Hrev_master [Emergency Care Journal 2016; 12:6252] [page 69] Severe symptomatic bradycardia after a dinner of spicy oleander soup Andrea Tampieri, Fabrizio Mucci, Valeria Palmonari, Eugenio Giovannini, Tiziano Lenzi, Patrizia Cenni Emergency Department, S.M. Scaletta Hospital, Imola (BO), Italy Abstract Cardiac glycosides similar to digoxin are produced by different plants in nature. Nerium oleander, commonly grown as an ornamental shrub, can be found worldwide in temperate countries. Intentional or accidental ingestion of any part of the plant can lead to clinically rel- evant intoxication. A 63-year-old woman came to the emergency department with acute dys- peptic symptoms after eating vegetable soup flavored with unfamiliar flowers she have col- lected herself. However, the electrocardiogra- phy (ECG) showed abnormalities that raised suspicions for an overdose of digoxin-like car- diac glycosides. The patient was not on treat- ment with digoxin and a careful anamnesis revealed that she had eaten oleander leaves. Digoxin specific Fab antibody fragments were administered for marked bradycardia that was not responding to atropine administration, after counseling with the reference toxicology center. The patient was also treated with acti- vated charcoal and magnesium sulphate, intra- venous fluids and pantoprazole. Four days later she was discharged as asymptomatic, with nor- mal sinus rhythm. Emergency physicians should be aware of this type of poisoning, especially in cases with typical ECG alterations in patients not treated with digoxin and med- ical history of plants ingestion. Cardio-active glycosides are present in different plants, often used inappropriately, with potential toxic effects and harmful drug interactions. Introduction Digoxin-like cardiac glycosides are found in nature in a diverse group of plants including Digitalis purpurea and Digitalis lanata (fox- gloves), Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander). All cardiac glycosides bind to a site on the cell membrane, producing reversible inhibition of the sodium-potassium pump and subsequently increasing intracellular calcium concentra- tions in myocytes. Cardiac glycosides also have vagotonic effects that can result in bradycardia and heart block. Cardiovascular and gastroin- testinal systems are primarily affected. Prolonged refractory period in atrioventricular (AV) node, shortened refractory periods and decreased resting membrane potential in myocytes may lead to potentially lethal arrhyth- mias such as sinus or AV block or refractory ventricular dysrhythmias. Nausea, vomiting and dyspeptic symptoms are also typical. Life threatening human toxicity may occur after ingestion of leaves, flowers, or seeds from plants containing cardiac glycosides. Intoxication by Nerium oleander (NO) is an uncommon event but occasional cases have been reported, and many of these exposures occurred in children and are usually uninten- tional. Mortality is rare but possible. We describe a symptomatic case of accidental ole- ander poisoning in an adult, diagnosed through electrocardiographic changes and a careful history collection and treated with digoxin specific FAB antibody fragments. Case Report A 63-year-old woman with a medical history of hypertension, diabetes and hypothyroidism came to the Emergency Department (ED) com- plaining of epigastric pain and vomiting that had started approximately 6 hours after a din- ner of vegetable soup, and she was the only person who had eaten it. She was on treatment with beta blockers (bisoprolol 5 mg once daily in the morning), oral antidiabetic (metformin 500 mg o.d.), and levo-tiroxin (75 mcg in the morning). On arrival at the ED the patient was conscious with adequate perfusion. Her heart rate was of 60 beats/minute, blood pressure of 120/70 mm/hg, oxygen saturation of 96% in air and body temperature 36.9°C. The abdomen was soft without signs of peritoneal irritation, and an abdominal ultrasound evaluation did not show gallstones nor other abnormalities. ECG on arrival (Figure 1) showed sinus rhythm with a markedly prolonged first degree AV block and a diffused ST depression with upper concavity. Reported symptoms and ECG alterations could be suggestive for myocardial ischemia (considering the cardiovascular risk factors involved), as well as for food-induced abdominal colic in patients with left ventricu- lar hypertrophy, but also for intake of digoxin or digoxin-like substances although our patient was not on treatment with digoxin. A transthoracic echocardiogram was performed without detection of cardiac anomalies. Laboratory tests including complete blood count, hepatic, renal and thyroid function test, glycaemia, serum electrolytes, amylase, myocardial necrosis enzymes, and hemo-gas analysis were collected and resulted normal, while the serum digoxin level was 0.9 ng/mL (our therapeutic range for digoxin is between 0.9 and 2 ng/mL). A more careful anamnesis revealed that her dinner had been dressed with oleander leaves. The patient denied intention of self-harm and reported to have used NO as a garment in substitution of laurel, not being aware of its toxic potential. ECG modifications, suggestive also for digoxin-like cardiac glycosides intoxication, were probably due to NO poisoning. In our laboratory a spe- cific method for oleandrin is not available and a Digoxin Flex reagent cartridge by Siemens is used for sampling digoxin with an immunoas- say technique. This method presents only a limited cross reactivity for NO glycosides so the actual level of oleandrin or other digoxin- like cardiac glycosides was probably underesti- mated. After telephone counseling with the local toxicology center, the patient was treated with an oral administration of 50 g of activated charcoal together with 30 g of magnesium sul- phate, intravenous fluids and 40 mg of panto- prazole. The patient was subsequently admit- ted to the acute medicine ward for observation with ECG monitoring and treatment with repeated administration of activated charcoal (5 g every two hours for the first day and 5 g every six hours for 2 days). In the subsequent hours her cardiac rhythm varied between sinus rhythm with first-degree AV block, sec- ond-degree Mobitz type-I AV block (Figure 2) evolving into severe bradycardia (Figure 3) sustained by Mobitz type-II AV block not responding to atropine administration (0.5 mg i.v). Administration of 400 mg of intravenous digoxin specific Fab antibody fragments was agreed on with the poison control center for the arrhythmic events observed. Six hours after Fab administration, the digoxin level was lower than our therapeutic range (0.5 ng/mL), the ECG improved with regression of the AV block from second to first degree and sinus rhythm was subsequently maintained. Emergency Care Journal 2016; volume 12:6252 Correspondence: Andrea Tampieri, Emergency Department, S.M. Scaletta Hospital, Imola (BO), Italy. Tel: +39.0542.662711. E-mail: andrea.tampieri@libero.it Key words: Plant poisoning; Nerium oleander; Cardiac glycosides; Digoxin antibodies FAB frag- ments; Cardiac dysrhythmia. Received for publication: 30 August 2016. Accepted for publication: 6 September 2016. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright A. Tampieri, et al., 2016 Licensee PAGEPress, Italy Emergency Care Journal 2016; 12:6252 doi:10.4081/ecj.2016.6252 Non co mmerc ial us e o nly [page 70] [Emergency Care Journal 2016; 12:6252] Abnormalities of repolarization (ST depression with the typical upper concavity) still persist- ed. Four days after admission, the patient was discharged in good health and electrocardiog- raphy abnormalities had regressed completely, as shown in Figure 4. Discussion Oleander is a native evergreen ornamental shrub in the Mediterranean area and is plant- ed in many subtropical areas of the world. It is commonly used in landscaping motorway medians in mild-winter states and can also be found in colder countries, usually grown inside greenhouses. Flower colour varies from white to deep red. Every part of the plants, from root to flowers, contain many cardiac glycosides (of which oleandrin is the most studied and repre- sented) that are structurally similar to digoxin.1 The highest concentration has been reported in the seeds, followed by the leaves and fruit.2 Even if it is commonly regarded as a poisonous plant, accidental ingestion of NO parts has been described both in adults and children. Other causes of intoxication include deliberate self-poisoning or ingestion of medicinal preparations. Intake of any part of the plant can cause symptoms similar to digox- in poisoning. Oral ingestion of 5 to 15 leaves of NO has resulted in fatal poisoning in adults3 and even one leaf has been suggested as potentially toxic for children.4 However, the exact lethal dose is hard to establish, as in many reported cases the specific ingested dose was not established.5 There is also a large vari- ation among individuals in the amount of absorption of cardio-active toxins. Cardiac gly- cosides inactivate the Na+/K+ ATPase pump on the cytoplasmic membrane of cardiac cells, raising the intracellular Ca++ concentration and leading to inotropic effect, hyperkalaemia, and alterations of electrical impulse conduc- tion. Symptoms of intoxication usually arise a few hours after ingestion.5 Drinking infusions made with leaves or roots is often associated with a faster onset compared to ingestion of unprepared plant parts.6,7 The typical clinical presentation includes gastrointestinal symp- toms such as nausea, vomiting, abdominal pain, increased salivation or diarrhoea, togeth- er with cardiac dysrhythmias and hyper- kalaemia. The more frequent cardiac dysrhyth- mias are conduction defects that affect the sinus or AV node, atrial fibrillation, ventricular ectopic beats or, less commonly, ventricular fibrillation. Neurological symptoms such as tremor, ataxia or visual alterations can be associated with oleander intoxication. A care- ful history collection (part of plant ingested, quantity, time since ingestion and symptoms) together with the ECG are important diagnos- tic elements for oleander poisoning. In our specific case, gastrointestinal symp- toms could be attributed to intoxication from a digoxin-like substance. Typical ECG alterations (progression of AV-block, diffuse ST depres- sion with upper concavity, QTc interval short- ened despite marked bradycardia in Figure 3) in a patient not treated with digoxin, together with a careful anamnesis, led to the diagnosis of NO poisoning. An interaction of cardiac gly- cosides with beta-blockers in the induction of bradycardia cannot be definitely excluded, however it seems unlikely considering that the half-life of bisoprolol (taken in the morning) is estimated about 10 hours, while the patient came to the ED later in the evening and it was immediately suspended. Whereas a specific test for NO cardiac glycosides is not available, the laboratory is of limited use, as many com- monly-used tests for digoxin present only lim- ited cross reactivity for other digoxin-like gly- cosides, which might prove to be undervalued. Despite the gastrointestinal decontamination performed 6 hours after NO ingestion, AV- block and bradycardia worsened during hospi- talisation, suggesting an inappropriate timing in treatment. Atropine administration could have counteracted the vagotonic glycosides effect, but was not found to be effective on the treatment of bradycardia. Conversely, AV-block has regressed after Fab fragments infusion. Given the occasional nature of NO intoxica- tion, there is no treatment supported by a strong evidence in the literature. Few ran- domised-controlled trials are actually avail- able8-10 and all of them addressed poisoning by Yellow Oleander (Thevetia peruviana) that contains slightly different cardiac glycosides from NO, commonly used for deliberate self- poisoning in Sri Lanka.11 Actually, intoxication from common or yellow oleander is managed in the same way. Mainstays of treatment include supportive care with ECG monitoring, gastrointestinal decontamination and specific antidote administration.5,12 Control of elec- trolytes and fluid balance is obviously essential in patients with vomiting or diarrhoea. Rapid correction of electrolyte alterations is of para- mount importance to minimise cardiac arrhythmic complications. Marked bradycardia with hypotension can be treated with bolus doses of atropine or temporary pacing if anti- digoxin Fab is not immediately available (even if in the case of extreme intoxication, cardiac cells with severe electric alterations can be refractory to external depolarisation). Gastro- enteric decontamination is actually discussed. Repeated activated charcoal administration Case Report Figure 1. First electrocardiography on arrival showing sinus rhythm with first degree AV block (markedly prolonged PR interval with P positive wave in DI and negative in aVR on the end of the T wave, and within the T wave in DII-black arrows) and a diffused ST depression with upper concavity. Figure 2. Electrocardiography monitoring of the second lead with second degree Mobitz type I AV block (progressively lengthened PR interval before a P wave not followed by any QRS complex) and an ectopic ventricular beat. Non co mmerc ial us e o nly [Emergency Care Journal 2016; 12:6252] [page 71] has been studied in two randomised controlled trials with conflicting results. Silva et al.8 found multiple-dose activated charcoal admin- istration (50 g every 6 hours for 3 days) effec- tive in reducing deaths and life-threatening cardiac arrhythmias in patients admitted up to 24 hours after yellow oleander poisoning. A subsequent study by Eddleston et al.10 instead did not find significant changes in mortality related to charcoal administration either in single or in multiple doses. Given that treat- ment with activated charcoal was safe in both studies8,10 and that it could increase the rate of elimination of cardiac glycosides,13-15 its use is generally recommended even if its effective- ness in reducing mortality is uncertain. Whole bowel irrigation has also been considered to reduce enteric absorption.4 Today, however, there is insufficient data to evaluate this treat- ment. As for specific antidotes for cardiac gly- cosides, polyclonal anti-digoxin Fab fragments are actually available and of clear benefit if administered for digoxin poisoning.16 These antibodies can also bind to oleandrin in vitro and reduce its active concentration.17 A ran- domised controlled trial by Eddleston et al.9 addressed the use of 1200 mg of intravenous Fab antibodies for life-threatening cardiac arrhythmias in patients with yellow oleander poisoning, reporting a highly significant response to treatment. Alternatively, 400 mg in 20 minutes followed by an infusion of 400-800 mg over 6-8 hours has also been suggested.5 In case of advanced AV block, severe sinus node block and ventricular tachyarrhythmia, admin- istration of anti-digoxin Fab is appropriate in patients with oleander poisoning, independ- ently from serum digoxin concentration, as routinely used digoxin assays are at best semi- quantitative for other digoxin-like sub- stances.9,18,19 Hyperkalaemia (serum potassi- um >5.5 mEq/L) could also be an indication for Fab administration in oleander poisoning, as the antibodies decrease potassium concentra- tions significantly within 2 hours.9,18 Conclusions NO is a plant commonly found in many countries worldwide. Cases of intoxication are uncommon but emergency physicians should be aware of this poisoning, especially in the case of typical ECG alterations in patients not treated with digoxin and with a medical histo- ry of plants ingestion. Both diagnosis and first treatment are often possible and can be man- aged by ED physicians. Principles of treatment are similar to those of digoxin intoxication. Electrolyte imbalances and cardiac arrhyth- mias should be corrected promptly. Gastric decontamination strategies must be evaluated and treatment with specific FAB antibodies is recommended in case of life-threatening arrhythmic events or severe hyperkalaemia. ECG monitoring should be maintained until complete resolution of the arrhythmic events. References 1. Langford, SD, Boor PJ. Oleander toxicity: an examination of human and animal toxic exposures. Toxicology 1996;109:1-13. 2. Karawya MS, Balbaa SI, Khayyal SE. Estimation of cardenolides in Nerium ole- ander. Planta Med 1973;23:70-3. 3. Osterloh J, Herold S, Pond S. Oleander interference in the digoxin radioim- munoassay in a fatal ingestion. J Am Med Assoc 1982;247:1596-7. 4. Shaw D, Pearn J. Oleander poisoning. Med J Aust 1979;8:267-9. 5. Bandara V, Weinstein SA, White J, Eddleston M. A review of the natural histo- ry, toxicology, diagnosis and clinical man- agement of Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander) poisoning. Toxicon 2010;56:273- 81. 6. Haynes BE, Bessen HA. Oleander tea: herbal draught of death. Ann Emerg Med 1985;14:350-3. 7. Le Couteur DG, Fisher AA. Chronic and criminal administration of Nerium olean- der. J Toxicol Clin Toxicol 2002;40:523-4. 8. de Silva HA, Fonseka MMD, Pathmeswaran A, et al. Multiple-dose acti- vated charcoal for treatment of yellow ole- ander poisoning: a single-blind, ran- domised, placebo-controlled trial. Lancet 2003;361:1935-8. 9. Eddleston M, Rajapakse S, Rajakanthan K, et al. Anti-digoxin Fab fragments in car- diotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000;355:967-72. 10. Eddleston M, Juszczak E, Buckley NA, et al. Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet 2008;371;579-87. 11. Eddleston M, Sheriff MHR, Hawton K. Deliberate self harm in Sri Lanka: an over- looked tragedy in the developing world. Brit Med J 1998;317:133-5. 12. Rajapakse S. Management of yellow olean- der poisoning. J Toxicol Clin Toxicol 2009;47:206-12. 13. Chyka PA, Holley JE, Mandrell TD, et al. Correlation of drug pharmacokinetics and effectiveness of multiple-dose activated charcoal therapy. Ann Emerg Med 1995; 25:356-62. 14. Lalonde RL, Deshpande R, Hamilton PP, et Case Report Figure 3. Electrocardiography monitoring: marked bradycardia (30 bpm) with non-con- ducted P wave (black arrows) as in Mobitz type II AV block, escape ventricular beat (black diamond), and mild shortened QTc interval. Figure 4. Electrocardiography at discharge showed a normal SE and a regression of ST- segment abnormalities. Non co mmerc ial us e o nly [page 72] [Emergency Care Journal 2016; 12:6252] al. Acceleration of digoxin clearance by activated charcoal. Clin Pharmacol Ther 1985;37:367-71. 15. Ibanez C, Carcas AJ, Frias J, Abad F. Activated charcoal increases digoxin elim- ination in patients. Int J Cardiol 1995; 48:27-30. 16. Antman EM, Wenger TL, Butler VP, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a multicenter study. Circulation 1990;81:1744-52. 17. Dasgupta A, Hart AP. Rapid detection of oleander poisoning using fluorescence polarization immunoassay for digitoxin. Effect of treatment with digoxin-specific Fab antibody fragment (ovine). Am J Clin Pathol 1997;108:411-6. 18. Eddleston M, Ariaratnam CA, Sjostrom L, et al. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhyth- mias, electrolyte disturbances, and serum cardiac glycoside concentrations on pres- entation to hospital. Heart 2000;83:301-6. 19. Osterloh J, Harold S, Pond S. Oleander interference in the digoxin radioim- munoassay in a fatal ingestion. J Am Med Assoc 1982;247:1596-7. Case Report Non co mmerc ial us e o nly