Introduction

A 2-year-old 5.1-kg (11.2-lb) sexually intact male Maltese was evaluated because of vomiting and seizures after the owner saw the dog ingest up to 1,050 mg (206 mg/kg [93.6 mg/lb]) of the owner's extended-release formulation of lamotrigine.^a On presentation, the dog was having a seizure; however, the seizure stopped before interventional treatment, and the dog became obtunded and had horizontal nystagmus and delayed menace responses bilaterally. In addition, the dog was tachycardic (240 beats/min; reference range, 60 to 140 beats/min) with frequent, monomorphic ventricular premature complexes witnessed on multiparameter ECG and was hypertensive (indirect systolic blood pressure [measured with a Doppler ultrasonic flow detector combined with sphygmomanometry], 210 mm Hg; reference range, 80 to 120 mm Hg). The dog was normothermic (rectal temperature, 38.7°C [101.6°F]; reference range, 37.2°C to 39.2°C [99°F to 102.5°F]), and the remainder of findings on triage physical examination and from the medical history were unremarkable. No previous results for blood work were available.

A venous blood sample was collected; hematologic evaluations, including blood gas analyses, revealed a high anion gap metabolic acidosis (time, T0; Table 1). Treatment was initiated with hypertonic saline (3% NaCl) solution (5.3 mL/kg [2.4 mL/lb], IV bolus over 15 minutes), maropitant (1 mg/kg [0.45 mg/lb], IV), levetiracetam^b (20 mg/kg [9.1 mg/lb], IV), and undiluted 20% ILE^c (1.5 mL/kg [0.7 mL/lb], IV bolus over 30 minutes followed by 0.25 mL/kg/min [0.11 mL/lb/min], IV CRI for 30 minutes; 38.25 mL total). After completion of the prescribed ILE treatment, administration of an isotonic multiple electrolyte solution^d (4 mL/kg/h [1.8 mL/lb/h], IV) was initiated, and the dog was transferred to the intensive care unit for fluid diuresis, seizure observation, and continuous ECG monitoring. Supportive care was continued, and hematologic evaluations repeated an hour after presentation revealed that the dog's blood lactate concentration had lowered to within reference limits and that the patient's acid-base status had improved (time, T1). The dog showed signs of gradual clinical improvement, with normal sinus rhythm and a heart rate of 110 beats/min evident on ECG and greater LOC within 3 hours after presentation.

At approximately 4 hours after presentation, the dog suddenly developed ventricular tachycardia that progressed to ventricular fibrillation evident on ECG, then vocalized and collapsed in CPA. Cardiopulmonary resuscitation and intubation were immediately initiated. Epinephrine (0.01 mg/kg [0.0045 mg/lb], IV) was administered, and increasing doses of energy for defibrillation (4, 6, and 10 J/kg at 4, 6, and 10 minutes after CPA, respectively) were delivered amid several cycles of CPR. Fourteen minutes into resuscitation efforts, ILE (4 mL/kg, IV) was administered rapidly as a bolus while CPR continued. Approximately 2 minutes later, ROSC was achieved; the dog had a ventricular rhythm of 180 beats/min (measured with ECG) and an end-tidal CO₂ concentration of 18 mm Hg (reference range, 30 to 40 mm Hg; measured with capnography). A meaningful blood pressure measurement could not be obtained, likely owing to hypotension, and the dog was hypothermic (36.2°C [97.2°F]). A venous blood sample was drawn for analyses, which revealed lipemic serum and severe mixed respiratory and metabolic acidosis (time, T4.5; Table 1). Administration of hypertonic saline solution (5.3 mL/kg, IV over 20 minutes) was repeated and followed with administration of balanced crystalloid solution^d (20 mL/kg [9.1 mL/lb], IV over 20 minutes). For persistent hypoperfusion, CRIs of norepinephrine (0.5 μg/kg/min [0.2 μg/lb/min]) and vasopressin (0.0004 U/kg/min [0.0002 U/lb/min]) were started. A ventricular rhythm with a rate of 140 beats/min developed and persisted, and 15 minutes following initiation of vasopressor treatment, the dog's indirect systolic blood pressure was 110 mm Hg. Again, 20% ILE (1.5 mL/kg, IV over 15 minutes) was administered. The dog also received mannitol (0.5 g/kg, IV over 30 minutes), and fluid therapy was changed to maintenance with a crystalloid solution^d (3 mL/kg/h [1.4 mL/lb/h], IV) with added potassium (0.18 mEq/kg/h [0.08 mEq/lb/h], IV).

The dog remained intubated and was intermittently manually ventilated until it breathed adequately on its own (approx 3 hours after CPA) and was then extubated. Supportive care and ECG were continued, vasopressin was discontinued, and norepinephrine was reduced to 0.25 μg/kg/min. Approximately 20 minutes later, the dog's blood pressure had stabilized within reference limits, and norepinephrine was discontinued. Approximately 5 hours after CPA, the dog developed ventricular tachycardia (200 beats/min); therefore, a CRI of lidocaine (2 mg/kg [0.9 mg/lb], IV bolus followed by 50 μg/kg/min [22.7 μg/lb/min], IV) was initiated. Afterward, the dog's tachycardia resolved, but a ventricular rhythm persisted. Supportive care continued, and hematologic assessments on venous blood samples revealed improved but persistent metabolic acidosis (times, T6 and T9; Table 1).

Approximately 8 hours after CPA, the dog developed an idioventricular tachyarrhythmia (140 to 160 beats/min) characterized with intermittent R-on-T complexes and episodic sinus arrest. Results of venous blood gas analyses indicated persistent, uncompensated metabolic acidosis (time, T12; Table 1). Therefore, treatment with a hypertonic (8.4%) solution of NaHCO₃ in sterile water (1 mEq/kg, IV over 30 minutes) was administered. Afterward, blood gas analyses (time, T12.5) revealed improved metabolic acidosis, and continuous ECG revealed less frequent R-on-T complexes and improved heart rate (88 beats/min). Treatment with NaHCO₃ in sterile water (1 mEq/kg, IV over 30 minutes) was repeated but yielded no substantial improvement in the dog's acid-base status (time, T13.5). Therefore, a higher dose of NaHCO₃ in sterile water (2 mEq/kg, IV over 30 minutes) was administered. Afterward, blood gas analyses revealed improved blood pH (7.35; time, T15.5), and continuous ECG revealed sinus rhythm with a heart rate of 126 beats/min with rare ventricular premature complexes. Over the next several hours, the dog's LOC and vital signs gradually improved and stabilized.

On day 2 of hospitalization, the dog remained stable with sinus rhythm and vital signs within reference limits. At 20 hours after presentation (15.5 hours after CPA), hematologic assessments were repeated and revealed blood gas analytes within reference limits, mild anemia, and hypoproteinemia (time, T20; Table 1). In addition, results of a CBC and serum biochemical analyses indicated mild mature neutrophilia (22.3 neutrophils/μL; reference range, 3.0 to 12.7 neutrophils/μL), mild hypoproteinemia (total plasma protein concentration, 4.0; reference range, 6.5 to 8.0 g/dL), hypertriglyceridemia (593 mg/dL; reference range, 20 to 150 mg/dL), and moderately high activities of serum creatine kinase (6,884 U/L; reference range, 10 to 200 U/L), alanine aminotransferase (2,753 U/L; reference range, 18 to 121 U/L), aspartate aminotransferase (1,431 U/L; reference range, 16 to 55 U/L), and alkaline phosphatase (322 U/L; reference range, 5 to 160 U/L). The remaining results, including those indicative of renal function, were within reference limits. Thoracic radiography was performed, and findings were unremarkable.

At 36 hours after presentation (31.5 hours after CPA), the dog was ambulating and eating and appeared clinically normal on physical and neurologic examinations. Results of hematologic assessments indicated continued improvement with resolved anemia and other variables within reference limits (time, T36; Table 1). The owner declined further diagnostic procedures, and the dog was discharged with a prescription for levetiracetam (24 mg/kg [10.9 mg/lb], PO, q 8 h for 2 weeks) approximately 48 hours after presentation. The owner was instructed to have the dog re-evaluated if any abnormalities developed, including recurrent seizures or signs of systemic illness. During a follow-up telephone discussion 6 months later, the owner reported that no abnormalities had been noticed since the dog was discharged.

Discussion

The present report described severe neurologic signs and cardiovascular collapse in a dog after ingesting ≤ 206 mg/kg of lamotrigine, which is a commonly prescribed anticonvulsant drug for humans.¹ Lamotrigine is a phenyltriazine drug that predominantly inhibits voltage-gated sodium channels, reducing presynaptic release of excitatory neurotransmitters such as glutamate.² To a lesser extent, lamotrigine inhibits high-voltage activated-calcium channels² and has inhibitory effects on delayed rectifier potassium channels³ and serotonin reuptake by serotonin 5-HT₃ receptors.⁴ Because of its diverse properties, lamotrigine is used to treat partial or complex seizures and bipolar disorder in people.⁵

Pharmacokinetic studies^5,6 of lamotrigine in people show immediate and nearly complete absorption (98% bioavailability) with peak plasma concentrations for standard and extended-release formulations of 1 to 3 hours and up to 11 hours, respectively, after ingestion of the drug. The half-life of lamotrigine in people is 24 to 30 hours, and renal excretion predominates.⁵ Lamotrigine has a wide safety margin in people; the most common method of overdose is self-poisoning.⁵

Lamotrigine-associated toxicoses affecting the heart occur secondary to sodium channel blockade that leads to delayed conduction in the cardiac myocytes and prolonged PR intervals, QT intervals, and QRS complexes, predisposing patients to ventricular arrhythmias and cardiac arrest.^7,8,9 Two large metaanalyses^5,10 of lamotrigine overdose in people show that lamotrigine cardiotoxicosis was uncommon, sinus tachycardia and QRS-complex widening were the most common arrhythmias, and cardiac arrest primarily occurred in people who had ingested doses of lamotrigine > 25 mg/kg (11.4 mg/lb).¹⁰ In dogs, dose-dependent cardiotoxic effects further occur after hepatic metabolism of lamotrigine to a toxic 2-N-methyl metabolite, which occurs minimally in human patients. Toxicoses secondary to this metabolite in dogs manifest as arrhythmias, including bundle branch block, prolonged PR interval, QRS complex widening, and complete atrioventricular block.⁶ The dog of the present report developed ventricular fibrillation and cardiac arrest after ingesting a dose of lamotrigine up to 206 mg/kg, which greatly exceeded the suspected cardiotoxic threshold dose of lamotrigine in humans (25 mg/kg).¹⁰

Central nervous system signs (eg, agitation, seizures, and coma), rhabdomyolysis, serotonin syndrome, and various dermatologic abnormalities have been reported with lamotrigine toxicoses in people.^5,10,11,12 Results of the aforementioned 2 meta-analyses^5,10 of lamotrigine overdose in people indicate that CNS signs (eg, reduced LOC, nystagmus, seizures, and severely altered mental status) are the most commonly reported signs of toxicosis. Similarly, the dog of the present report was having a seizure when it arrived at our hospital; however, to our knowledge, the mechanism by which lamotrigine induces seizures is not fully known.

Despite the common use of lamotrigine in humans, there is a paucity of information in the veterinary literature regarding the clinical characteristics of lamotrigine toxicosis in animals. To our knowledge, there have only been 2 previous case reports^13,14 describing lamotrigine toxicosis in dogs, and both describe CNS and cardiac signs similar to those observed in people who had overdosed with the drug. The more severely affected of those 2 dogs was a 2-year-old English Bulldog that had ingested 26 mg/kg (11.8 mg/lb) of lamotrigine and later was obtunded, had tachyarrhythmias, and was treated with lidocaine, magnesium sulfate, ILE, and a low dose of NaHCO₃ (0.5 mEq/kg, IV, twice).¹³ That dog was ultimately discharged after 3 days of hospitalization; however, there was no reported change in the dog's blood pH or cardiac rhythm.¹³ In contrast, the dog of the present report received higher doses of NaHCO₃ (1 mEq/kg, IV over 30 minutes, twice; 2 mEq/kg, IV over 30 minutes, once), and the resulting improvement in its blood pH likely contributed to the conversion of its refractory ventricular arrhythmia to sinus rhythm.

Between 2003 and 2011, the ASPCA APCC received reports of 128 dogs and 10 cats that ingested lamotrigine.⁶ Of those 138 animals, 23 dogs and 1 cat survived without persistent clinical signs; however, most affected animals (95 dogs and 8 cats) were lost to follow-up. Similar to the dog of the present report, those 138 affected animals commonly had cardiovascular (eg, tachycardia [n = 20], bradycardia [8], or other arrhythmias [15]) or neurologic (eg, ataxia [35], seizures [20], or tremors [15]) abnormalities, alone or in combination.⁶ Five of the 8 animals that died had cardiac arrest witnessed while hospitalized.⁶ Between 2011 and 2019, an additional 1,040 dogs and 49 cats that ingested lamotrigine alone and 791 dogs and 57 cats that ingested lamotrigine along with other agents (co-ingestions) were reported to the ASPCA APCC.^e

The LD₅₀ of lamotrigine has not been evaluated in dogs but is 245 mg/kg (111.4 mg/lb) in mice and 205 mg/kg (93.2 mg/lb) in rats.^d In dogs, minor signs (eg, lethargy and vomiting) may occur after ingestion of as little as 5 mg/kg (2.3 mg/lb), whereas agitation, tremors, and disorientation may occur at doses of 6 to 16 mg/kg (2.7 to 7.3 mg/lb), and more severe signs (eg, seizures, hypotension, and tachy- or brady-arrhythmias) may occur at doses > 37 mg/kg (16.8 mg/lb).⁶ Dogs that ingest > 60 mg/kg (27.3 mg/lb) of lamotrigine may have arrhythmias (eg, bradycardia, ventricular premature complexes, ventricular tachycardia, or complete atrioventricular block), extensor rigidity, or sudden death, alone or in combination.⁶ Clinical signs of lamotrigine toxicoses in dogs generally begin 4 to 12 hours after ingestion and can last for 24 to 48 hours, depending on the formulation ingested,⁶ and treatment is largely supportive and based on evolving clinical signs because the drug is too rapidly absorbed for gastric decontamination to be effective, and even when identified early, affected dogs may have already developed neurologic impairment that prevents traditional decontamination at presentation, as was the case with the dog of the present report. Treatment of arrhythmias and seizures is paramount. Lidocaine is considered a first-line treatment for ventricular arrhythmias, and systemic alkalization through the administration of NaHCO₃ can also be considered. In the dog of the present report, life-threatening ventricular arrhythmias persisted, despite treatment with lidocaine, and the dog had persistent, severe metabolic acidosis after CPA; therefore, treatment with NaHCO₃ was performed.

The mechanisms by which administration of NaHCO₃ treats sodium channel–blocker toxicoses have not been fully elucidated. The 4 prevailing theories involve ion trapping, increased availability of albumin to bind the free drug, provision of additional available sodium ions, or alteration of the cellular electrochemical gradient.¹⁵ Lamotrigine is a weak base with a pKa of 5.7,⁸ and in acidic conditions, a weak base can accept an H⁺ ion and become positively charged (ionized) as explained by the Henderson-Hasselbach equation.¹⁶ Thus, the administration of NaHCO₃ to raise an affected patient's blood pH (alkalization of the patient) greater than the pKa of lamotrigine results in more of the lamotrigine being in its neutral form, compared with its ionized form that can to bind sodium channels, and thereby attenuates the drug's availability to cause toxicoses. In addition, by increasing the proportion of the neutral form of lamotrigine in the bloodstream, lamotrigine will cross plasma membranes to parts of the body where subsequent ionization may occur, the ionized form is trapped, and processes allow for excretion of the drug. This ion trapping depends on the pKa of the drug and differences in pH across cell membranes.¹⁵ The administration of NaHCO₃ also leads to a sodium load that can overwhelm sodium channel blockade and increase the electrochemical gradient across cardiac cell membranes, potentially attenuating the lamotrigine-induced blockade of sodium channels.^17,18 Although success rates for treatment with NaHCO₃ vary, the dog of the present report responded with the resolution of arrhythmias and neurologic signs. To our knowledge, successful treatment with alkalization by administration of NaHCO₃ in a dog with lamotrigine toxicoses had not been reported previously, and such patient alkalization is only sporadically reported in human medicine.^5,10,17

The dog of the present report had CPA, and successful ROSC was achieved following defibrillation. An adjunctive treatment that may have contributed to this successful outcome was the 20% ILE that was administered during CPR because ROSC was achieved shortly thereafter. Injectable lipid emulsion is proposed to function in part as a lipid sink by expanding the lipid phase of plasma and sequestering lipophilic compounds, thereby preventing them from reaching their target sites of action.¹⁹ This treatment was initially described for the treatment of cardiac arrest secondary to bupivacaine toxicoses in people.²⁰ The efficacy of ILE in treating toxicoses depends on the lipophilicity (described by the logP value [lipid-to-aqueous partition coefficient]) of the involved drug, and a value of logP > 1.0 suggests that treatment with ILE may be beneficial.²¹ The logP for lamotrigine is reported as 1.19 (at pH 7.6).²¹ Although we could not conclusively determine that ILE administration to the dog of the present report contributed to its ROSC, our findings were consistent with reports of ILE use in similar situations in human medicine,^7,20,22 and we believe this illustrates a potential role for ILE in treatment of patients with cardiac arrest secondary to toxicoses from lipid-soluble drugs.

The dog of the present report had moderately high creatine kinase activity, which could have been caused by the dog's seizure or prolonged CPR with defibrillation. Rhabdomyolysis secondary to lamotrigine overdose has been reported^9,10 in people, in some of whom the severity was enough to lead to acute kidney injury. The mechanism by which this occurs is not fully known, and no kidney damage was detected in the dog of the present report. High activities of liver enzymes were also detected in the dog and could have been from various factors, including hepatocellular injury secondary to hepatic metabolism of lamotrigine or secondary to seizures or CPR. The dog's hypertriglyceridemia was likely attributable to ILE administration.

Lamotrigine is one of the most commonly prescribed anti-epileptics in human medicine, and animal exposure is not uncommon. Although the use of ILE appears promising for the treatment of lamotrigine-associated cardiotoxicosis, safety and efficacy studies in human and veterinary medicine are lacking. The use of ILE in the dog of the present report was temporally associated with ROSC after prolonged CPR, suggesting a potential place for ILE in the treatment of CPA in dogs with lamotrigine toxicoses. In addition, treatment with NaHCO₃ for QRS-complex widening associated with sodium channel–blocker toxicoses, as occurred in the dog of the present report, also led to documented increases in the dog's blood pH and likely contributed to the resolution of the dog's ventricular arrhythmias. Therefore, we believe that NaHCO₃ administration should be considered when appropriate resuscitation fails to resolve metabolic acidosis and ventricular arrhythmias in dogs with lamotrigine toxicoses.