Introduction

A 12-year-old 13.2-kg (29.0-lb) spayed female crossbreed dog was referred to a veterinary hospital after the ingestion of Nerium oleander leaves. The owner reported multiple episodes of vomiting, sialorrhea, and lethargy. On arrival, the dog had signs of depression. The dog had a body condition score of 5/9, pink mucous membranes, capillary refill time ≤ 2 seconds, and rectal temperature of 37.5°C (99.5°F). Cardiac auscultation revealed a regular rhythm with a heart rate of 120 beats/min; heart sounds were considered normal. Femoral and tarsal pulses were normal and synchronous with the heartbeat. Lung auscultation revealed no abnormalities with a respiratory rate of 36 breaths/min. The remainder of the initial physical examination findings were unremarkable.

Results of initial venous blood gas analysis were unremarkable, except for evidence of mild dehydration (microhematocrit, 56% [reference interval, 37% to 55%]; serum total protein concentration, 8.4 mg/dL [reference interval, 5.2 to 7.8 mg/dL]). Electrocardiography performed with an anesthesia monitor at the time of hospital admission revealed sinus rhythm. The dog was hospitalized for monitoring and supportive treatment. Overnight (4 hours after hospitalization), the ECG monitor indicated a tachyarrhythmia, which was interpreted as a ventricular tachycardia; IV administration of lidocaine was ineffective. Later, the dog developed hemorrhagic diarrhea and hematemesis. At that time, the diagnostic evaluation included a CBC, serum biochemical analysis, coagulation profile, thoracic radiography, abdominal ultrasonography, echocardiography, and 6-lead ECG. The CBC revealed severe thrombocytopenia (0 × 10³ platelets/μL; reference interval, 148 × 10³ to 484 × 10³ platelets/μL), moderate eosinopenia (0.02 × 10³ eosinophils/μL; reference interval, 0.06 × 10³ to 1.23 × 10³ eosinophils/μL), and mild lymphopenia (0.80 × 10³ lymphocytes/μL; reference interval, 1.05 × 10³ to 5.10 × 10³ lymphocytes/μL). The serum biochemical profile revealed severely high activities of lipase (918 U/L; reference interval, 20 to 160 U/L) and creatine kinase (1,032 U/L; reference interval, 40 to 150 U/L); moderately high activities of amylase (2,186 U/L; reference interval, 338 to 1,800 U/L), aspartate transaminase (81 U/L; reference interval, 10 to 44 U/L), and alkaline phosphatase (260 U/L; reference interval, 16 to 119 U/L); and mildly high activity of alanine transaminase (88 U/L; reference interval, 15 to 78 U/L). Results of a coagulation profile were considered normal. Thoracic radiography revealed no abnormalities. Abdominal ultrasonography revealed severe gastric stasis and enterocolitis. Echocardiographic findings included reduced left ventricular end-diastolic diameter (24.7 mm; reference interval, 27.12 to 39.5 mm), reduced end-systolic diameter (11.3 mm; reference interval, 16 to 28.4 mm), and increased end-diastolic septal thickness (11.3 mm; reference interval, 5.3 to 10.99 mm),¹ all of which were compatible with pseudohypertrophy secondary to dehydration. Serial 6-lead ECG recordings were obtained when the dog was in right lateral recumbency.

ECG Interpretation

The initial 6-lead ECG recording obtained 7 hours after hospitalization (Figure 1) indicated that the dog had a regularly irregular rhythm with a variable ventricular rate (158 to 176 beats/min). The atrial rate was 150 P waves/min. The P waves appeared uniform and of normal duration and amplitude (40 milliseconds and 0.25 mV, respectively); the sinus mean electric axis was +60°, indicating a single sinus origin. The P-P intervals were regular (duration, 400 milliseconds). The QRS complexes had 1 of 2 distinct morphologies that alternated with every other beat; both were wide and bizarre with a right bundle branch block morphology. One QRS-complex morphology was wide (duration, 90 milliseconds) with slurring of the ascending segment of the S wave (lead II) and was predominantly negative in leads I, II, aVL, and aVF with right-axis deviation (−150°); the complex was followed by a positive T wave. The other QRS-complex morphology was slightly less wide (duration, 70 milliseconds), with a notch on the descending segment of the single negative wave (lead II), and was predominantly negative in leads I, II, III, and aVF with right axis-deviation (105°); the complex was followed by a positive T wave. The R-R intervals were regularly irregular, alternating between 340 and 380 milliseconds in duration. The differential diagnoses for the 2 QRS-complex morphologies were the presence of 2 distinct ectopic foci alternating every other beat, a single ectopic focus with 2 different conduction pathways, or delayed afterdepolarizations.^2,3

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Six-lead ECG tracings obtained 7 hours after hospitalization of a 12-year-old spayed female crossbred dog that was evaluated because of ingestion of Nerium oleander leaves. At the initial ECG examination with an anesthesia monitor, sinus rhythm was present. Overnight (4 hours after hospitalization), ECG monitoring revealed a tachyarrhythmia that was interpreted as ventricular tachycardia, which did not respond to IV lidocaine boluses. At 7 hours after hospitalization, the P waves are normal and uniform, P-P intervals are regular (400 milliseconds), and atrial rate is 150 P waves/min. Notice the presence of atrioventricular (AV) dissociation. The PQ interval is variable, and P waves march in and out of the QRS complexes and are superimposed occasionally on the ST segment or T wave. The QRS complexes have 1 of 2 distinct bizarre morphologies alternating every other beat, both with a right bundle branch block morphology and a variable axis deviation. Notice slurring of the ascending limb of the S wave (lead II; black arrowhead) associated with one QRS-complex morphology (black arrow) and notching of the descending limb of the single negative wave (lead II; white arrowhead) associated with the other QRS-complex morphology (white arrow). The R-R intervals are regularly irregular, and the ventricular rate is between 158 and 176 beats/min. Paper speed = 50 mm/s; 1 cm = 1 mV.

Citation: Journal of the American Veterinary Medical Association 258, 8; 10.2460/javma.258.8.847

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The PQ interval was variable, and P waves were seen marching in and out of the QRS complexes, superimposing occasionally on the ST segment or T wave. This supported the finding of atrioventricular (AV) dissociation. On the basis of the ECG findings, 2 possible differential diagnoses were considered: accelerated idioventricular rhythm and bidirectional ventricular tachycardia (VT).

The antidote for N oleander intoxication (digoxin-specific antibody fragments [dsFab]) was not administered to the dog because of the owner's cost restrictions. The dog continued to receive supportive treatment with IV fluids (crystalloids and colloids), activated charcoal, amoxicillin–clavulanic acid, anti-emetics (maropitant and ondansetron), and gastroprotective drugs (ranitidine and omeprazole). No specific treatment for the arrhythmia was administered. The ECG monitoring of the dog was continuous, and the rhythm remained unchanged until 4 hours after the first 6-lead ECG. At that time, repeated 6-lead ECG was performed. Atrioventricular dissociation persisted, with apparently normal P waves, regular P-P intervals, and variable PQ intervals (Figure 2). The QRS complexes were bizarre, predominantly negative in leads I, II, and aVL, and displayed pleomorphism by loss of the regular alternation of the 2 complex morphologies previously identified; QRS-complex duration ranged from 60 to 80 milliseconds. The R-R intervals became irregular, with a ventricular rate of 143 to 214 beats/min (mean rate, 180 beats/min). The ECG diagnosis was monomorphic VT with pleomorphism. Later the same day, the dog received a fresh frozen plasma transfusion. After 3 days, ECG revealed that the rhythm became regular, AV association was present, and mean heart rate was 140 beats/min (Figure 3). The P waves were uniform and considered normal (mean electric axis, +70°; duration, 40 milliseconds; and amplitude, 0.3 mV), as were the QRS complexes (mean electric axis, +85°; duration, < 70 milliseconds; and amplitude, 1.4 mV). The PQ intervals were constant and > 130 milliseconds (ie, 160 milliseconds), indicating first-degree AV block.

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Six-lead ECG tracings recorded from the dog in Figure 1 four hours later. Atrial activity has the same features as previously identified, and AV dissociation persists. The QRS complexes are bizarre and have multiple morphologies but without a beat-to-beat variation, suggesting the presence of pleomorphism. Notching of the descending and slurring of both the descending and ascending limb of the single negative wave of the QRS complex (lead II) are present. Ventricular rate is increased, ranging from 143 and 214 beats/min (mean rate, 180 beats/min). The diagnosis is monomorphic ventricular tachycardia with QRS-complex pleomorphism. The presence of narrow QRS complexes (duration, < 70 milliseconds) could be a result of activation of the ventricles along the His-Purkinje system.³ Paper speed = 50 mm/s; 1 cm = 1 mV.

Citation: Journal of the American Veterinary Medical Association 258, 8; 10.2460/javma.258.8.847

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Six-lead ECG tracings recorded from the dog in Figure 1 three days later. Atrioventricular association is now present, indicating a sinus rhythm with heart rate of 140 beats/min. The P waves and QRS complexes appear normal and uniform. The PQ interval is constant (160 milliseconds) but exceeds the upper reference limit (130 milliseconds), indicative of first-degree AV block. Paper speed = 50 mm/s; 1 cm = 1 mV.

Citation: Journal of the American Veterinary Medical Association 258, 8; 10.2460/javma.258.8.847

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Discussion

Nerium oleander–associated toxicosis is attributable to oleandrin and other steroidal glycosidic cardenolides (types of cardiac glycosides [CGs]) that are present in the leaves, fruits, flowers, stems, and roots of N oleander. Any portion of the plant has a sufficient concentration of CGs to cause clinical signs, which can appear within 45 minutes after plant ingestion and can last for 4 to 5 days.^4,5

The cardenolides in N oleander are structurally and pharmacologically similar to digitalis, and like any other CGs, their mechanism of toxicity is based on the inhibition of the Na⁺, K⁺-ATPase pump, which leads to an increase in intracellular sodium and calcium concentrations and in extracellular potassium concentration.^5,6,7 These electrolyte imbalances, along with an effect on both vagal and sympathetic tones, cause positive inotropic and bathmotropic effects and negative chronotropic and dromotropic effects on the heart.^8,9,10 The combination of suppression (conduction delays) and excitation (enhanced automaticity and triggered activity owing to the delayed afterdepolarization phenomenon) of cardiac tissue can lead to a wide range of arrhythmias, such as ventricular premature complexes, variable AV blocks, sinus arrest, junctional rhythms, idioventricular rhythms, various types of VT, and supraventricular tachycardias.^5,6,11–17 Because of the many possible ECG manifestations, there are no arrhythmias that are pathognomonic of CG intoxication. However, toxicosis is strongly suggested by the presence of both features of enhanced automaticity (Figures 1 and 2) and depressed conduction (Figure 3).^12,13,17 Moreover, frequent ventricular premature complexes are common ECG findings for humans with digitalis toxicosis, and multifocal origin and variable morphology of these ventricular premature complexes are 2 features that are commonly reported with this condition.^{13,16,17,18,19} For the dog of the present report, the initial ECG recording had QRS complexes of 2 morphologies. One proposed explanation for the 2 alternating QRS-complex morphologies was that they had a multifocal origin, namely the presence of 2 ectopic sites that alternately discharged.^2,3 A second explanation was that ventricular beats arose from a single ectopic focus, but they were conducted through different conduction pathways (eg, different exit sites of a stationary reentrant circuit).^2,3 Even the delayed afterdepolarization phenomenon could have been involved in the generation of the different QRS-complex morphologies.² Similar mechanisms could have been responsible for the observed QRS-complex pleomorphism. Depending on the definition used, the alternating QRS-complex morphologies observed in the initial ECG recording for the dog of the present report could be representative of bidirectional VT. Bidirectional VT is a very rare form of VT, but its presence can be highly suggestive of CG intoxication given that digitalis toxicosis is the most common cause.^2,16,17,18 This type of arrhythmia is defined as a VT characterized by a wide QRS complex with a beat-to-beat alternation of the frontal axis or morphology.^2,20 Slurring and notching of QRS complexes were suggestive of transient myocardial damage or ischemia.

Other common clinical signs of oleander poisoning in dogs include vomiting and diarrhea with or without blood, sialorrhea, and lethargy,^4,14,15 and these signs were all observed in the case described in the present report. Thrombocytopenia was an unusual finding, but it has already been described for a dog¹⁵ and 2 humans^21,22 with N oleander poisoning; however, the mechanism by which thrombocytopenia might develop is still unclear.

The specific antidote for digitalis intoxication in both humans and dogs is administration of dsFab, especially to reverse the cardiotoxic effects and the related arrhythmias.^23,24 Given the structural and pharmacological similarities between CGs found in N oleander and digoxin, dsFab have also been proven to be efficacious in the treatment of N oleander–associated toxicosis.^7,15,25 In the case described in the present report, the antidote was available at a local poison control center, but the owner declined to purchase it because of cost concerns. Consequently, the dog was carefully monitored before starting treatment with common antiarrhythmic drugs. Fructose-1,6-diphosphate, which stimulates Na⁺, K⁺-ATPase, has been evaluated in dogs with N oleander–associated toxicosis in an experimental setting, and the results were promising.²⁶ Its use has not been advocated in human medicine as yet, to the authors’ knowledge.^10,27 If dsFab are not affordable or readily available for veterinary patients, fructose-1,6-diphosphate may be an inexpensive option with no reported adverse effects for treatment of dogs with N oleander–associated toxicosis. The dog of the present report was treated with IV fluids and activated charcoal, which is recommended to prevent enterohepatic recycling of the toxins. Antiemetic and gastroprotective drugs were also administered to the dog for gastrointestinal tract support, and amoxicillin–clavulanic acid was given as a prophylactic measure. A fresh frozen plasma transfusion became necessary because of the poor response to the standard crystalloid therapy and the persistence of severe hypovolemia and hemorrhagic diarrhea. After 3 days of hospitalization, AV association was present and sinus rhythm with first-degree AV block was established. Gastrointestinal signs resolved and blood volume was restored by the fourth day of hospitalization. The dog's platelet count progressively increased in the following days and returned to within the reference interval after 2 weeks. One month after hospital discharge, 6-lead ECG revealed sinus rhythm, and no arrhythmic events were identified.