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PLANTS-THEVETIA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) An ornamental shrub widespread in the tropical and subtropical regions, including the southern United States and Hawaii.

Specific Substances

    1) Ahouai (Antilles.)
    2) Ahouai des Antilles
    3) Bastard Oleander
    4) Be-Still Tree
    5) Bois Saisi (Haiti)
    6) Cablonga
    7) Cascavelerira (Brazil)
    8) Cerebra thevitia
    9) China Karab (Bengal)
    10) Cook Tree
    11) Exile Oleander
    12) Flor del Peru
    13) Joro-joro (Dutch Guiana)
    14) Kokilpul (India)
    15) Lucky Nut
    16) Lucky Seed (Jamaica)
    17) Milk Bush
    18) Noho-Malie (Hawaiian)
    19) Pachhai alasi (Tamil)
    20) Pila Kanir (India)
    21) Retama
    22) Serpent
    23) Thevetia nereifolia (Juss.)
    24) Thevetia peruviana (Merr.)
    25) Tiger Apple
    26) Tree Daffodil
    27) Yellow Oleander

Available Forms Sources

    A) FORMS
    1) The cardiac glycosides thevetin A and B (cerebroside), alpha-L- thevetosides, glucosyl- and gentiobiosyl-x-L-thevetosides of digitoxigenin, cannogenin, cannogenol, uzarigenin, x-L- acofrioside, c-nor-D-homo-cardenolide, and peruvoside have been found (Abe et al, 1992; Thilagar et al, 1986; Kyerematen et al, 1985). The plant also contains gums, rubber, a phytosterolin, ahouain, kohilphin, ruvoside, fixed oils and nerifolin (Saravanapavananthan & Ganeshamoorthy, 1988; Pearn, 1987; Frohne & Pfander, 1984; Tampion, 1977).
    2) Amount of glycoside by plant part (Saravanapavananthan & Ganeshamoorthy, 1988):
    1) Leaf: 0.070%
    2) Fruit: 0.045%
    3) Seed Kernel: 4.8%
    4) Milk (Sap): 0.036%
    B) USES
    1) An ornamental tree or shrub that is usually found outdoors in the tropics or subtropics. Poisoning may occur after accidental ingestion, suicide, or homicide, or after inhalation of smoke from fires in which oleander is burning (Pearn, 1987).
    a) In an Australian study from 1972 to 1978, oleander ingestions accounted for about 27% of all plant poisonings in children, however there were no mortalities (Shaw & Pern, 1979).
    2) It is used as an ornamental plant, and the seeds have been used in suicides and homicides (Saraswat et al, 1992). Various parts have been used in folk medicine and as insecticides, rodenticides, and fish poisons (Oji & Okafor, 2000; Oji et al, 1994; Pahwa & Chatterjee, 1990; Morton, 1971). The seeds have been polished and worn as pocket charms (Chopra & Mukerjee, 1933).
    3) Because of its toxicity, it is rarely used for therapeutic applications, but an alcoholic preparation of the bark (1:5), in doses of 30 to 60 drops, has been used as an emetic (Chopra & Mukerjee, 1933). Bark extracts containing cardenolides have also been investigated as cytotoxic agents in cancer research (Decosterd et al, 1994).
    4) In the 1930's, yellow oleander glycosides were shown to be effective in the treatment of heart failure and atrial fibrillation, but use was discontinued due to high toxicity (primarily cardiac and gastrointestinal) (Eddleston & Warrell, 1999; Eddleston et al, 1999).

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: This plant is an ornamental shrub and is not used in pharmaceuticals. Thevetia plants are ornamental shrubs and are widespread in tropical and subtropical regions including the southern United States and Hawaii.
    B) PHARMACOLOGY: Cardiac glycosides inhibit sodium and potassium ATPases, gradually increasing calcium ions which affect electrical conduction and results in bradycardia and dysrhythmias.
    C) TOXICOLOGY: All parts of the plant contain cardiac glycosides. However, the seeds have the highest concentration. Effects of the glycosides are similar to digitalis but with a more rapid onset.
    D) EPIDEMIOLOGY: Serious cases are uncommon, possibly due to the bitter taste and spontaneous vomiting, but exposures occur frequently. There is potential for serious toxicity and death. Poisoning may occur after accidental ingestion, suicide, homicide, or after inhalation of smoke from fires in which oleander is burning. Approximately 13% of cases never develop symptoms. Poisoning due to deliberate ingestion of yellow oleander seeds (Thevetia peruvian) has resulted in significant morbidity and mortality in South Asia.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: INGESTION: May result in vomiting, diarrhea, abdominal pain, dizziness and palpitations. DERMAL: Dermal exposures may result in blistering or dermatitis.
    2) SEVERE TOXICITY: May result in ECG changes such as AV block, bradycardias, T-wave changes, ST depression, and ectopic beats. Hypertension followed by hypotension may also occur. Severe hyperkalemia has occurred. Severely poisoned patients often die of persistent ventricular fibrillation.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Significant bradycardia has been reported following exposure.
    2) Hypertension has been reported initially, followed by hypotension secondary to bradycardia.
    0.2.4) HEENT
    A) Irritation of the eyes may be caused by the thick, white sap of this tree. Irritation and a burning sensation may also develop in the mouth and throat after chewing the leaves. Tingling, dryness of the throat, and dilated pupils may occur.
    0.2.20) REPRODUCTIVE
    A) Thevitin, the active glycosides of yellow oleander, may cross the placenta.

Laboratory Monitoring

    A) These cardiac glycoside compounds are best identified by radioimmunoassay.
    B) Monitor vital signs and fluid status following an exposure. Monitor electrolytes as necessary if GI loss is significant.
    C) Serum potassium should be monitored as severe hyperkalemia may develop as related to cardiac toxicity. In addition, monitor serum calcium and magnesium.
    D) Obtain an immediate ECG and serials ECGs following an exposure. Institute continuous cardiac monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Obtain an ECG and institute continuous cardiac monitoring. Vomiting and diarrhea can develop following ingestion. Monitor fluid status and replace fluids with IV therapy. Antiemetics (eg, metoclopramide, ondansetron) may be necessary following persistent symptoms. Monitor potassium, magnesium and calcium; correct electrolyte abnormalities as necessary. Monitor vital signs. Hypotension can develop. Initially treat with IV fluids, followed by dopamine, norepinephrine as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor ECG and institute continuous cardiac monitoring. Monitor fluid status. Consider treatment with Digoxin Immune Fab in a patient who develops significant hyperkalemia or dysrhythmias; the optimal dose is unknown. It has been suggested that a higher dose is required than observed in digoxin poisoning. If digoxin immune Fab is not available, atropine, cardiac pacing are alternatives to treat dysrhythmias.
    a) BRADYCARDIA/BRADYARRHYTHMIAS: Atropine may be used to treat bradycardia, symptomatic bradyarrhythmias (ie, AV block). Initially treat with bolus doses of 2 to 3 mg followed by small doses of 0.3 to 0.6 mg or an infusion (0.6 mg/hour) to keep the heart rate between 70 to 90 beats per minute to avoid the development of tachycardia and/or tachyarrhythmias, including ventricular fibrillation. Temporary cardiac pacing may be needed in patients that develop significant bradycardia (ie, heart rate below 40 beats per minute), bradyarrhythmias (ie, sick sinus syndrome or heart block) unresponsive to atropine.
    b) TACHYARRHYTHMIAS: Lidocaine is the preferred agent to treat ventricular tachyarrhythmias. It has also been shown to terminate complete heart block and increase heart rate. Immediate cardioversion is indicated to treat unstable rhythms. The role of IV magnesium therapy in this setting is unknown. CONTRAINDICATED: Amiodarone, quinidine, and calcium channel blockers are contraindicated because it may increase digitalis concentrations, and beta-blockers may worsen heart block.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be considered if the exposure is recent and potentially toxic and the patient is awake and able to protect their airway.
    2) HOSPITAL: A single dose of activated charcoal is suggested following a recent ingestion in patients that are awake or the airway can be protected. Repeated doses of activated charcoal: Studies on mutli-dose activated charcoal (MDAC) in yellow oleander ingestions show a potential benefit to its administration; however, clinical trials have shown conflicting results. DOSE: Optimal dose not established. ADULT: Initial dose of 50 to 100 g activated charcoal, administer subsequent doses at 1, 2 or 4 hour intervals at a dose equivalent to 12.5 g/hour. CHILD (1 to 12 years): Initial dose of 25 to 50 g activated charcoal, administer subsequent doses at 1, 2 or 4 hour intervals at a rate equivalent to 6.25 g/hr. Continue until clinical and laboratory parameters are improving. Use of cathartics are NOT routinely recommended. Evaluate frequently for ability to protect airway and evidence of decreased peristalsis or obstruction.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a mild to moderate exposure; airway management may be necessary following severe toxicity (ie, cardiac toxicity; unstable tachyarrhythmias).
    E) ANTIDOTE
    1) Based on evidence from clinical trials, Digoxin Immune Fab is the treatment of choice for moderate to severe poisoning; however, the ideal dose regimen is unknown. A suggested dose: 400 mg over 20 minutes followed by 400 to 800 mg over 4 to 8 hours by IV infusion to provide a therapeutic concentration for a longer period.
    F) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion have not been shown to be effective following cardiac glycoside poisoning due to their large volume of distribution; however, these effects have not been studied in yellow oleander. Forced diuresis is also not known to be effective.
    G) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Observation is only appropriate in a 24 hour observation unit with a high level of care.
    2) ADMISSION CRITERIA: All patients should have continuous ECG monitoring and be admitted for 24 hour observation.
    3) CONSULT CRITERIA: Consult a medical toxicologist or poison center if the diagnosis is unclear or further support is necessary. Consult a cardiologist as needed.
    H) PITFALLS
    1) Do not underestimate the potential for significant cardiac toxicity.
    I) TOXICOKINETICS
    1) Well-absorbed orally. Elimination half-life is 5 hours in cats.
    J) DIFFERENTIAL DIAGNOSIS
    1) Organophosphates may also result in vomiting and bradycardia, although this cholinergic toxidrome should be distinguishable from cardiac glycoside toxicity. Make every attempt to accurately identify the causative agent.
    0.4.4) EYE EXPOSURE
    A) Remove contact lenses and irrigate eyes with copious amounts of room temperature sterile saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Remove contaminated clothing and wash exposed area thoroughly with soap and water.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established; toxicity appears to vary depending on the part of the plant ingested, toxin concentration of a particular plant part and general health and age of the individual exposed. One to 2 fruits are thought to be potentially fatal in a child and as few as 8 to 10 T. peruviana seeds can be fatal in an adult. Death has occurred in 2 to 20 hours following ingestion. Ingestion of 5 to 15 N. oleander leaves had been fatal and it has been suggested that even one leaf may be fatal in a child. The dried fruit also remains toxic.

Clinical Effects

Summary Of Exposure

    A) USES: This plant is an ornamental shrub and is not used in pharmaceuticals. Thevetia plants are ornamental shrubs and are widespread in tropical and subtropical regions including the southern United States and Hawaii.
    B) PHARMACOLOGY: Cardiac glycosides inhibit sodium and potassium ATPases, gradually increasing calcium ions which affect electrical conduction and results in bradycardia and dysrhythmias.
    C) TOXICOLOGY: All parts of the plant contain cardiac glycosides. However, the seeds have the highest concentration. Effects of the glycosides are similar to digitalis but with a more rapid onset.
    D) EPIDEMIOLOGY: Serious cases are uncommon, possibly due to the bitter taste and spontaneous vomiting, but exposures occur frequently. There is potential for serious toxicity and death. Poisoning may occur after accidental ingestion, suicide, homicide, or after inhalation of smoke from fires in which oleander is burning. Approximately 13% of cases never develop symptoms. Poisoning due to deliberate ingestion of yellow oleander seeds (Thevetia peruvian) has resulted in significant morbidity and mortality in South Asia.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: INGESTION: May result in vomiting, diarrhea, abdominal pain, dizziness and palpitations. DERMAL: Dermal exposures may result in blistering or dermatitis.
    2) SEVERE TOXICITY: May result in ECG changes such as AV block, bradycardias, T-wave changes, ST depression, and ectopic beats. Hypertension followed by hypotension may also occur. Severe hyperkalemia has occurred. Severely poisoned patients often die of persistent ventricular fibrillation.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Significant bradycardia has been reported following exposure.
    2) Hypertension has been reported initially, followed by hypotension secondary to bradycardia.
    3.3.4) BLOOD PRESSURE
    A) Blood pressure may initially be elevated, which can be follow by hypotension.
    3.3.5) PULSE
    A) Bradycardia can develop (Fonseka et al, 2002) and was reported frequently (49.5%) in one case series of 170 patients (Saravanapavananthan & Ganeshamoorthy, 1988).

Heent

    3.4.1) SUMMARY
    A) Irritation of the eyes may be caused by the thick, white sap of this tree. Irritation and a burning sensation may also develop in the mouth and throat after chewing the leaves. Tingling, dryness of the throat, and dilated pupils may occur.
    3.4.3) EYES
    A) Dilated pupils may occur (Morton, 1971).
    B) Eye irritation may be caused by the thick, white sap of this tree (Pearn, 1987).
    3.4.6) THROAT
    A) An initial burning sensation of the mouth after chewing is followed by tingling and dryness of the throat (Saravanapavananthan & Ganeshamoorthy, 1988; Morton, 1971).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension has been reported initially (Morton, 1971) followed by hypotension secondary to bradycardia.
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) The following ECG changes were reported in one case series of 170 patients (Saravanapavananthan & Ganeshamoorthy, 1988):
    1) Atrial Ectopic Beats - 2.8%
    2) AV Block - 52.4%
    3) Bradycardia - 49.5%
    4) ST Depression - 23.8%
    5) T Wave Changes - 35.2%
    6) Ventricular Ectopy - 6.6%
    b) Multiple and varying cardiac rhythms (associated with sino- atrial and atrio-ventricular blocks), ST depression, ventricular excitability, and poor response to atropine are signs of poor prognosis (Sreeharan, 1985).
    c) In a study of 351 patients, most symptomatic patients had conduction defects at the sinus node and/or the atrio-ventricular (AV) node. Moderately toxic patients developed PR interval prolongation proceeding to AV dissociation. Severely poisoned patients died of persistent ventricular fibrillation. The mean cardiac glycoside level in patients with AV block was 2.88 nmol/L (range 1.25 to 4.46), while those with sinus node dysfunction was 2.68 nmol/L (range 1.82 to 3.84) and in both AV block and sinus node dysfunction was 3.10 nmol/L (range 2.24 to 4.16) (Eddleston et al, 2000).
    d) In a study of 300 yellow oleander seed ingestions with suicidal intent, 12% of the patients had palpitations, while 46% had some type of dysrhythmia. Sinus bradycardia was present in 49% of the patients and ischemic ECG changes were noted in 39% of the patients (Bose et al, 1999).
    e) In a study of 65 patients that intentionally ingested yellow oleander seeds (amount not described), conduction abnormalities including the sinus node or AV node occurred in 84% of cases. Bradyarrhythmias, similar to digitalis toxicity, occurred in 58.5% of patients. First degree heart block was commonly observed among patients with bradyarrhythmias and atrial fibrillation was common in patients with tachyarrhythmias. Twelve patients (18.4%) developed life-threatening (ie, second-degree heart block type II, third-degree heart block and nodal bradycardia) arrhythmias. Two patients died following the development of third-degree heart block and ventricular fibrillation (Pirasath & Arulnithy, 2013).
    C) HEART BLOCK
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a series of 168 patients with yellow oleander poisoning, 6 deaths occurred and 4 were related to third-degree heart block. The estimated number of seeds ingested was a mean of 2.07 seeds (median 3, range 1-10). Of the remaining 162 patients, 25 patients (14.8%) developed dysrhythmias including 10 patients that required temporary cardiac pacing due to second-degree heart block (Mobitz Type II) (n=4), and third-degree heart block (n=6) (Fonseka et al, 2002).
    b) First degree heart block was noted in one patient approximately 6 to 8 hours after ingestion of yellow oleander seeds, with complete heart block occurring one hour later (Ahlawat et al, 1994).
    c) SMOKE INHALATION: A family of 4 (2 adults and 2 children) living in rural India developed oleander (thevetia peruviana) toxicity following chronic exposure to smoke from burning oleander twigs for 3 months as an energy source for both heating and cooking in a poorly ventilated room. A 32-year-old healthy woman developed initial symptoms of weakness and dizziness and a syncopal episode 2 days prior to admission. Her heart rate was 36 beats/min with a blood pressure of 70/40 mm Hg; an ECG showed a second-degree type I atrioventricular heart block. Routine laboratory studies were normal. Her 2 children, an 8 year-old boy and a 14 year-old girl, also developed weakness. They both had irregular heart rates in the 40s. Sinus bradycardia with second-degree block was noted in the boy, while first-degree atrioventricular block was observed in the girl. The husband, a manual worker who spent more time outside the home, was asymptomatic but had a heart rate of 48 beats/min with occasional premature ventricular contractions and diffuse ST depression in lateral leads with a short QT interval on ECG. All 4 individuals had a digoxin concentration drawn and were as follows: 8.69 (mother), 5.24 (son), 4.65 (daughter) and 3.98 (husband) mmol/dL. The mother developed the most severe toxicity and it was found that she spent 4 to 6 hours daily exposed to the smoke. No other source for toxicity was found. Testing of the food (ie, possibly stirring the food with an oleander stick or leaving the food uncovered) and water source were negative for the oleander toxin; however, oleander toxin could not be confirmed in the blood. Each family member recovered uneventfully following decontamination with activated charcoal and normalization of rhythm over several days (Senthilkumaran et al, 2011).
    D) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a series of 168 patients with yellow oleander poisoning, 29 (17.3%) patients developed a heart rate between 40 to 60 bpm and 15 patients (9%) developed a heart rate of less than 40 bpm. The estimated number of seeds ingested was a mean of 2.07 seeds (median 3, range 1 to 10) (Fonseka et al, 2002).
    b) Bradycardia has been reported following ingestions from one-half to 15 yellow oleander seeds and may be prolonged (Eddleston et al, 2000; Bose et al, 1999; Ahlawat et al, 1994). One patient who ingested an unknown number of seeds developed a heart rate of 30 beats per minute, was unresponsive to atropine administration, and died (Ahlawat et al, 1994).
    E) HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Subendocardial and perivascular hemorrhage with focal myocardial edema was found during autopsies of 14 patients who died following yellow oleander seed ingestions (Bose et al, 1999).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Giddiness or dizziness were reported in 35.9% of the patients in one study (Saravanapavananthan & Ganeshamoorthy, 1988).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting is a common early symptom of yellow oleander ingestion (Pirasath & Arulnithy, 2013; Frohne & Pfander, 1984), occurring in 68.2% in one large series (Saravanapavananthan & Ganeshamoorthy, 1988). Vomiting may occur with most plant parts, including the seed and the flowers (Ahlawat et al, 1994). In a study of 300 ingestions involving one-half to 15 crushed yellow oleander seeds, vomiting was present in 30.66% of the cases (Bose et al, 1999). In another study of 65 patients that intentionally ingested yellow oleander seeds, vomiting occurred in 81.5% (n=53) (Pirasath & Arulnithy, 2013).
    B) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Numbness and a burning sensation of the mouth may develop after chewing a seed (Saravanapavananthan & Ganeshamoorthy, 1988; Morton, 1971).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may occur after ingestion of various plant parts (Morton, 1971), with an incidence of 22.3% in one large series (Saravanapavananthan & Ganeshamoorthy, 1988). It usually presents with vomiting (most common) and abdominal pain (Pirasath & Arulnithy, 2013).
    D) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain may occur with most plant parts, including the seed and the flowers (Ahlawat et al, 1994). Abdominal pain usually presents with vomiting (most common) and diarrhea (Pirasath & Arulnithy, 2013).
    b) In one study of 300 ingestions involving one-half to 15 crushed yellow oleander seeds, 4% of the patients developed epigastric pain and 4% of the patients reported a burning sensation over the abdomen (Bose et al, 1999).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DIARRHEA BLOODY
    a) Bloody diarrhea has been reported in animals poisoned by ingestion (Pearn, 1987).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) The sap of this tree may cause blistering or dermatitis on contact (Morton, 1971). Erythematous and painful rash on the face and lips were symptoms often reported in cases of childhood ingestion (Ansford & Morris, 1981) (Shaw & Pearn, 1979).
    B) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Erythema around the mouth and face was reported in a fatal poisoning in a 3-year-old child (Ansford & Morris, 1981).

Reproductive

    3.20.1) SUMMARY
    A) Thevitin, the active glycosides of yellow oleander, may cross the placenta.
    3.20.2) TERATOGENICITY
    A) SEIZURES
    1) Seizures were noted in a neonate approximately 40 hours after birth following maternal ingestion of 2 yellow oleander seeds 12 hours prior to delivery. At birth, the child had normal heart rate and reflexes. There were no congenital abnormalities, birth injury, birth asphyxia, or cardiac dysrhythmias, and blood and CSF laboratory values were normal. The child did not develop further seizures during the hospital stay of 3 days, and has stayed seizure-free for the first 3 years of life (Thilagar et al, 1986). Because there were no glycoside levels drawn, the association between the seizures of the neonate and maternal ingestion of oleander seeds is primarily circumstantial.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) These cardiac glycoside compounds are best identified by radioimmunoassay.
    B) Monitor vital signs and fluid status following an exposure. Monitor electrolytes as necessary if GI loss is significant.
    C) Serum potassium should be monitored as severe hyperkalemia may develop as related to cardiac toxicity. In addition, monitor serum calcium and magnesium.
    D) Obtain an immediate ECG and serials ECGs following an exposure. Institute continuous cardiac monitoring.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum potassium (Lampe & McCann, 1985) as severe hyperkalemia may develop.
    2) Monitor serum calcium and magnesium in symptomatic patients.
    B) OTHER
    1) FAB FRAGMENTS: Serum digoxin concentrations will rise precipitously after the administration of Digibind(R) if magnetic or inert solid phase antibody separation methods are used (Gibb et al, 1983). If polyethylene glycol or dextran coated charcoal is used, digoxin levels will decrease after Digibind(R) (Gibb et al, 1983).
    2) Serum digoxin concentration can be clinically misleading when digoxin Fab fragments are present because the Fab fragments interfere with digitalis immunoassay measurements (Personal Communication, 1989).
    3) An evaluation of 28 assay methods showed 7 methods that could accurately measure free digoxin in the presence of Fab fragments. These assays were (Hansell, 1989):
    1) Abbott PEG
    2) Baxter Healthcare STRATUS
    3) Becton Dickinson ARIA HT
    4) Becton Dickinson ARIA II
    5) Becton Dickinson Solid Phase
    6) Leeco Diagnostics
    7) Nuclear Medical Laboratories
    4) Unbound, biologically active digoxin was accurately measured in the presence of Fab in serum obtained from a 19-month-old child by the Stratus(R) fluorometric enzyme immunoassay (Baxter) (Senecal et al, 1991).
    C) LABORATORY INTERFERENCE
    1) Glycosides found in oleander may cross-react with antibodies found in most radioimmunoassay kits and result in digoxin being reported as being present (Langford & Boor, 1996; Shumaik et al, 1988; Haynes et al, 1985). Anti-digitoxin antibody will react with thevetin B genin, which is structurally identical to digitoxigenin (Uber-Bucek et al, 1992).
    a) Although early studies showed there is no correlation of the serum level and toxicity in yellow oleander cases (Osterloh, 1988), a study of 351 cases showed that, in general, higher serum cardiac glycoside concentrations were associated with hyperkalemia, cardiac dysrhythmias requiring specialized treatment, and conduction defects affecting both the sinus and atrio-ventricular nodes (Eddleston et al, 2000).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Should be performed in cases of significant exposure. A baseline ECG should be considered even for asymptomatic patients (Pearn, 1987).
    b) EKGs done while patients were taking thevetin orally showed digitalis-like changes, including increased P-R interval, inverted T-waves, changes in the ST segments and QRS complexes (Arnold et al, 1935).

Methods

    A) IMMUNOASSAY
    1) These cardiac glycoside compounds are best identified by radioimmunoassay.
    2) The Abbott TDx analyzer, used with Digoxin II reagent will help identify these glycosides in the serum. Although cross-reactivity exists, the concentration relationship is not linear (Cheung et al, 1989).
    3) Fluorescence polarization immunoassay can be used to determine thevetin B (cardiac glycoside). The thevetin B genin is structurally identical to digitoxigenin. A 94% cross-reactivity was found for these two agents, within the concentrations of 5 to 80 nanograms/milliliter (ng/mL) (Uber-Bucek et al, 1992).

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 should have continuous ECG monitoring and be admitted for 24 hour observation.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center if the diagnosis is unclear or further support is necessary. Consult a cardiologist as needed.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Observation is only appropriate in a 24 hour observation unit with a high level of care.

Monitoring

    A) These cardiac glycoside compounds are best identified by radioimmunoassay.
    B) Monitor vital signs and fluid status following an exposure. Monitor electrolytes as necessary if GI loss is significant.
    C) Serum potassium should be monitored as severe hyperkalemia may develop as related to cardiac toxicity. In addition, monitor serum calcium and magnesium.
    D) Obtain an immediate ECG and serials ECGs following an exposure. Institute continuous cardiac monitoring.

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) MULTIPLE DOSE ACTIVATED CHARCOAL
    1) SUMMARY: Single dose activated charcoal administration may not be effective in the treatment of cardiac glycosides intoxication as seen with yellow oleander ingestions. Multiple-dose activated charcoal administration has been shown to increase excretion of digoxin in humans and may be useful in yellow oleander poisoning (Eddleston & Warrell, 1999; Eddleston et al, 1999). Its suggested that activated charcoal may act to prevent the initial absorption of the toxic glycosides found in yellow oleander, as well as prevent the reabsorption of the toxin after intestinal secretion from systemic circulation (deSilva et al, 2008).
    2) In a single-blind, randomized, placebo-controlled trial, 401 patients who had ingested yellow oleander received one dose of activated charcoal, and were then randomly assigned to receive 50 g of activated charcoal every 6 hours for 3 days or sterile water. Of the 201 patients who received multiple-dose activated charcoal, 5 (3%) died as compared to 16 (8%) patients in the placebo (n=200) group (95% CI 0.16 to 10.3; p=0.025). Multiple-dose activated charcoal also reduced the number of individuals requiring intensive supportive care (5 treatment vs. 16 placebo), temporary pacing (0 treatment vs. 11 placebo), and antidigoxin antibody Fab fragments (0 treatment vs. 7 placebo). The authors concluded that multiple-dose activated charcoal was effective in reducing both morbidity and mortality following yellow oleander exposure (deSilva et al, 2008).
    3) In a single blind, randomized, placebo-controlled study, multiple dose activated charcoal was found to be safe and effective in reducing death (relative risk 0.31, 95% Confidence Interval [CI] 0.12 to 0.83) and life-threatening cardiac dysrhythmias (relative risk 0.21, 95% CI 0.06 to 0.71) after yellow oleander poisoning (Roberts & Buckley, 2006; de Silva et al, 2003).
    4) MULTIPLE DOSE ACTIVATED CHARCOAL
    a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
    b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
    c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
    d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
    e) Vomiting is a common adverse effect; antiemetics may be necessary.
    f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
    g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).
    B) WHOLE BOWEL LAVAGE
    1) Whole bowel lavage may be useful in removing plant material from the gastrointestinal tract after large ingestions
    a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.
    1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.
    b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
    c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
    d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Obtain an ECG and institute continuous cardiac monitoring. Vomiting and diarrhea can develop following ingestion. Monitor fluid status and replace fluids with IV therapy. Antiemetics (eg, metoclopramide, ondansetron) may be necessary following persistent symptoms. Monitor potassium, magnesium and calcium; correct electrolyte abnormalities as necessary. Monitor vital signs. Hypotension can develop. Initially treat with IV fluids, followed by dopamine, norepinephrine as necessary.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor ECG and institute continuous cardiac monitoring. Monitor fluid status. Consider treatment with Digoxin Immune Fab in a patient who develops significant hyperkalemia or dysrhythmias; the optimal dose is unknown. It has been suggested that a higher dose is required than observed in digoxin poisoning. If digoxin immune Fab is not available, atropine, cardiac pacing are alternatives to treat dysrhythmias.
    1) BRADYCARDIA/BRADYARRHYTHMIAS: Atropine may be used to treat bradycardia, symptomatic bradyarrhythmias (ie, AV block). Initially treat with bolus doses of 2 to 3 mg followed by small doses of 0.3 to 0.6 mg or an infusion (0.6 mg/hour) to keep the heart rate between 70 to 90 beats per minute to avoid the development of tachycardia and/or tachyarrhythmias, including ventricular fibrillation. Temporary cardiac pacing may be needed in patients that develop significant bradycardia (ie, heart rate below 40 beats per minute), bradyarrhythmias (ie, sick sinus syndrome or heart block) unresponsive to atropine.
    2) TACHYARRHYTHMIAS: Lidocaine is the preferred agent to treat ventricular tachyarrhythmias. It has also been shown to terminate complete heart block and increase heart rate. Immediate cardioversion is indicated to treat unstable rhythms. The role of IV magnesium therapy in this setting is unknown. CONTRAINDICATED: Amiodarone, quinidine, and calcium channel blockers are contraindicated because it may increase digitalis concentrations, and beta-blockers may worsen heart block.
    B) ELECTROCARDIOGRAPHIC PROCEDURE
    1) Obtain a baseline ECG and institute continuous cardiac monitoring.
    2) All cases should have electrocardiographic monitoring and be admitted overnight. A baseline ECG should be obtained even in asymptomatic cases (Pearn, 1987).
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) DIGOXIN IMMUNE FAB (OVINE)
    1) SUMMARY
    a) There is limited human experience in the use of digoxin immune FAB for the treatment of cardiac glycoside toxicity from plants. Consider the use of digoxin immune FAB in patients with significant cardiac dysrhythmias (ie, AV node and/or severe sinus node block, ventricular arrhythmias) or hyperkalemia (potassium greater than 5.5) following a Thevetia ingestion. Optimal dose is not known. A suggested dose: 400 mg over 20 minutes followed by 400 to 800 mg over 4 to 8 hours by IV infusion to provide a therapeutic concentration for a longer period (Bandara et al, 2010).
    b) In a randomized controlled trial, anti-digoxin Fab antitoxin decreased the presence of cardiac dysrhythmias 2 hours post-administration (relative risk 0.60, 95% Confidence Interval [CI] 0.44 to 0.81) (Roberts & Buckley, 2006; Eddleston et al, 2000a).
    c) CASE REPORTS
    1) ADULT: A patient suspected of ingesting Nerium oleander (containing glycosides similar to yellow oleander) was given 5 vials of digoxin immune FAB (Digibind(R)) with subsequent increase in his heart rate from 30 to 45 with irregular beats to 56 beats per minute (Shumaik et al, 1988).
    2) In a study of more than 300 patients with a history of oleander ingestion, 15 of 33 patients who had conduction defects of dysrhythmias and had received treatment with digoxin immune FAB, reverted to normal sinus rhythm two hours later, while in the control group, only 2 of 32 patients reverted to normal sinus rhythm (Eddleston & Warrell, 1999).
    d) ANIMAL STUDY
    1) Large doses (60 mg/kg) of digoxin immune FAB were effective in reversing dysrhythmias induced by tincture of Nerium oleander in dogs (Clark et al, 1991).
    E) CONDUCTION DISORDER OF THE HEART
    1) SUMMARY
    a) If digoxin immune Fab is available it should be administered to patients with significant dysrhythmias or hyperkalemia after a Thevetia ingestion. If digoxin immune Fab is NOT available other modalities must be considered.
    2) ATROPINE
    a) Cardiac output may be maintained in some poisonings by administering atropine (Pearn, 1987).
    b) BRADYCARDIA/BRADYARRHYTHMIAS: Atropine may be used to treat bradycardia and/or symptomatic bradyarrhythmias (ie, AV block). Initially treat with bolus doses of 2 to 3 mg followed by small doses of 0.3 to 0.6 mg or an infusion (0.6 mg/hour) to keep the heart rate between 70 to 90 beats per minute to avoid the development of tachycardia and/or tachyarrhythmias, including ventricular fibrillation (Rajapakse, 2009). For children the dose is 0.01 to 0.02 mg/kg/dose IV (maximum 0.4 mg/dose, may repeat every 4 to 6 hours) (Pagliaro & Levin, 1979).
    c) If there is no response to a trial dose, consider inserting a pacemaker.
    3) TEMPORARY CARDIAC PACING
    a) Consider temporary pacing if severe bradycardia occurs due to AV block (Bandara et al, 2010; Eddleston & Warrell, 1999; Eddleston et al, 1999; Pearn, 1987). Temporary cardiac pacing may be needed in patients that develop a heart rate below 40 beats per minutes and/or bradyarrhythmias (ie, sick sinus syndrome or heart block) that are unresponsive to atropine (Rajapakse, 2009). First degree block without ventricular extra systoles and a non-deteriorating condition does not require cardiac pacing.
    4) CARDIOVERSION
    a) In the absence of digoxin immune Fab, treat ventricular fibrillation (VF) with low energy DC cardioversion (Bandara et al, 2010).
    F) VENTRICULAR ARRHYTHMIA
    1) SUMMARY
    a) Lidocaine is the preferred agent to treat ventricular tachyarrhythmias. It has also been shown to terminate complete heart block and increase heart rate. Immediate cardioversion is indicated to treat unstable rhythms. The role of IV magnesium therapy in this setting is unknown (Rajapakse, 2009).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    G) HYPERKALEMIA
    1) MONITORING: Potassium levels should be followed hourly, along with continuous cardiac monitoring and serial ECGs.
    2) TREATMENT: Consider the use of digoxin immune FAB in patients with significant hyperkalemia. If digoxin immune Fab is NOT available, give insulin/glucose for a potassium of greater than 5.5 (Bandara et al, 2010). These agents can shift potassium intracellularly. Do NOT give calcium.
    H) CONTRAINDICATED TREATMENT
    1) POTASSIUM: Potassium is contraindicated in acute massive glycoside overdose unless there is a demonstrated hypokalemia.
    2) CALCIUM: The effects of cardiac glycosides on the myocardium are increased by elevated serum calcium levels. Administration of parenteral calcium to a digitalized patient should be accomplished with extreme caution, to avoid the possible precipitation of cardiac arrhythmias. If necessary, calcium should be administered slowly and in small quantities (Hansten & Horn, 1989) (Zucchero & Hogan, 1990).
    3) OTHER DRUG THERAPIES: Amiodarone, quinidine, and calcium channel blockers are contraindicated because it may increase digitalis concentrations, and beta-blockers may worsen heart block (Rajapakse, 2009).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) GLYCOSIDE BINDING
    1) The cardiac glycoside digoxin is similar to the oleander glycosides. The enterohepatic circulation of digoxin is reduced by administration of the bile salt binding resin, cholestyramine (Langford & Boor, 1996).
    B) LACK OF INFORMATION
    1) Hemodialysis and hemoperfusion have not been shown to be effective following cardiac glycoside poisoning due to their large volume of distribution; however, these effects have not been studied in yellow oleander (Rajapakse, 2009).
    C) LACK OF EFFECT
    1) DIALYSIS and forced diuresis are NOT of use to remove the toxin (Lampe & McCann, 1985).

Abstracts

Case Reports

    A) INFANT
    1) An 18-month-old girl was brought to the hospital 8 to 12 hours after ingesting yellow oleander fruit with lime mistaken for betel nut. The child had profuse vomiting and developed bradycardia and heart block. Symptomatic treatment was given, and the child was discharged four days later (Vince et al, 1984).
    B) PEDIATRIC
    1) A 3-year-old child was brought to a physician after several hours of vomiting. She was found to have heart block, was weak, shaking, and diaphoretic. The history involved playing under a yellow oleander tree late that afternoon. She was transferred to the hospital and had a cardiac arrest in transit. She died shortly thereafter (Ansford & Morris, 1981).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established; toxicity appears to vary depending on the part of the plant ingested, toxin concentration of a particular plant part and general health and age of the individual exposed. One to 2 fruits are thought to be potentially fatal in a child and as few as 8 to 10 T. peruviana seeds can be fatal in an adult. Death has occurred in 2 to 20 hours following ingestion. Ingestion of 5 to 15 N. oleander leaves had been fatal and it has been suggested that even one leaf may be fatal in a child. The dried fruit also remains toxic.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Although once considered as a potential therapeutic agent, the margin of safety between a therapeutic and toxic amount of thevetin is too small for safe administration (Chopra & Mukerjee. 1933). Various parts are still used today in Third World countries (Pahwa & Chatterjee, 1990).

Minimum Lethal Exposure

    A) SUMMARY
    1) Deaths have been reported in India, Florida, the Hawaiian Islands, and Australia (Pahwa & Chatterjee, 1990; Pearn, 1987; Hardin & Arena, 1974) and, in some instances, was due to cardiogenic shock (Saraswat et al, 1992).
    2) A toxic dose has not been established; toxicity appears to vary depending on the part of the plant ingested, toxin concentration of a particular plant part and general health and age of the individual exposed. Ingestion of 5 to 15 N. oleander leaves had been fatal and it has been suggested that even one leaf may be fatal in a child (Bandara et al, 2010).
    B) CASE REPORTS
    1) A level of 19 nanomoles per kilogram of cardiac glycosides was found in the heart muscle of a child lethally poisoned by yellow oleander (Ansford & Morris, 1981).
    2) One to two fruits are thought to be potentially lethal in children (Tampion, 1977) and 8 to 10 seeds in an adult. Death has occurred in 2 to 20 hours following ingestion (Saravanapavananthan & Ganeshamoorthy, 1988; Pearn, 1987; Morton, 1971; Arnold et al, 1935).
    3) In a study of 65 patients that intentionally ingested yellow oleander seeds (amount not described), conduction abnormalities including the sinus node or AV node occurred in 84% of cases. Two patients died following the development of third-degree heart block and ventricular fibrillation (Pirasath & Arulnithy, 2013).

Maximum Tolerated Exposure

    A) SUMMARY
    1) In a retrospective study of 13 patients, who intentionally ingested yellow oleander seeds, it was found that adult patients who ingested 2 or fewer seeds had few symptoms. Those that took two or more had gastrointestinal and cardiovascular effects. If a patient reported to the hospital in less than 4 hours after ingestion and had taken 4 or fewer seeds, symptomatic and supportive treatment was adequate. If the amount was greater than 4 seeds and the patients presented later than 4 hours, the prognosis was poor (Saraswat et al, 1992).
    2) SMOKE INHALATION: A family of 4 (2 adults and 2 children) living in rural India developed oleander toxicity (thevetia peruviana) following exposure to smoke from burning oleander twigs for 3 months as an energy source for both heat and cooking in a poorly ventilated room. A 32-year-old healthy woman developed initial symptoms of weakness and dizziness and a syncopal episode. Her heart rate was 36 beats/min with a blood pressure of 70/40 mm Hg; an ECG showed a second-degree type I atrioventricular heart block. Routine laboratory studies were normal. Her 2 children, an 8 year-old boy and a 14 year-old girl, also developed weakness and had irregular heart rates in the 40s. Second-degree block was noted in the boy, while first-degree atrioventricular block was observed in the girl. The husband was asymptomatic but had a heart rate of 48 beats/min with occasional premature ventricular contractions and diffuse ST depression in lateral leads with a short QT interval on ECG. All 4 individuals had a digoxin level drawn and were as follows: 8.69 (mother), 5.24 (son), 4.65 (daughter) and 3.98 (husband) mmol/dL. The mother developed the most severe toxicity and it was found that she spent 4 to 6 hours daily exposed to the smoke. No other source for toxicity was found. Testing of the food (ie, possibly stirring the food with an oleander stick or leaving the food uncovered) and water source were negative for the oleander toxin. Oleander toxin could not be confirmed in the blood. Each family member recovered uneventfully following decontamination with activated charcoal (Senthilkumaran et al, 2011).
    3) In a study of 65 patients that intentionally ingested yellow oleander seeds (amount not described), early symptoms of toxicity included vomiting (81.5%, n=53), abdominal pain and diarrhea. Similar to digitalis toxicity conduction abnormalities including the sinus node or AV node were also common and occurred in 84% of cases. Bradyarrhythmias, similar to digitalis toxicity, occurred in 58.5% of patients. First degree heart block was commonly observed among patients with bradyarrhythmias and atrial fibrillation was common in patients with tachyarrhythmias. Twelve patients (18.4%) developed life-threatening (ie, second-degree heart block type II, third-degree heart block and nodal bradycardia) arrhythmias. Two patients died following the development of third-degree heart block and ventricular fibrillation (Pirasath & Arulnithy, 2013).
    B) ANIMAL STUDIES
    1) Frog minimal systolic dose: 0.004 to 0.005 mg/gram (Middleton & Chen, 1936)
    2) "one cat unit": 0.85 mg/kg (Middleton & Chen, 1936).

Pharmacology Toxicology

Toxicologic Mechanism

    A) There are at least 50 toxins isolated from oleanders (Jager et al, 1959). Actions include cytotoxicity, cardiac toxicity, and antibiotic activity (Pearn, 1987). In decreasing order of toxicity, the most toxic glycosides in yellow oleander are: peruvoside, ruvoside, thevetin A, nerifolin, cerebrin, and thevetin B (Ahlawat et al, 1994).Based on studies in cats, thevetin is thought to be one-seventh as potent and toxic as ouabain (Osol & Farrar, 1955; Arnold et al, 1935).
    B) The effects of the glycosides thevetin A and B and peruvoside appear to be similar to digitalis, increasing the force and speed of cardiac muscle contractions, but they have a more rapid onset (Langford & Boor, 1996; Morton, 1971). The cardiac toxins decrease the action of the molecular pump that removes sodium from cells. This inhibition of sodium and potassium ATPases gradually increases calcium ions which affects cardiac electrical conduction and results in bradycardia and arrhythmias (Langford & Boor, 1996; Ahlawat et al, 1994; Pearn, 1987).
    C) T. peruviana contains a number of toxins including thevetin A and B, nerifolin, thevetoxin, peruvoside, ruvoside, fixed oils and various gums and rubbers (Pearn, 1987; Watt & Breyer-Brandwijk, 1962; Chen & Chen, 1934). Phytosterolins, ahouain, and kokilphin were also found (Saravanapavananthan & Ganeshamoorthy, 1988).
    D) Thevetin A: Is the toxin most often studied. Thevetin has a stimulatory affect on the intestine and urinary bladder walls, and effects the heart by attaching to cell surface receptors and producing toxicity as described above (Pearn, 1987). In the mammalian heart, in small amounts, it stimulates cardiac output and coronary output, but in larger doses it cases bradycardia, T-wave inversion, P-R prolongation, A-V dissociation, ventricular tachycardia, and ventricular fibrillation (Arnold et al, 1935).

Physicochemical

Physical Characteristics

    A) Thevetin is a crystalline solid with a bitter taste (Arnold et al, 1935; Windholz et al, 1983).

Molecular Weight

    A) Not applicable

Animal Toxicology

Clinical Effects

    11.1.13) OTHER
    A) OTHER
    1) Animals ordinarily do not choose to graze on this plant, but will do so in harsh conditions (Everst, 1981). Pigs, cattle, poultry, and sheep have all been poisoned, as have fish (by the bark). The most common symptom is gastroenteritis (Pearn, 1987). This plant remains toxic even if dried (Seawright, 1982).
    2) Animal exposure can also be from drinking water or feed contaminated with oleander (Langford & Boor, 1996).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) GENERAL
    1) There are marked differences between species in the toxicity of oleander and is dependent on the affinity the oleander glycosides have with sodium and potassium ATPases of the various species. Humans, monkeys, cats, and dogs are relatively sensitive, while rodents and birds are not (Langford & Boor, 1996).
    11.3.4) MINIMUM LETHAL DOSE
    11.3.4.1) TOXICITY VALUES
    A) HORSE
    1) An estimated lethal dose is 15 to 20 g of green or dried foliage (Pearn, 1987).

References

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