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wikitox:2.3.4.1.1_yellow_oleander

Link to 2.1.6.1.1 Cardiac glycoside teaching resources


Yellow Oleander (Thevetia peruviana)

The yellow oleander tree (Thevetia peruviana, T. neriifolia, previously Cerbera peruviana) is a tree from the family Apocynacae. It has characteristic funnel shaped flowers that are typically yellow (sometimes peach) and green fruits containing one seed. It is found commonly through much of the tropics and subtropics.

yellow_oleander.jpg

OVERVIEW

A number of cardenolides have been identified in the bark, leaves, sap, seeds or fruits of the yellow oleander. Thevetin A and Thevetin B (cerebroside) are most common; others include peruvoside, neriifolin, thevetoxin, and ruvoside. Drying or heating of plant material does not inactivate the cardenolides. These cardenolides are structurally similar to those derived from Digitalis purpurea so investigations and treatments developed for digoxin and digitoxin may be useful in the management of yellow oleander poisoning.

Yellow oleander poisoning causes primarily gastrointestinal and cardiotoxic effects.

MECHANISM OF TOXIC EFFECTS

Gastrointestinal effects are secondary to local effects, although central stimulation may also contribute to this. Cardiotoxicity appears to follow inhibition of Na+ -K+ -ATPase similar to the digitalis glycosides. Animal studies suggest Thevetia cardenolides bind with increased potency, but that other mechanisms of toxicity may also be present. An increase in vagal tone may contribute to some of the toxicity noted (eg. abdominal colic and bradycardia).

KINETICS IN OVERDOSE

Absorption

Animal studies have demonstrated rapid absorption, with a bioavailability of approximately 50%. In humans, however, the absorption kinetics of Thevetia cardenolides appears to be slow and unpredictable.

Self-poisoning by ingestion of the seed may be associated with ongoing absorption for up to 50h in some patients. In others, significant absorption may not occur until 6h post-ingestion. The influence of external factors such as intravenous atropine or the extent of crushing/grinding of the seed is not known.

Distribution

The volume of distribution has not been determined in humans. In rats, neriifolin has a volume of distribution of 3-7L/kg. Animal and volunteer studies suggest that Thevetia cardenolides distribute and bind to the Na+ -K+ -ATPase more rapidly than digoxin and digitoxin.

Metabolism - Elimination

Thevetia cardenolides appear to be metabolised to active (eg. Thevetin B is converted to peruvoside; Thevetin A to neriifolin) and inactive products. There is debate regarding the extent to which these cardenolides undergo enterohepatic recycling. Renal clearance appears to be the most important route of clearance.

CLINICAL EFFECTS

Acute poisoning with yellow oleander causes primarily gastrointestinal and cardiotoxic effects. Mortality varies between 3 and 10%, depending on the resources available for treatment.

Gastrointestinal effects

Nausea, vomiting, abdominal colic and diarrhoea are seen most often. With severe poisoning, vomiting may be persistent.

Cardiac effects

Cardiac dysrhythmias such as bradycardia or an irregular pulse are the most common findings on examination. Blood pressure is generally preserved until the patient is pre-arrest. Changes in the ST segment on ECG, and conduction blocks are noted with increasing severity (see clinical grading of toxicity).

The time course for progression and resolution of cardiotoxicity is variable. It is not uncommon for patients to interchange between mild, moderate and severe cardiotoxicity frequently. The mechanism for this is not known, but may relate to the absorption kinetics from the seed. Some patients were asymptomatic for 24h before developing toxicity, while others had mild toxicity for 72h before developing severe toxicity. Up to 40% of patients with severe cardiotoxicity may revert to sinus rhythm after a number of hours without specific treatment, but there is insufficient information to determine which patients will revert and which will require specific treatment.

Cardiac arrest occurs with severe poisoning, usually due to ventricular fibrillation which is often resistant to electrical cardioversion. Ventricular ectopics and tachydysrhythmias are otherwise rare in patients with yellow oleander poisoning without coexistent heart disease.

Central nervous system effects

Weakness, dizziness, confusion or coma and have been reported, but these effects are rare.

Metabolic effects

Hyperkalaemia may be noted in severe poisoning, although it is neither a sensitive nor specific marker of severity.

Other effects

Renal and hepatic abnormalities have been reported, but these effects are rare. Transient increases in creatinine have been noted in some patients.

DETERMINATION OF SEVERITY

The assessment of severity of toxicity is determined by clinical grading of toxicity.

Ingested dose

There is a poor correlation between the number of seeds ingested and the severity of cardiotoxicity. Death has occurred after ingestion of one or two seeds; in contrast, patients have survived without after consuming ten or more seeds without requiring specialised treatments.

Clinical grading of toxicity

Patients with acute poisoning with yellow oleander seeds must be closely monitored for changes in severity of cardiotoxicity. Death generally occurs 6-24h post-exposure.

Asymptomatic No abnormalities on physical or laboratory examination
Mild Predominantly gastrointestinal symptoms with flattening or inversion of the T wave and depression of the ST segment
Moderate First degree heart block, sinus bradycardia, sick sinus syndrome (sinus arrest or sinus block)
Severe Second or third degree heart block Ventricular fibrillation Death

INVESTIGATIONS

Biochemistry

Patients should have serum electrolytes, creatinine and urea.

Because of the structural similarities of the cardenolides with digoxin, digoxin assays may be used to measure the concentration of digoxin cross-reacting substances (DXS) in the plasma. Since these assays measure an unknown proportion of these compounds, the correlation with the actual plasma concentration of cardenolides is unknown. Although higher plasma concentrations of DXS are associated with increased toxicity, these concentrations do not appear to provide prognostic information, or guide therapy.

When two different brands of digoxin assay are used to measure the DXS concentration in patients who have ingested non-digoxin cardenolides, different concentrations are reported. In contrast, similar results are noted with digoxin. This simple test may be useful to confirm the diagnosis of non-digitalis cardenolide poisoning.

ECG

Baseline then as indicated clinically. Continuous cardiac monitoring is recommended in all patients with mild, moderate or severe poisoning.

TREATMENT

Supportive

  • Cardiac monitoring should be available, and patients who have ingested yellow oleander seeds should be monitored for 72h if possible
  • Antiemetics should be administered as required
  • Hypotension should be treated initially with intravenous fluids
  • Hypokalaemia and hypomagnesaemia should be corrected
  • On the basis of current data, hyperkalaemia should not be reversed
  • Temporary cardiac pacing has been advocated for treatment of severe cardiotoxicity despite administration of antidotes. Efficacy data regarding this treatment is lacking, and there are theoretical concerns regarding electrical pacing of an irritable myocardium with elevated intracellular calcium

Antidotes

Atropine
Atropine (0.6mg bolus) may be useful for reversing bradycardia on the basis of clinical experience, although no studies have assessed the efficacy of this treatment. No data is available for which to recommend anti-arrhythmics and isoprenaline (isoproterenol) infusions are not recommended for treatment of bradycardia given its potential to precipitate ventricular ectopy.

Digoxin antibodies
Anti-digoxin Fab antitoxin, if available, is the first line treatment for reversal of cardiotoxicity from cardenolide poisoning. The indications for use will vary between institutions depending on resources available. The randomised controlled trial which established the safety of Fab antitoxin (Eddleston et al 2000) administered Fab using the following criteria: 2nd or 3rd degree AV block, sinus bradycardia <40 beats/min, sinus arrest or exit block, atrial tachyarrhythmias, hypotension (SBP<80mmHg) and bradycardia or ventricular tachycardia associated with shock. Since the dose of cardenolide is not known, an empiric intravenous dose of 1200mg of Fab is recommended. It is important to note that some patients may redevelop dysrhythmias after treatment with anti-digoxin Fab antitoxin, which may relate to ongoing absorption or redistribution of the cardenolides to the central circulation. Monitoring for 24-48h post-administration of the Fab antitoxin is therefore recommended.

GI Decontamination

Oral activated charcoal should only be given if the patient presents within 1 hour of ingestion. Since the duration of absorption phase may be prolonged, administration of activated charcoal beyond that time may be appropriate in patients who are cooperative.

Given the prolonged absorption phase following ingestion of the seeds, and because cardiotoxicity is usually delayed, whole bowel irrigation may be useful. There is limited experience with this treatment in the management of acute yellow oleander poisoning.

Elimination enhancement

Multiple doses of activated charcoal (MDAC) have been proposed as a treatment for yellow oleander poisoning given the potential for enterohepatic recycling of the cardenolides. Two randomised controlled trials have assessed the efficacy of MDAC for acute yellow oleander poisoning, with conflicting results. The true effect of MDAC is unclear since these studies differed in their design (n=401, 50g q6h for 12 doses (de Silva 2003); n=1571, 50g q4h for 6 doses (Eddleston 2005)). It is therefore not unreasonable to administer MDAC to cooperative patients, although it should not be used in preference to other treatments.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis should include other cardenolide poisonings, depending on regional variations.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP

Long-term sequale have not been reported.

REFERENCES

Roberts DM, Eddleston M. Yellow oleander poisoning. In: Nayyar V, editor. Critical Care Update 2004. 1 ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2005. p. 189-200
Eddleston M, Rajapakse S, Jayalath S, Sjostrom L, Santharaj W, Thenabadu PN et al. Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000;355(9208):967-72.
Eddleston M, Juszczak E, Buckley NA, Senarathna L, Mohomed F, Sheriff MHR et al. Randomised controlled trial of routine single or multiple dose superactivated charcoal for self-poisoning in a region with high mortality. Clin.Toxicol. 2005;43:442-3
de Silva HA, Fonseka M, Pathmeswaran A, Alahakone D, Ratnatilake GA, Gunatilake SB et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet 2003;361(9373):1935-8
Juurlink DN, Sivilotti MLA. Multidose activated charcoal for yellow oleander poisoning. Lancet 2003;362:58
Eddleston M, Ariaratnam CA, Sjostrom L, Jayalath S, Rajakanthan K, Rajapakse S et al. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart 2000;83(3):301-6.
Eddleston M, Senarathna L, Mohammad FK, Buckley N, Juszczak E, Sheriff MHR et al. Deaths due to a lack of an affordable antitoxin for plant poisoning. Lancet 2003;362:1041-4
Eddleston M, Ariaratnam CA, Meyer WP, Perera G, Kularatne AM, Attapattu S et al. Epidemic of self-poisoning with seeds of the yellow oleander tree (Thevetia peruviana) in northern Sri Lanka. Tropical Medicine & International Health 1999;4(4):266-73.
Saravanapavananthan N, Ganeshamoorthy J. Yellow oleander poisoning - a study of 170 cases. Forensic Sci.Int. 1988;36:247-50.
Fonseka MM, Seneviratne SL, de Silva CE, Gunatilake SB, de Silva HJ. Yellow oleander poisoning in Sri Lanka: outcome in a secondary care hospital. Hum Exp.Toxicol 2002;21(6):293-5
Langford SD, Boor PJ. Oleander toxicity: an examination of the human and animal toxic exposures. Toxicol. 1996;109:1-13.
Rao EV. Cardiac glycosides of Thevetia peruviana and Cerbera odollam. The Indian Journal of Pharmacy 1973;35(4):107-13
Cheung K, Hinds JA, Duffy P. Detection of poisoning by plant-origin cardiac glycosides with the Abbott TDx analyser. Clin.Chem. 1989;35:295-7.


wikitox/2.3.4.1.1_yellow_oleander.txt · Last modified: 2018/09/01 09:00 (external edit)