|Year : 2022 | Volume
| Issue : 2 | Page : 82-88
Review of current evidence in management of oleander poisoning
Vineeth Varghese Thomas, Nalini Newbigging, Jacob Johnson, Murugabharathy Kalimuthu, Karthik Gunasekaran, Ramya Iyadurai
Department of General Medicine, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
|Date of Submission||14-Dec-2021|
|Date of Decision||24-Jan-2022|
|Date of Acceptance||03-Feb-2022|
|Date of Web Publication||07-May-2022|
Dr. Vineeth Varghese Thomas
Christian Medical College and Hospital, Vellore - 632 002, Tamil Nadu
Source of Support: None, Conflict of Interest: None
India has a high incidence of poisoning, especially in the rural setting with plant-based compounds being used as a common agent. Oleander poisoning is a common shrub seen throughout the tropics including nearly all parts of India. It continues to remain an important cause for both accidental and deliberate self-harm in the community with all parts of the plant containing toxin sufficient to cause poisoning. There is enough evidence to show that oleander poisoning continues as one of the more common plant-based causes for poisoning. This review looks at the common management principles and provides an update on the currently available treatment strategies and evidence for them.
Keywords: Nerium oleander, oleander, plant toxin, Thevetia peruviana
|How to cite this article:|
Thomas VV, Newbigging N, Johnson J, Kalimuthu M, Gunasekaran K, Iyadurai R. Review of current evidence in management of oleander poisoning. Curr Med Issues 2022;20:82-8
|How to cite this URL:|
Thomas VV, Newbigging N, Johnson J, Kalimuthu M, Gunasekaran K, Iyadurai R. Review of current evidence in management of oleander poisoning. Curr Med Issues [serial online] 2022 [cited 2022 May 25];20:82-8. Available from: https://www.cmijournal.org/text.asp?2022/20/2/82/344926
| Introduction|| |
Plant-based compounds are a common cause of poisoning in India which has a large floral biodiversity. The use of these compounds is estimated to be as high as 65% in rural populations. Although there is no national or state-wise breakdown of these data, cardiac glycoside toxicity secondary to oleander poisoning is still common in our community due to its availability in most parts of the country and its toxin profile. There has been a wealth of research in the assessment of severity and management of poisoning. A previous study involving plant-based poisoning in this institute found that 7% of all deliberate self-harm was due to plant poisons with a mortality rate of 20%., This review aims to review current concepts concerning cardiac glycoside poisoning and to review the current evidence for the management of this population.
| Cardiac Glycosides|| |
Cardiac glycosides are compounds that increase the cardiac output of the heart by increasing the stroke volume. These are not new compounds and there is evidence that it was used as a poison. They are naturally occurring organic compounds that consist of a steroid attached to a sugar and an R group. They are present in nature and can be divided into the cardenolides which are purely plant based or the bufadienolides which are extracted from the venom of Bufo marinus (cane toad) which is native to South America. [Table 1] comprises the classification of cardiac glycosides and their source.
|Table 1: Classification of glycosides based on their plant species and toxin|
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| Mechanism of Toxicity|| |
Cardiac glycosides have a mechanism of action similar to digoxin. They act by inhibiting the activity of the Na-K-ATPase pump present on the cellular membrane of the myocardium. This, in turn, increases intracellular Na+ ions in plasma which affects the normal functioning of the Na-Ca exchanger. This results in increased intracellular calcium which results in increased inotropic effect or cardiac contractility.,
The effects of the toxin on cardiac conduction based on previous studies have shown that although there is some action affecting the effective refractory period on the atrium, it is at the atrioventricular (AV) node where its maximum effect can be appreciated, thereby reducing the heart rate. In pharmacological studies of denervated hearts, this action was very negated. This negative chronotropic effect is mediated via augmentation of vagal activity.
Digitalis is extracted from the dried leaves of Digitalis purpurea while the toxin from oleander (or yellow oleander) has a different toxin compound. The toxins from Digitalis and oleander are from the same family of cardenolides which are cardiac glycosides. While they are not the exact compound, there is minor cross-reactivity in biochemical analysis.
| Characteristics of Oleander Plant|| |
Both oleander (Nerium oleander) and yellow oleander (Thevetia peruviana) are from the same family “Apocynaceae” and produce cardenolide toxins.
The differences between them are:,
- Target organs
- Nerium: Glycosides that induce cardiac arrhythmias and eventually death
- Thevetia: Glycosides with Digitalis-like action on the heart and severe gastrointestinal (GI) irritation.
- Primary toxin
- Nerium: Oleandrin, oleandrine, and oleandrigenin
- Thevetia: Thevetin A and thevetin B
- Poisonous parts
- Nerium: All parts are toxic including the sap, either fresh, dried, or boiled.
A single leaf has also been reported to be lethal.
- Thevetia: All parts are poisonous; seeds are especially toxic owing to the high concentration of cardiac toxins which act directly on the heart. The whole plant exudes a milky white juice which is very poisonous.
Concentration of toxin: Seeds (4.8%), leaves (0.07%), fruit (0.045%), and milk (0.036%).
- Clinical features
- Nerium: Early: Nausea, vomiting, abdominal pain, and diarrhea
Late: Cardiovascular: Different degrees of AV block, ventricular tachycardia/ventricular fibrillation (VF) (severe)
Neurological: Tremor, drowsiness, ataxia, seizures infrequently.
- Thevetia: Early: Numbness and burning of the mouth, vomiting, abdominal pain, and diarrhea.
Late: Cardiac arrhythmias, coma, and convulsions. Death is due to VF.
- Special identification features:
- Nerium: The flower is 1-2 inches in diameter and sweet scented [Figure 1].
The fruit is pod-like brown and 2-9 inches long
- Thevetia: Flowers are bright yellow or orange with milky latex.
The fruit encases a large seed and is reddish black in color
- Kinetics of toxin
- Oleandrin which is the primary toxin in Nerium oleander is well absorbed orally. An autopsy study revealed high concentrations of the toxin in blood, liver, lung, heart, spleen, and kidney.
- Thevetin toxin produced by Thevetia is easily absorbed in the GI tract and has higher concentrations in heart muscle than in blood.
- Analysis of toxin in toxicological screening.
Identification of the plant based on history and the patient's clinical features is the primary modality for diagnosis. However, if the diagnosis cannot be made, the plant specimen (preferably flower and leaf) should be transported on a paper sheet. Vomitus can also be sent for analysis, however, in a suitable isolated container. Analysis by such a modality can be expensive and is impractical in most settings.
Since the toxins in these plants act as cardiac glycosides on the same receptor, there is a level of cross-reactivity with digoxin immunoassay that can be used for diagnostic purposes. While there have been attempts to correlate serum levels with toxicity, the cardiac glycoside concentration which would be more reflective of severity does not consistently correlate with serum concentration., Hence, digoxin immunoassay is used predominantly for diagnostic purposes and does not have a role in assessing severity.
| Determinants of Severe Poisoning|| |
All patients with a history of oleander poisoning would require a detailed history and examination with investigations being used as a supplement for risk stratification and monitoring. The most important is the electrocardiogram (ECG) and serum potassium. Most of the deaths due to poisoning occur within the first 24 h, however, its observation can be extended up to 5 days in view of the late progression.
| History|| |
The amount consumed can predict severity although it has not been consistent across all studies.
- A: In oleander poisoning, between 15 and 20 leaves or 15 g of the root can be fatal if consumed. Consumption of 0.5 mg/kg of leaves is considered to be lethal, however, these were performed in animal studies with no evidence available for human toxicological analysis
- B: In the case of yellow oleander which is considered more toxic than pink oleander, the usual fatal dose is 8–10 seeds or 16–20 g of the root. What should be kept in mind though is that all parts of the plant are toxic with concentrations varying depending on the part of the plant that is consumed.
Time of ingestion
The time of ingestion does not have a direct bearing on the severity of toxicity. It is usefulness comes wherein lavage, especially within the first 1 h with activated charcoal (AC), can reduce the amount of toxin that is absorbed from the gut and thereby decrease systemic toxicity.
| Physical Examination|| |
- The examination should focus on vitals, especially the pulse and blood pressure. Vomiting, diarrhea, and abdominal pain are the most common presenting complaints in more than 60% of cohorts. On examination, most patients appear dehydrated. Neurological status is an important indicator of underlying cerebral hypoperfusion or can be due to direct toxicity. Vitals including blood pressure are generally well preserved until the prearrest stage
- A study of 101 patients in South India revealed that presentation with altered mental status and clinical shock were significantly associated with mortality. In a retrospective study of 170 cases, along with predominant GI symptoms at presentation, 50% had presented with bradycardia. The mortality in the cohort was 2.5%.
While differentiation between Nerium and Thevetia is unreliable based on physical examination alone, a good description and examination of the plant consumed would be better to make an accurate diagnosis.
| Investigations|| |
The most common cause of death is cardiac dysrhythmias. Hence, evaluation based around cardiac electrical activity and electrolytes have a major role to play in risk stratification.
An ECG at arrival would identify any rhythm or conduction abnormality. Patients would require continuous cardiac monitoring for at least 48 h with some reports suggesting an extension to even 72 h.
Two large retrospective studies had found that at presentation, 50% had features of AV block while ST-T abnormalities were noted in 10%–25% of their cohort., Another large study of 170 patients had found that a similar 40% had presented with AV conduction abnormalities with a mortality of 18%.
Sinus rhythm was the most common rhythm at presentation, however, sinus bradycardia and second-degree heart blocks were the most common arrhythmias followed by junctional arrhythmias.,,
A complete electrolyte panel needs to be performed in all patients at admission as there is a strong association between electrolyte disturbances, particularly hyperkalemia and mortality.
A large study of 351 patients found that serious arrhythmias were associated with hyperkalemia. In a similar study involving cardiac glycoside poisoning, hyperkalemia of more than 5.5 meq/dl was strongly associated with higher mortality than patients with normal serum potassium.
Disturbance in serum magnesium levels has been noted in previous studies with the most common being hypomagnesemia. Due to its close relationship with potassium and predisposition to serious arrhythmias, correction is advisable.
The renal function test should also be monitored due to its association with electrolyte abnormality and toxin kinetics. Because cardiac glycosides are predominantly excreted in the kidneys, clearance may be delayed in renal impairment. In a case series of acute poisoning causing renal failure in an urban center in South India, oleander poisoning presented in renal failure was 14% with none requiring HD or death.
A summary of investigations, monitoring, and management are detailed in [Table 2].
|Table 2: Summary of important investigations, monitoring, and management|
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| Management|| |
In the management of cases with oleander poisoning the quick assessment and assessment of airway, breathing and circulation should be performed as early as possible. The establishment of intravenous access and continuous ECG monitoring preferably in the setting of a high dependency unit would ensure prompt treatment and detection of any arrhythmias.
Patients' toxins are presenting to the emergency department with acute oleander poisoning within 1–2 h can be considered for AC decontamination. The charcoal functions to adsorb the toxin which is present in the GI tract and thereby reduces the amount of toxin being absorbed into the bloodstream. It is administered at a standard dose of 1 g/kg.
Multi-dose AC (MDAC) also known as “gastrointestinal dialysis” is the repeated administration of AC to enhance the elimination of toxins from the body. MDAC helps in interrupting the enterogastric and enteroenteric circulation which enhances nonrenal elimination for the drug. A 2003 randomized control trial (RCT) in patients with yellow oleander poisoning revealed a significant mortality benefit with MDAC compared to standard AC (2.5% vs. 8%). The study also showed a reduction in the number requiring ICU care, a temporary pacemaker, or anti-digoxin Ab. An RCT published in 2008 looked at the benefits of standard AC versus MDAC in poisoning with up to 35% of study patients with oleander poisoning. Results did not show any mortality benefit in either group or subgroup as the previous study had. A 2006 study that looked at serum levels of digoxin in acute yellow oleander poisoning revealed that both standard AC and MDAC had similar efficacy of drug elimination with no other subgroup benefit. Moreover, while the administration of MDAC greater care for airway protection and risk of aspiration needs to be considered. Current recommendations are unclear as to the benefit of MDAC in oleander poisoning, and more studies would be required before further recommendations can be made.
Due to the similarities in the biochemical structure of the cardenolide group of cardiac glycosides, there has been a lot of study into the use of digoxin Ab in oleander poisoning. From previous studies, it is clear that serum cardiac glycoside levels correlate with serious dysrhythmias. A previous study was conducted to test the sensitivity to detect oleandrin with digoxin assays which is used to monitor levels with therapy.
In a large multicentric study of 150 patients treated with digoxin Ab, 90% of the cohort had improvement of symptoms with complete resolution of all signs and symptoms in 80% of them. This response was evident within 1 h and complete by 4 h after administration of the full dose. Of those who had died, 25% had no response to treatment. Serum analysis for toxins performed in the study showed a fall to undetectable levels in all cases. An RCT was performed in oleander poisoning in Sri Lanka which gave a fixed dose of 1200 mg of digoxin Ab. They found that at 2 h and 8 h, 50% and 75% of the intervention arms had complete resolution of the arrhythmia versus control (5% and 15%, respectively). Safety analysis found that 20% had an allergic reaction that responded to prompt therapy.
Indications for digoxin Ab administration:
- Life-threatening dysrhythmia
- Serum potassium over 5 meq/L.
Note: Asymptomatic patients with elevated serum toxin screen are not an indication for starting therapy.
The dose of Ab fragment to be administered:
- Adults: An empiric dose of 10 vials
- Children: An empiric dose of 5 vials.
The other methods of calculation of dose based on quantity consumed and tox screen do not correlate well for glycoside toxicity other than digoxin/digitoxin. Hence, empiric administration in situations like oleander poisoning is the recommended therapeutic approach. Limitation for digoxin Ab use in South India is the availability and cost of the drug.
Atropine which is a centrally acting anticholinergic increases heart rate and antagonizes the vagomimetic effect in oleander poisoning. Their role, however, seems to be limited to patients presenting with asymptomatic bradycardia. In two retrospective studies in secondary care centers in South Asia, atropine use in mild toxicity was associated with good outcome. The dose administration of atropine was boluses of (0.6–2.0) mg with a target heart rate of 80/min., It should be, however, emphasized that this is maybe inadequate in patients with features of severe toxicity like life-threatening arrhythmias or hyperkalemia.
Temporary cardiac pacing
The pacing of cardiac rhythm is indicated in the setting of severe toxicity where features of sick sinus or conduction block can lead to severe bradyarrhythmias. The presence of hyperkalemia which is also a high risk for precipitation of arrhythmias is also an indication for pacing. In a large study done in a tertiary care center in South India, 50% of the patients in the cohort required pacing with the most common indication being symptomatic second-degree AV block. Subgroup analysis did not reveal any mortality benefit with pacing, however, hospital stay was increased by 2 days. Other concerns with pacing pertain to the cost, unavailability, and expertise required to perform the procedure along with the theoretical risk of pacing an irritable myocardium. There are, however, no guidelines available for pacing and further research is required before it can be recommended in oleander poisoning.
Oleandrin which is one of the toxins has been shown to affect the ryanodine receptor calcium release channels in cardiac myocytes. This results in a dose-dependent increase in intracellular calcium ions with retention of calcium which results in calcium overload and cessation of cardiac contraction. It is this theoretical risk with which there has been a general aversion to avoid intravenous calcium, especially in the setting of hyperkalemia, as it may worsen arrhythmias. This is based on animal data which showed results of sudden cardiac death. However, there are few case reports which challenge this thinking.,
Diuresis and hemodialysis
Cardiac glycosides have a large volume of distribution (7–8 L/kg) and only 20%–25% is protein bound. The efficiency of hemodialysis is even reported as low as 5% in certain cases., A large systematic review in 2016 had concluded that there is no role in cardiac glycoside toxicity.
A summary of the management of patients presenting with poisoning is presented in [Figure 2].
| Conclusion|| |
In patients with oleander poisoning, severity can be assessed based on the number of seeds consumed, time of consumption, presence of ECG abnormalities at admission, and hyperkalemia. Management includes early GI decontamination and correction of hyperkalemia, digoxin Ab when indicated with supportive care, and monitoring an essential adjunct. Further research is required into the need for temporary pacing in management.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]