primarily in Turkey) is sold as an alternative health product.
    C) TOXICOLOGY: Grayanotoxins bind to sodium channels in cell membrane and prevents inactivation of these sodium channels. Excitable nerve and muscle cells are thus maintained in a state of depolarization.
    D) EPIDEMIOLOGY: Toxicity from ingestion of plant parts containing grayanotoxins is extremely rare. Most poisonings are secondary to ingestion of honey made from nectar from these plants. In modern medical literature, the majority of mad honey poisonings are from honey produced in Turkey. However, cases of mad honey toxicity have occurred in Nepal with a similar clinical course and outcome.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting and bradycardia are common. Mouth burning, perioral numbness and tingling, diarrhea, diaphoresis, excessive salivation and paresthesias may occur.
    2) SEVERE TOXICITY: In severe cases, hypotension, bradydysrhythmias, AV conduction disturbances, complete AV block, and even asystole may develop. Altered mental status, seizures, coma, transient blindness, blurred vision, generalized muscle weakness, circumoral and extremity paresthesias, confusion, and ataxia have been reported. In most reported cases of mad honey intoxication, significant hypotension and bradycardia are present (over 90%), diaphoresis, dizziness and altered mental status occur in about 70% of patients, and syncope in 30%. Non ST-segment elevation myocardial infarction has rarely been reported after ingestion of mad honey.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Monitor blood pressure and cardiac rate/rhythm.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression with CNS depression of a profound nature may be seen. Respiratory rate may decrease. Protect airway if seizures develop. To date, no cases requiring assisted ventilation have been recorded.
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) In significant exposures, hypotension may be expected (blood pressure 50 to 90 mmHg) (Poon et al, 2008; Lee et al, 2007; Gunduz et al, 2006; Yilmaz et al, 2006; Bruneton, 1999; Sutlupinar et al, 1993).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Bradydysrhythmias are classical for severe poisonings, but tachydysrhythmias may also be noted (Poon et al, 2008; Lee et al, 2007; Gunduz et al, 2006; Yilmaz et al, 2006; Ergun et al, 2005; Ozhan et al, 2004; Sutlupinar et al, 1993).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Transient blindness and blurred vision have been reported.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Temporary blindness and blurred vision have been reported.
    2) CLOUDY VISION was reported in 88% of patients (n=66) with honey poisonings following ingestion of honey produced from the nectar of the Rhododendron ponticum. The amount of honey ingested was estimated to be between 5 and 30 g (mean: 13.45 +/- 5.39 g) (Yilmaz et al, 2006)
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Excessive thirst may be a complaint; upon initial ingestion, a burning sensation may be noted.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) Due to sodium channel binding of grayanotoxins to myocardial tissue, sodium permeability is increased, perhaps by opening voltage dependent sodium channels (probably both fast and slow channels) in excitable membranes. A positive inotropic action is exerted (Ergun et al, 2005; Balazs, 1981; Catterall, 1980). Vagal responses may contribute to both bradycardia and hypotension.
    b) CHRONIC EXPOSURE
    1) CASE SERIES: In a prospective study of 173 patients referred for further evaluation of bradydysrhythmias and/or pacemaker insertion, 5 patients (aged between 17 to 65 years; median age: 34) were found to have ingested mad honey (noncommercial product) for 3 months or longer. All of the patients had various degrees of AV conduction abnormalities with narrow QRS complexes and had complaints of dizziness and presyncope. No patient required hospitalization. There was a rapid improvement in symptoms and ECG abnormalities following the discontinuation of the honey. Holter monitoring at 1 and 3 months was normal for each patient (Aliyev et al, 2009).
    B) MYOCARDIAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 41-year-old healthy man with no risk factors for cardiac disease, developed severe chest pain, ST-segment depression, hypotension (60/30 mm Hg), and elevated troponin 1 and creatine kinase isoenzyme MB levels (peak values 0.4 and 18.1 ng/mL) after ingesting mad honey (nectar of the Rhododendron ponticum). Following therapeutic care, angina symptoms resolved, and he had a normal ECG and blood pressure within 2 hours of admission. A coronary angiography showed normal coronary arteries. Although small vessel disease could not be ruled out, the author's concluded that the underlying mechanism was the ingestion of the honey which produced severe hypotension resulting in the non-ST segment elevation myocardial infarction (Yildirim et al, 2008). A similar case was described in a 66-year-old man who complained of chest pain and was admitted with hypotension and bradycardia. He had a 4-day history of ingesting mad honey brought from the Black Sea area. An ECG revealed sinus bradycardia and ST elevation in the inferior leads. Coronary angiography revealed normal coronary arteries and an echocardiogram demonstrated mild septal and apical hypokinesia. All signs and symptoms had resolved at follow-up one month later (Akinci et al, 2008).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Clinical reports have noted hypotension in combination with various conduction defects and bradydysrhythmias, with occasional tachydysrhythmias (Sohn et al, 2014; Oguzturk et al, 2012; Gunduz et al, 2006; Ergun et al, 2005; Biberoglu et al, 1988; Yavuz et al, 1991).
    b) In one series of cases, blood pressure was 60 to 90 mmHg diastolic (Sutlupinar et al, 1993).
    c) In another case series (n=19), hypotension (arterial systolic BP less than 90 mmHg) occurred in 15 patients several hours after ingesting about 30 to 180 grams of "mad" honey. Following supportive treatment, all patients recovered without further sequelae (Ozhan et al, 2004).
    d) CASE SERIES: In a series of honey poisonings (n=66) following ingestion of honey produced from the nectar of the Rhododendron ponticum, the mean systolic blood pressure was 70.08 +/- 14.89 (ranging from 80 to 100) mmHg. The mean diastolic blood pressure was 45.25 +/- 8.48 (ranging from 30 to 60) mmHg. With supportive care, the hypotension resolved in all patients. The amount of honey ingested was estimated to be between 5 and 30 grams (mean 13.45 +/- 5.39 grams) (Yilmaz et al, 2006).
    e) In another case series from patients in Turkey, 8 patients were treated for "mad honey" intoxication. The blood pressures ranged from systolics of 70 to 90 mmHg and diastolics in the 40 mmHg range (Gunduz et al, 2006).
    f) In a case report from Korea, a 76-year-old man presented with hypotension (70/50 mmHg) and sinus bradycardia with a pulse rate of 45 beats/minute (Lee et al, 2007).
    D) ACUTE CORONARY SYNDROME
    1) WITH THERAPEUTIC USE
    a) MIMIC ACUTE CORONARY SYNDROME: A 65-year-old man living in Turkey, with a history of diabetes mellitus and no history of heart disease, was admitted with dizziness, sweating and tickling in the throat about 3 hours after taking 60 mL of honey. Upon admission he was somnolent with bradycardia (52 beats/min), hypotension (70/40 mm Hg) and tachypnea (25 beats/min). An ECG showed biphasic T wave in inferior leads. IV fluids and atropine were started; laboratory studies and troponin l were within normal range. He gradually improved and became more alert. Coronary angiography showed normal coronary arteries. The authors suggested that mad honey may mimic acute coronary syndrome (Dur et al, 2014).
    E) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) Bradycardia and bradydysrhythmias have been seen with plant and contaminated honey ingestion (Sohn et al, 2014; Oguzturk et al, 2012; Lee et al, 2007; Gunduz et al, 2006; Ergun et al, 2005; Ozhan et al, 2004; Sutlupinar et al, 1993). The severity of bradycardia appears to be proportional to the amount of grayanotoxins ingested (Bruneton, 1999).
    2) INCIDENCE: In a review of the literature, cardiac dysrhythmias were commonly observed following grayanotoxin exposure, with sinus bradycardia (n=37) or bradysrhythmias (n=13) reported in up to 75% (n=69) of patients (Gunduz et al, 2008).
    3) Case studies have reported sinus bradycardia, nodal rhythm, complete atrioventricular block (Gunduz et al, 2006; Biberoglu et al, 1988; Yavuz et al, 1991), Wolff-Parkinson-White syndrome (Biberoglu et al, 1988; Yavuz et al, 1991) and sinus bradycardia, multiple atrial premature beats, intermittent sinus node arrest followed by atrioventricular escape beats, second degree atrioventricular block and an undefined tachydysrhythmia (Gossinger et al, 1983).
    b) CASE REPORTS/CASE SERIES
    1) CASE REPORT: A 56-year-old man developed bradycardia and hypotension after eating a large amount of honey. An ECG revealed complete atrioventricular block with a ventricular rate of 38 bpm. Following treatment with atropine sulfate (1 mg IV), he recovered completely without further sequelae (Ergun et al, 2005).
    a) CASE REPORT: In another case, a 56-year-old man developed a heart rate of 30 beats/minute and a systolic blood pressure of 80 mmHg with complete atrioventricular block after ingesting 75 mL of honey. The patient required a temporary transvenous ventricular pacemaker due to a lack of response to atropine. Within 12 hours, the patient was hemodynamically stable with a normal ECG (Dursunoglu et al, 2007).
    b) CASE REPORT/INFANT: A two-month old infant developed bradycardia, hypotension (BP 62/33 mmHg) and seizure activity after being given a decoction of Rhododendron simsii used as a home remedy. The infant required mechanical ventilation for several days and gradually improved. No permanent sequelae occurred (Poon et al, 2008).
    2) CASE SERIES: Grayanotoxin poisoning occurred in 15 patients after ingesting 47 cc (mean dose) of mad honey from Nepal. Initially, all patients developed hypotension (systolic 68.3 +/- 11.2; diastolic 47.6 +/- 10.8) and bradycardia (40.9 bpm (+/- 5.8)). The average time to onset of symptoms was 36 minutes. ECG findings included sinus bradycardia in 8 patients, junctional bradycardia in 4 patients, complete atrioventricular block in 2 patients and a single case of atrial fibrillation with slow ventricular response. Most patients (n=11) were treated with atropine (mean dose, 1 mg) and IV saline. Vital signs returned to normal within 24 hours in all patients; 10 patients were discharged within the first 24 hours. The remaining patients (n=5) were admitted for intensive care monitoring and all were discharged by the third day (Sohn et al, 2014).
    3) CASE SERIES: In a series of 152 azalea ingestions, no deaths were reported, and only one patient required short-term hospitalization (Klein-Schwartz & Litovitz, 1985).
    4) CASE SERIES: In one case series (n=19), several hours after ingesting about 30 to 180 g of "mad" honey, sinus bradycardia and complete atrioventricular block occurred in 15 and 4 patients, respectively. Following supportive treatment, all patients recovered without further sequelae (Ozhan et al, 2004).
    5) CASE SERIES: In a series of honey intoxications (n=66) following ingestion of honey produced from the nectar of the Rhododendron ponticum, a pulse rate of less than 60 beats/minute was reported in 87% of patients and a pulse rate of less than 50 beats/minute was reported in 55.3% of patients. The ECG showed sinus rhythm in all patients. With supportive care, all of the patients recovered. The amount of honey ingested was estimated to be between 5 and 30 g (mean 13.45 +/- 5.39 g) (Yilmaz et al, 2006).
    6) CASE SERIES: In a series of 8 "mad honey" intoxications, sinus bradycardia and AV block were reported (Gunduz et al, 2006).
    7) CASE REPORT: A 76-year-old man presented with hypotension (70/50 mmHg) and bradycardia with a pulse of 45 beats/minute after ingesting 10 Rhododendron mucronulatum blossoms (Lee et al, 2007).
    c) CHRONIC EXPOSURE
    1) CASE SERIES: In a prospective study of 173 patients referred for further evaluation of bradydysrhythmias and/or pacemaker insertion, 5 patients (aged between 17 to 65 years; median age: 34) were found to have ingested mad honey (noncommercial product) for 3 months or longer. All of the patients had various degrees of AV conduction abnormalities with narrow QRS complexes and had complaints of dizziness and presyncope. No patient required hospitalization. There was a rapid improvement in symptoms and ECG abnormalities following the discontinuation of the honey. Holter monitoring at 1 and 3 months was normal for each patient (Aliyev et al, 2009).
    F) COMPLETE ATRIOVENTRICULAR BLOCK
    1) WITH POISONING/EXPOSURE
    a) In review of the literature, heart blocks of varying degrees were present in 25% (n=69) of patients following grayanotoxin poisoning. Nodal rhythms were present in 11%, with 8.7% of patients having a complete heart block and 2.9% had a second degree heart block (Gunduz et al, 2008).
    b) CASE REPORT: A 45-year-old healthy woman developed complaints of dizziness, nausea and sweating about 2 to 3 hours after ingesting 2 to 3 tablespoons of honey from the East Black Sea region. On admission, she was hypotensive (BP 70/50 mmHg) with complete atrioventricular block and a heart rate of 44 bpm. Cardiac enzymes and other laboratory parameters were normal. She was treated with atropine and IVFs; her vital signs returned to normal within 24 hours. By the following day, she was asymptomatic and in normal sinus rhythm (Oguzturk et al, 2012).
    c) CASE REPORT: Complete atrioventricular block with a ventricular rate of 31 beats/minute occurred in an adult following the ingestion of a 100 mL of honey, which contained 10% Rhododendron species. Signs and symptoms rapidly improved with atropine and a saline infusion. The patient was monitored for 24 hours with no further cardiac manifestations. Upon follow-up, 24-hour Holter monitoring was normal (Cagli et al, 2009).
    d) CASE REPORT: A 56-year-old man developed a heart rate of 30 beats/minute and a systolic blood pressure of 80 mmHg with complete atrioventricular block after ingesting 75 mL of honey. The patient required a temporary transvenous ventricular pacemaker due to a lack of response to atropine. Within 12 hours, the patient was hemodynamically stable with a normal ECG (Dursunoglu et al, 2007).
    G) ATRIAL FIBRILLATION
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Atrial fibrillation has been reported infrequently following mad honey exposure from the Black Sea region and Nepal (Sohn et al, 2014; Bayram et al, 2012; Cakar et al, 2011).
    b) CASE REPORT: A 36-year-old man was admitted with syncope, fatigue and dizziness that began about 4 to 5 hours after ingesting 2 or 3 teaspoons of honey he purchased from the eastern Black Sea region. Vital signs: heart rate 56 beats/min and blood pressure 110/55 mmHg. Atrial fibrillation with a slow ventricular response was observed on ECG. An infusion of physiologic saline was given. Following ongoing atrial fibrillation with a rate of 76 beats/min, an amiodarone infusion was started. The patient converted to normal sinus rhythm approximately 25 hours after admission. No further arrhythmias were noted and the patient was discharged to home on hospital day 2 (Bayram et al, 2012).
    c) CASE REPORT: A 46-year-old man living in the Black Sea region ingested a few spoonfuls of honey and developed palpitations and dizziness. On admission, the ECG showed a wide QRS complex atrial fibrillation (rate 172 beats/minute) and blood pressure was 90/60 mmHg. The patient improved rapidly with a saline infusion. A repeat ECG showed a normal sinus rhythm, shortened PR intervals, delta waves and a minimally widened QRS complex, suggesting Wolf-Parkinson White Syndrome (WPWS). He was monitored for 48 hours with no further episodes of atrial fibrillation. The patient was discharged and then transferred for electrophysiology testing and ablation therapy (Cakar et al, 2011).
    H) ASYSTOLE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Asystole occurred in a 60-year-old man living in the Black Sea region after ingesting a few spoonfuls of honey from the nectar of a Rhododendron species (R. luteum and R. ponticum are the main sources of grayanotoxin in this area). Immediate treatment with intravenous atropine (0.5 mg) resolved symptoms. A temporary pacemaker was inserted for several days. The patient completely recovered and was discharged on hospital day 4 (Gunduz et al, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) LACK OF EFFECT
    1) No direct pulmonary effects have been noted, and, to date, no patients requiring assisted ventilation have been reported.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Circumoral and extremity paresthesias and general weakness are reported (Bruneton, 1999).
    b) In one case series (n=19), dizziness and weakness occurred in all patients several hours after ingesting about 30 to 180 g of "mad" honey. Following supportive treatment, all patients recovered without further sequelae (Ozhan et al, 2004).
    B) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Anecdotal reports of disorientation, ataxia and confusion exist (Leach, 1982).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) In severe intoxications, seizures may occur (Lampe, 1988; Gossinger et al, 1983).
    b) CASE REPORT: A 57-day-old infant was given a decoction of Rhododendron simsii used as a home remedy and developed twitching in all limbs. He became cyanotic and unresponsive twenty minutes after exposure. Upon admission the patient was bradycardic and hypotensive; mechanical ventilation was required along with an intravenous benzodiazepine infusion. Seizure activity resolved within 2 hours. He gradually improved and was extubated 48 hours after admission. The infant was discharged to home on day 8 with no evidence of permanent sequelae. Grayanotoxin I was detected in both the decoction and the infant's urine (Poon et al, 2008).
    D) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headaches, fatigue, and fainting have been reported following poisonings (Bruneton, 1999).
    E) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Dizziness and weakness were reported in 100% of patients (n=66) with honey poisoning following ingestion of honey produced from the nectar of the Rhododendron ponticum. All of the patients recovered with supportive care. The amount of honey ingested was estimated to be between 5 and 30 g (mean: 13.45 +/- 5.39 g) (Yilmaz et al, 2006).
    F) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Syncope occurred 17.6% of patients (n=66) with honey intoxication following ingestion of honey produced from the nectar of the Rhododendron ponticum. The amount of honey ingested was estimated to be between 5 and 30 g (mean: 13.45 +/- 5.39 g) (Yilmaz et al, 2006).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting are common early findings (Sutlupinar et al, 1993). Vomiting and abdominal pain occurred 2.5 hours after ingesting an unknown amount of rhododendron leaves (Westbrooks & Preacher, 1986).
    b) CASE SERIES: In one case series (n=19), nausea and vomiting occurred in all patients several hours after ingesting about 30 to 180 g of "mad" honey. Following supportive treatment, all patients recovered without further sequelae (Ozhan et al, 2004).
    c) CASE SERIES: Nausea and vomiting were reported in 45.4% and 31.8% of patients (n=66), respectively, with honey intoxication following ingestion of honey produced from the nectar of the Rhododendron ponticum. The amount of honey ingested was estimated to be between 5 and 30 g (mean: 13.45 +/- 5.39 g) (Yilmaz et al, 2006)
    B) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Increased salivation occurred in 4.7% of patients (n=66) with honey intoxication following ingestion of honey produced from the nectar of the Rhododendron ponticum. The amount of honey ingested was estimated to be between 5 and 30 g (mean 13.45 +/- 5.39 g) (Yilmaz et al, 2006)

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) In man, hepatic damage has not been reported; however, animals may show evidence of mild hepatic injury under certain circumstances (Frohne & Pfander, 1983) (Kingsbury, 1964).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) NEPHRITIS
    1) WITH POISONING/EXPOSURE
    a) Renal injury has not been reported in human literature, but acute nephritis with renal tubular necrosis has been described in animals (Kingsbury, 1964).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Although not reported, prolonged hypotension and bradycardia may induce tissue hypoperfusion and metabolic (lactic) acidosis.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Skin rashes have been reported with individuals exposed to plants of the Ericaceae family, but components other than grayanotoxins are probable etiologic factors. Burning and itching of the skin may occur after ingestions (Frohne & Pfander, 1983).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Profuse diaphoresis may occur (Biberoglu et al, 1988).
    b) In one case series (n=19), sweating occurred in all patients several hours after ingesting about 30 to 180 grams of "mad" honey. Following supportive treatment, all patients recovered without further sequelae (Ozhan et al, 2004).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) Generalized muscle weakness may occur after significant exposures (Bruneton, 1999; Biberoglu et al, 1988).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES/LACK OF EFFECT: A prospective study was conducted between June 2006 and October 2007 in an urban hospital in Turkey to assess possible alterations in blood glucose following mad honey poisoning. Of the 46 cases of mad honey poisoning, the age ranged between 10 and 93 years. The mean glucose level was 116.7 +/- 49.9 mg/dL. Twenty-eight (60.9%) patients had a normal blood glucose level (70 to 110 mg/dL) and 18 (39.1%) patients had an elevated blood glucose reading. No case of hypoglycemia was reported. In addition, alterations in blood pressure (ie, low or high diastolic blood pressure) due to differences in glucose level was not found to be statistically significant. Although an animal study found that grayanotoxins can produce lower blood glucose levels due to an increase in the secretion of insulin from the pancreas, hypoglycemia was not observed in this case series (Uzun et al, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital sign and mental status.
    B) Institute continuous cardiac monitoring and obtain serial ECGs in patients with bradycardia and hypotension.
    C) Other laboratory or radiologic studies may be guided by symptoms such as electrolytes for patients with paresthesias or serial troponin levels in patients with cardiovascular symptoms.
    D) No readily available testing of blood or urine exists for grayanotoxins. However, contaminated honey may possibly be submitted to health departments for analysis as chromatographic techniques do exist to determine the presence of grayanotoxins in honey.

Methods

    A) CHROMATOGRAPHY
    1) No methods are currently clinically available to confirm or quantitate grayanotoxins in human biological samples. Chromatographic techniques have been developed to determine the presence of grayanotoxins in honey for research purposes (Scott et al, 1971). Suspect honey may be analyzed for pollens of the Ericaceae family of plants (White & Riethof, 1959).
    2) Liquid chromatography-mass spectrometry methods were described for the quantitative determination of grayanotoxins I, II, and III in bovine rumen contents, caprine feces, and caprine and ovine urine. Using this method, the detection limits were 0.2 mcg/g in bovine rumen contents, 0.05 to 0.2 mcg/g in caprine feces, and 0.05 mcg/g in ovine urine (Holstege et al, 2001; Puschner et al, 2001).
    3) Thin-layer chromatography was performed for initial quantitative determination of grayanotoxins I, II, and III following ingestion of an azalea branch by 3 goats. The detection limits in the fecal samples of the affected goats were 0.2 mcg/g (Puschner et al, 2001).
    B) HIGH RESOLUTION MASS SPECTROMETRY
    1) High-resolution mass spectrometry (HRMS) was used for the detection of grayanotoxins in a contaminated honey sample that caused typical symptoms of intoxication in an adult. Tandem mass spectrometry data were acquired using TSQ Vantage (Thermo Fisher Scientific, San Jose, CA). The findings did show that the sample was contaminated with high amounts of grayanotoxins and other toxins belonging to grayanane-type diterpenoids. A total of 15 individual grayanotoxins were identified by this method (These et al, 2015).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) All patients with persistent symptoms should be admitted to a monitored setting until symptoms resolve. Patients with bradycardia, AV conduction disturbances, or hypotension should be admitted to an intensive care setting.
    B) Patients that do not respond to therapy or who develop significant bradydysrhythmias or third-degree or complete heart block require further cardiac support (e.g., temporary pacing, vasopressors).
    1) In most cases, the most severe toxic effects of mad honey usually last about 24 hours (Cagli et al, 2009; Gunduz et al, 2009).
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with inadvertent exposures to plant parts can be managed at home. Asymptomatic adults without underlying cardiac disease can be managed at home after inadvertent exposure to mad honey. Patients with minimal symptoms that are improving or asymptomatic may potentially remain at home after exposure to grayanotoxins.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for symptomatic patients and those for whom the diagnosis is unclear. For intentional self-harm exposures, psychiatry consultation is necessary. Depending on the severity of the illness, critical care specialists might be needed
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) The following patients should be referred to a healthcare facility for evaluation and treatment: Any symptomatic patient, any patient with a self harm ingestion, any child ingesting mad honey, adults with underlying cardiac disease ingesting mad honey, any patient ingesting a decoction or infusion of grayanotoxin containing plants. Patients may be sent home or cleared for psychiatric evaluation if they are clearly improving or asymptomatic for a period of observation of 4 to 6 hours.
    B) Patients may be sent home or cleared for psychiatric evaluation if they are clearly improving or asymptomatic after a period of observation of 4 to 6 hours (Gunduz et al, 2009).

Monitoring

    A) Monitor vital sign and mental status.
    B) Institute continuous cardiac monitoring and obtain serial ECGs in patients with bradycardia and hypotension.
    C) Other laboratory or radiologic studies may be guided by symptoms such as electrolytes for patients with paresthesias or serial troponin levels in patients with cardiovascular symptoms.
    D) No readily available testing of blood or urine exists for grayanotoxins. However, contaminated honey may possibly be submitted to health departments for analysis as chromatographic techniques do exist to determine the presence of grayanotoxins in honey.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In substantial plant ingestions or for symptomatic patients, monitor cardiac rhythm and blood pressure. Hypotension and bradydysrhythmias are common, but hypertension and tachydysrhythmias have been reported.
    a) Patients seem to stabilize within a 24-hour period without sequelae if cardiac output and blood pressure are supported.
    B) MONITORING OF PATIENT
    1) Monitor vital sign and mental status.
    2) Institute continuous cardiac monitoring and obtain serial ECGs in patients with bradycardia and hypotension.
    3) Other laboratory or radiologic studies may be guided by symptoms such as electrolytes for patients with paresthesias or serial troponin levels in patients with cardiovascular symptoms.
    4) No readily available testing of blood or urine exists for grayanotoxins. However, contaminated honey may possibly be submitted to health departments for analysis as chromatographic techniques do exist to determine the presence of grayanotoxins in honey.
    C) BRADYCARDIA
    1) ATROPINE: Atropine is useful in the management of bradycardia due to grayanotoxin-induced effects of enhanced vagal tone.
    a) In a study of 47 patients with mad honey poisoning presenting to three healthcare centers, each patient returned to normal sinus rhythm following administration of intravenous fluids and atropine (between 0.5 and 2 mg). Upon admission, sinus bradycardia was observed in most patients (heart rate: 30 to 77 beats per minute (mean +/- SD, 46.6 +/- 12.1 per minute) and 6 (12.8%) patients had developed a nodal rhythm, 3 (6.4%) normal sinus rhythm, and one (2.1%) had complete atrioventricular (AV) block. The average length of hospitalization based on patient condition was 3.6 hours (+/- 2.2 hours) and 3.7 hours (+/- 1.7 hours) in two of the emergency centers (Gunduz et al, 2009).
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    3) PACEMAKER: Transcutaneous pacing or insertion of a transvenous pacemaker should be considered in those rare patients with severe bradycardia who fail to respond to atropine.
    D) HYPOTENSIVE EPISODE
    1) Pressor agents are generally not necessary to control hypotension secondary to grayanotoxin poisoning. Intravenous fluids and atropine (if there is associated bradycardia) should be sufficient. In severe cases of hypotension unresponsive to fluid management and atropine, dopamine or norepinephrine may be considered. In cases of hypotension, patients may respond to a direct vasopressor (i.e., norepinephrine) more quickly than an indirect vasopressor (i.e., dopamine).
    2) 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.
    3) 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).
    4) 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).

Enhanced Elimination

    A) SUMMARY
    1) No data exist to suggest that extracorporeal removal techniques, such as hemodialysis or hemoperfusion, would be of benefit in grayanotoxin poisoning, nor would such be likely to be necessary with good cardiovascular support.
    2) Likewise, no data exist to support the use of repeated doses of oral activated charcoal.

Abstracts

Case Reports

    A) ADULT
    1) ADVERSE EFFECTS
    a) BACKGROUND: In most reported cases (over 90%), significant hypotension (systolic blood pressure 70 mmHg) and bradycardia (pulse rate of 48 BPM) are present. Diaphoresis, dizziness, and altered mental status develop in about 70% of exposures, and syncope in about 30% of cases. Salivation has occurred in 14% of cases in one series. While it shares some features with a cholinergic toxidrome, lacrimation, urination, bronchorrhea and miosis have not been observed following exposure (Gunduz et al, 2008).
    2) In a series of 8 patients, sinus bradycardia or AV block were reported after ingesting honey in the Black Sea region of Turkey. All patients were treated symptomatically and were able to be discharged from the hospital (Gunduz et al, 2006).
    3) Biberoglu et al (1988) described 16 patients seen in a Turkish hospital for illness following ingestion of grayanotoxin-contaminated honey, the source being Rhododendron ponticum. The average amount of honey ingested was 50 g. Common complaints were dizziness, weakness, diaphoresis, nausea, and vomiting. Four had syncope. All had hypotension and bradydysrhythmias. Symptoms started approximately one hour following ingestion. Fourteen patients were treated successfully with fluids and atropine. One patient with W-P-W syndrome and one patient with third degree A-V block were treated with isoproterenol. All recovered without sequelae in an average of 24 hours (Biberoglu et al, 1988).
    4) A 27-year-old woman who purchased honey in Turkey, ingested 75 mL and shortly thereafter vomited, fell unconscious, and had a grand mal seizure. On presentation, she was diaphoretic with a blood pressure of 60/40 mmHg and heart rate of 52 beats/minute. Multiple bradydysrhythmias were noted, and a pacemaker was utilized. Fluids corrected her hypotension. He fully recovered within one day (Gossinger et al, 1983).
    5) Lee et al (2007) reported a case of Rhododendron mucronulatum poisoning in a 76-year-old man who ingested 10 blossoms. He developed hypotension (70/50 mmHg) and bradycardia with a pulse of 45 beats/minute. He was treated with 1 mg atropine sulfate with a resolution of symptoms. He was able to be discharged in 24 hours with complete recovery (Lee et al, 2007).

Range Of Toxicity

Summary

    A) In historical literature, deaths have been recorded but not in modern medical literature.
    B) Approximately, 50 to 75 mL of contaminated honey (bees utilizing nectar from selected plants of the Ericaceae family) have caused toxicity.
    C) Honey poisonings occurred in 66 adults following ingestion of 5 to 30 g (mean 13.45 +/- 5.39 g) of honey, produced from nectar of the Rhododendron ponticum.
    D) Eight adults ingested 20 to 150 g of "mad honey" and became intoxicated.
    E) Ingestion of 10 azalea blossoms (Rhododendron mucronulatum) caused toxicity in a 76-year-old man.

Maximum Tolerated Exposure

    A) SUMMARY
    1) PLANT INGESTION
    a) CASE REPORT: A 76-year-old man developed hypotension (70/50 mmHg) and sinus bradycardia of 45 beats/min after ingesting 10 Rhododendron mucronulatum flowers (Lee et al, 2007).
    2) CONTAMINATED HONEY
    a) Human reports of illness following ingestion of contaminated honey report doses in the range of 50 to 75 mL of honey (Dursunoglu et al, 2007; Biberoglu et al, 1988; Gossinger et al, 1983). Doses above 1 teaspoonful have produced symptoms (Bayram et al, 2012); 100 g produced significant symptoms (Sutlupinar et al, 1993).
    b) CASE REPORT: A 36-year-old man was admitted with syncope, fatigue and dizziness that began about 4 to 5 hours after ingesting 2 or 3 teaspoons of honey he purchased from the eastern Black Sea region. Bradycardia and hypotension were present. Atrial fibrillation with a slow ventricular response was observed on ECG. Following ongoing atrial fibrillation with a rate of 76 beats/min, an amiodarone infusion was started. The patient converted to normal sinus rhythm approximately 25 hours after admission. No further arrhythmias were noted and the patient was discharged to home on hospital day 2 (Bayram et al, 2012).
    c) CASE SERIES: Honey poisoning, consisting of dizziness, weakness, hypotension, bradycardia, syncope, excessive salivation, and nausea and vomiting, was reported in 66 adults following ingestion of 5 to 30 g (mean 13.45 +/- 5.39 grams) of honey. The honey was produced from the nectar of Rhododendron ponticum. All 66 patients recovered with supportive care (Yilmaz et al, 2006).
    d) CASE SERIES: Honey intoxication with nausea, vomiting, hypotension, and bradycardia occurred in 8 patients after ingesting 20 to 150 g of honey. All patients recovered with supportive care (including intravenous fluids and atropine administration) (Gunduz et al, 2006).
    e) CASE SERIES: Grayanotoxin poisoning occurred in 15 patients after ingesting 47 cc (mean dose) of mad honey from Nepal. Initially, all patients developed hypotension (systolic 68.3 +/- 11.2; diastolic 47.6 +/- 10.8) and bradycardia (40.9 bpm (+/- 5.8)). The average time to onset of symptoms was 36 minutes. ECG findings included sinus bradycardia in 8 patients, junctional bradycardia in 4 patients, complete atrioventricular block in 2 patients and a single case of atrial fibrillation with slow ventricular response. Most patients (n=11) were treated with atropine (mean dose, 1 mg) and IV saline. Vital signs returned to normal within 24 hours in all patients; 10 patients were discharged within the first 24 hours. The remaining patients (n=5) were admitted for intensive care monitoring and all were discharged by the third day (Sohn et al, 2014).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 2-5 mg/kg (Frohne & Pfander, 1983)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Grayanotoxins exert their effect by binding to sodium channels in cell membranes (Group II receptor site) (Narahashi & Seyama, 1974; Seyama & Narahashi, 1973). This effect can result in the activation potential of the modified sodium channel shifting towards hyperpolarization (Gunduz et al, 2008).
    B) Excitable cells, such as nerve and muscle, are maintained in a state of depolarization. These membrane effects are thought to account for the observed responses to grayanotoxins by skeletal and myocardial muscle, nerves, and the central nervous system (Lampe, 1988).
    1) Alpha-H2-GTX II (alpha dihydrograyanotoxin) was shown experimentally to depolarize both end-plate and non-end-plate regions of muscle fiber (Zushi et al, 1983).
    C) A study of 30 patients poisoned by mad honey was evaluated to determine if mad honey poisoning is associated with decrease pseudocholinesterase concentrations. The most common symptoms reported among the patients were vertigo and nausea. Plasma pseudocholinesterase (BChE) levels were drawn in each case and found to be normal in 27 (90%) patients and below normal in 3 (10%) patients. The mean levels were 7139.3 +/- 2316.41 U/L (normal levels: 5400 to 13200 U/L). Although the symptoms (ie, dizziness, vertigo, nausea, vomiting and syncope) and signs (eg bradycardia) of mad honey poisoning exhibit a similarity to cholinergic poisoning, BChE levels remained normal in most exposed individuals (Gunduz et al, 2012).

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) DERMAL EXPOSURE - Six dogs developed lethargy and unsteady gait after walking through a wood with shredded Rhododendron ponticum. Lassitude, yawning and head rubbing were seen in some animals. There was no ingestion, only paw and muzzle contact (Frape & Ward, 1993).
    1) The Rhododendrons are the suspected cause but the relationship was not proven. Three of the dogs were under care for other conditions.
    11.1.4) CAPRINE/GOAT
    A) Ingestion of an azalea (Rhododendron indica) branch by six Nubian goats resulted in 3 of the six goats developing bloat, profuse regurgitation, and signs of depression, intermittent head pressing, and fine muscle tremors in the hind limbs (Puschner et al, 2001).
    11.1.9) OVINE/SHEEP
    A) PIERIS JAPONICA - A number of sheep were killed after eating Pieris japonica variegata. Deaths were seen 24 to 48 hours postingestion. Signs included abdominal pain, staggering, and lateral recumbency with paddling motions of the limbs.
    B) The abdominal serosal surfaces showed scattered ecchymotic hemorrhages and slight hyperemia of the small intestines and abomasum (Powers et al, 1991).
    11.1.13) OTHER
    A) OTHER
    1) DONKEY - Symptoms seen in poisoning included tachycardia, dyspnea, green froth around the mouth, minimal gut activity, paralysis, and inability to open its jaws (Thiemann, 1991). It took 4 days for the paralysis to subside.

Treatment

    11.2.1) SUMMARY
    A) OTHER
    1) DONKEY - Treatment in poisoned donkeys included oral glucose, sodium bicarbonate, multivitamins (a less severely poisoned animal), and intravenous fluids, flunixin meglumine, liquid paraffin, cold tea, and Lectade solution (in a more severely poisoned animal) (Thiemann, 1991).
    B) CATTLE
    1) GOATS AND CATTLE - Treatments recommended in goats and cattle have included activated charcoal, atropine sulfate, magnesium hydroxide, sodium camphorsulfonide, ephedrine hydrochloride, caffeine, morphine, intravenous fluids, and laxatives (Cooper & Johnson, 1984; Humphrey et al, 1983; Yi et al, 1985; Whitehead et al, 1991; Puschner et al, 2001).
    C) GOAT
    1) GOATS AND CATTLE - Treatments recommended in goats and cattle have included activated charcoal, atropine sulfate, magnesium hydroxide sodium camphorsulfonide, ephedrine hydrochloride, caffeine, morphine, intravenous fluids, and laxatives (Cooper & Johnson, 1984; Humphrey et al, 1983; Yi et al, 1985; Whitehead et al, 1991; Puschner et al, 2001).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) OTHER
    1) DONKEY - Treatment in poisoned donkeys included oral glucose, sodium bicarbonate, multivitamins (a less severely poisoned animal), and intravenous fluids, flunixin meglumine, liquid paraffin, cold tea, and Lectade solution (in a more severely poisoned animal) (Thiemann, 1991).
    B) CATTLE
    1) GOATS AND CATTLE - Treatments recommended in goats and cattle have included activated charcoal, atropine sulfate, magnesium hydroxide, sodium camphorsulfonide, ephedrine hydrochloride, caffeine, morphine, intravenous fluids, and laxatives (Cooper & Johnson, 1984; Humphrey et al, 1983; Yi et al, 1985; Whitehead et al, 1991; Puschner et al, 2001).
    C) GOAT
    1) GOATS AND CATTLE - Treatments recommended in goats and cattle have included activated charcoal, atropine sulfate, magnesium hydroxide sodium camphorsulfonide, ephedrine hydrochloride, caffeine, morphine, intravenous fluids, and laxatives (Cooper & Johnson, 1984; Humphrey et al, 1983; Yi et al, 1985; Whitehead et al, 1991; Puschner et al, 2001).

References

General Bibliography

    1) Akinci S, Arslan U, Karakurt K, et al: An unusual presentation of mad honey poisoning: acute myocardial infarction. Int J Cardiol 2008; 129(2):e56-e58.
    2) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    3) Aliyev F , Turkoglu C , Celiker C , et al: Chronic mad honey intoxication syndrome: a new form of an old disease?. Europace 2009; 11(7):954-956.
    4) Balazs T: Cardiac Toxicology (Vol I), CRC Press, Inc, Boca Raton, FL, 1981.
    5) Bayram NA, Keles T, Durmaz T, et al: A rare cause of atrial fibrillation: mad honey intoxication. J Emerg Med 2012; 43(6):e389-e391.
    6) Biberoglu S, Biberoglu K, & Biberoglu B: Mad honey (letter). JAMA 1988; 269:1943.
    7) Bruneton J: Toxic Plants: Dangerous to Humans and Animals, Intercept LTD, Hampshire, UK, 1999.
    8) Cagli KE, Tufekcioglu O, Sen N, et al: Atrioventricular block induced by mad-honey intoxication: confirmation of diagnosis by pollen analysis. Tex Heart Inst J 2009; 36(4):342-344.
    9) Cakar MA, Can Y, Vatan MB, et al: Atrial fibrillation induced by mad honey intoxication in a patient with Wolf-Parkinson-White syndrome. Clin Toxicol (Phila) 2011; 49(5):438-439.
    10) Catterall WA: Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes. Ann Rev Pharmacol Toxicol 1980; 20:15-43.
    11) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    12) Cooper MR & Johnson AW: Poisonous Plants in Britain. Ministry of Agriculture Fisheries and Food. Ref Book 161, Her Majesty's Stationery Office, Norwich, UK, 1984.
    13) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    14) Dampc A & Luczkiewicz M : Labrador tea--the aromatic beverage and spice: a review of origin, processing and safety. J Sci Food Agric 2015; 95(8):1577-1583.
    15) Dur A, Sonmez E, Civelek C, et al: Mad honey intoxication mimicking acute coronary syndrome. J Pak Med Assoc 2014; 64(9):1078-1080.
    16) Dursunoglu D, Gur S, & Semiz E: A case with complete atrioventricular block related to mad honey intoxication. Ann Emerg Med 2007; 50(4):484-485.
    17) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    18) Ergun K, Tufekcioglu O, Aras D, et al: A rare cause of atrioventricular block: Mad honey intoxication (letter). Int J Cardiol 2005; 99:347-348.
    19) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    20) Frape D & Ward A: Suspected rhododendron poisoning in dogs. Vet Rec 1993; 132:219-220.
    21) Frohne D & Pfander HJ: A Colour Atlas of Poisonous Plants, Wolfe Publishing Ltd, London, England, 1983.
    22) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    23) Gossinger H, Hruby K, & Haubenstock A: Cardiac arrhythmias in a patient with grayanotoxin-honey poisoning. Vet Hum Toxicol 1983; 25:328-329.
    24) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    25) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    26) Gunduz A , Merice ES , Baydin A , et al: Does mad honey poisoning require hospital admission?. Am J Emerg Med 2009; 27(4):424-427.
    27) Gunduz A, Durmus I, Turedi S, et al: Mad honey poisoning-related asystole. Emerg Med J 2007; 24(8):592-593.
    28) Gunduz A, Kalkan A, Turedi S, et al: Pseudocholinesterase levels are not decreased in grayanotoxin (mad honey) poisoning in most patients. J Emerg Med 2012; 43(6):1008-1013.
    29) Gunduz A, Turedi S, Russell RM, et al: Clinical review of grayanotoxin/mad honey poisoning past and present. Clin Toxicol (Phila) 2008; 46(5):437-442.
    30) Gunduz A, Turedi S, Uzun H, et al: Mad Honey Poisoning. Am J Emerg Med 2006; 24(5):595-598.
    31) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    32) Holstege DM, Puschner B, & Le T: Determination of grayanotoxins in biological samples by LC-MS/MS. J Agricult Food Chem 2001; 49:1648-1651.
    33) Humphrey DJ, Stondnlski JBJ, & Stocker JG: Vet Rec 1983; 113:503.
    34) Klein-Schwartz W & Litovitz T: Azalea toxicity: an overrated problem?. Clin Toxicol 1985; 23:91-101.
    35) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    36) Lampe KF & McCann MA: AMA Handbook of Poisonous and Injurious Plants, American Medical Association, Chicago, IL, 1985.
    37) Lampe KF: Rhododendrons, mountain laurel, and mad honey (editorial). JAMA 1988; 259:2009.
    38) Leach DG: That's why the lady is a tramp. J Am Rhododendron Soc 1982; 151-152.
    39) Lee SW, Choi SH, Hong YS, et al: Grayanotoxin poisoning from flower of Rhododendron mucronulatum in humans. Bull Environ Contam.Toxicol 2007; 78(2):132-133.
    40) Narahashi T & Seyama I: Mechanism of nerve membrane depolarization caused by grayanotoxin I. J Physiol 1974; 242:471-487.
    41) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    42) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    43) Oguzturk H, Ciftci O, Turtay MG, et al: Complete atrioventricular block caused by mad honey intoxication. Eur Rev Med Pharmacol Sci 2012; 16(12):1748-1750.
    44) Ozhan H, Akdemir R, Yazici M, et al: Cardiac emergencies caused by honey ingestion: a single centre experience. Emerg Med J 2004; 21:742-744.
    45) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    46) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    47) Poon WT, Ho CH, Yip KL, et al: Grayanotoxin poisoning from Rhododendron simsii in an infant. Hong Kong Med J 2008; 14(5):405-407.
    48) Powers SB, O'Donnell PG, & Quirk EG: Pieris poisoning in sheep. Vet Rec 1991; 128:599-600.
    49) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    50) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    51) Puschner B, Holstege DM, & Lamberski N: Grayanotoxin poisoning in three goats. J Am Vet Med Assoc 2001; 218:573-575.
    52) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    53) Scott PM, Caldwell BB, & Wiberg GS: Grayanotoxins. Occurrence and analysis in honey and a comparison of toxicities in mice. FD Cosmet Toxicol 1971; 9:179-184.
    54) Seyama I & Narahashi T: Increase in sodium permeability of squid axon membranes by a-dihydro-grayanotoxin II. J Pharmacol Exper Ther 1973; 184:299-307.
    55) Sohn CH, Seo DW, Ryoo SM, et al: Clinical characteristics and outcomes of patients with grayanotoxin poisoning after the ingestion of mad honey from Nepal. Intern Emerg Med 2014; 9(2):207-211.
    56) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    57) Sutlupinar N, Mat A, & Satganoglu Y: Poisoning by toxic honey in Turkey. Arch Toxicol 1993; 67:148-150.
    58) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    59) These A, Bodi D, Uecker S, et al: A case of human poisoning by grayanotoxins following honey ingestion: elucidation of the toxin profile by mass spectrometry. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2015; 32(10):1674-1684.
    60) Thiemann A: Rhododendron poisoning. Vet Rec 1991; 128:411.
    61) Uzun H, Narci H, Tayfur I, et al: Mad honey intoxication: what is wrong with the blood glucose? a study on 46 patients. Eur Rev Med Pharmacol Sci 2013; 17(20):2728-2731.
    62) Westbrooks RG & Preacher JW: Poisonous plants of Eastern North America, University of South Carolina Press, Columbia, SC, 1986.
    63) White JW & Riethof ML: The composition of honey. III. Detection of acetylandromedol in toxic honey. Arch Biochem Biophys 1959; 79:165-167.
    64) Whitehead G, French J, & Ikin P: Practice 1991; 13:62.
    65) Yavuz H, Ozel A, & Akkus I: Honey poisoning in Turkey. Lancet 1991; 1:789-790.
    66) Yi HS, Yuan H, & Wan YR: Chinese J Vet Sci Tech 1985; 8:32.
    67) Yildirim N, Aydin M, Cam F, et al: Clinical presentation of non-ST-segment elevation myocardial infarction in the course of intoxication with mad honey. Am J Emerg Med 2008; 26(1):108-2.
    68) Yilmaz O, Eser M, Sahiner A, et al: Hypotension, bradycardia and syncope caused by honey poisoning. Resuscitation 2006; 68(3):405-408.
    69) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.