Introduction

Lamotrigine is a phenyltriazine compound used in human medicine to treat partial and generalized seizures as well as affective bipolar disorder. It is not routinely prescribed in veterinary medicine because of concerns regarding toxicity at low doses. Accidental ingestion by dogs and cats is recognized to cause cardiac and neurologic sequelae that have a reported fatality rate of 27% in dogs for whom follow-up information was available.¹ Current treatment regimens are aimed at reducing gastrointestinal absorption followed by subsequent monitoring and symptomatic treatment. Success of more specific therapy has not been documented in the veterinary literature. The present report describes the ingestion and serial serum concentration of a potentially toxic dose of lamotrigine and treatment with intravenous lipid emulsion (ILE) in a dog.

Case Report

A previously healthy, ∼1 yr old 7.4 kg female spayed dachshund/mixed-breed dog was evaluated by the Small Animal Emergency Service at the William R. Pritchard Veterinary Medical Teaching Hospital in Davis, California, following witnessed ingestion of 1000–1200 mg immediate-release oral lamotrigine (135–162 mg/kg), 40 min prior to presentation. The recommended dose in humans is 100–500 mg daily.² The owners reported that vomiting began within 10 min of ingestion, followed by an episode of diarrhea and persistent tremoring with altered mentation shortly thereafter.

On initial examination, the dog was moderately obtunded and nonambulatory with intermittent myoclonus and hyperesthesia. The heart rate was 160 bpm with no audible arrhythmia. An electrocardiogram (ECG) was performed upon admittance to the emergency room, which revealed a normal sinus rhythm with progression within 2–3 min to sinus tachycardia at a rate of 200 bpm. A Doppler blood pressure of 148 mmHg was obtained. A venous blood sample showed electrolyte values^a within the reference ranges, and a mild hyperlactatemia of 4.9 mmol/L (reference interval <2 mmol/L) was present.

An IV catheter was placed and ∼45 min after presentation, the patient received an infusion of 20% intralipid emulsion^b at 0.25 mL/kg/min for a 90 min period. Improvement in the patient's mentation and reduction in tremoring was noted within 20–30 min of commencing the lipid emulsion infusion.

The patient was admitted to the intensive care unit (ICU) for continuous ECG monitoring and observation. Initially, the heart rhythm was sinus tachycardia at 158 bpm, with infrequent, isolated, right bundle branch block morphology, ventricular premature complexes, and occasional ∼1 sec sinus pauses. No treatment for the ECG abnormalities was administered and the ventricular premature complexes resolved spontaneously within 2–3 hr of ICU admission.

Over the next several hours, mentation improved with the patient becoming ambulatory and more interactive. Minimal tremoring was present after 8 hr. The patient's heart rate decreased to 110–120 bpm while awake and 80–90 bpm while sleeping. Doppler systolic blood pressure averaged 115 mmHg consistently. The following morning, a complete blood count and serum biochemistry panel were obtained and showed no significant abnormalities, and a cardiac troponin I value^c of 1.02 ng/mL (reference interval 0.09–0.17 ng/mL) was obtained. The dog continued to improve and was discharged after 38 hr in the hospital with no clinical abnormalities on examination.

A board-certified cardiologist performed a six-lead ECG during hospitalization (1 hr, 18 hr, and 36 hr after presentation), with the predominant findings being prolonged corrected QT (QTc) intervals and sinus tachycardia (Figure 1). QTc values were calculated using four different formulas because the measured QT intervals appeared subjectively long for the degree of tachycardia. The use of four possible formulae was applied owing to lack of consensus on the most appropriate QT correction methodology in clinical canine cases.³ Briefly, the Bazet, Fredericia, Todt, and Van de Water formulas were calculated.^3,4 The QT interval was determined by evaluating all 6 leads and measured as an average of six consecutive QRST complexes.³ The R-R interval was calculated from an average of the six preceding complexes. Indeed, the QTc was initially prolonged according to values obtained from three of the four formula and ranged from 241 to 328 msec on presentation, but it gradually returned to normal after 18 hr (242–301 msec) and 36 hr (214–240 msec; reference range <260 msec).⁵ Over the course of hospitalization, the QTc reduced by 11–27%. No ventricular ectopy was identified beyond the single ventricular premature complexes noted during the first 3 hr of continuous ECG monitoring in the ICU. No atrioventricular block was observed at any time in this patient. Because of the improvement in ECG and clinical signs, the owners elected not to pursue an echocardiogram.

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Serial serum lamotrigine assays were measured at baseline, 30 min, 6 hr, 12 hr, and 38 hr following ILE treatment (Figure 2). Serum samples were analyzed using protein precipitation followed by dilution and liquid chromatography-mass spectrometry. Briefly, 100 µL of acetonitrile was added to 100 µL of serum and vortexed to mix. Then, 795 µL of high-performance liquid chromatography (HPLC)-grade water and 5 µL of a 10 µg/mL solution of ¹³C-¹⁴N₄-lamotrigine^d were added and the sample was again vortexed. The extract was centrifuged for 10 min at 40,000g and 100 µL of the supernatant was filtered into an autosampler vial for analysis. Further dilutions as necessary to bring extract concentrations within the calibration range were done with HPLC-grade water. Analysis of extracts was performed using a mass spectrometer^e interfaced with an HPLC system^f. Reverse-phase HPLC was employed using a 100 × 2.1 mm, 3.5 µm reverse-phase column^g. Gradient elution was used with mobile phases of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The mass spectrometer was run using electrospray ionization in positive ion selective reaction monitoring mode. Ion transitions of m/z 256 → 211 and m/z 256 → 159 were monitored for lamotrigine and m/z 261 → 214 monitored for the ¹³C-¹⁴N₄-lamotrigine internal standard. Lamotrigine concentrations in samples were determined using the internal standard method and a five-point calibration curve in the range of 5.0–500 ng/g (corresponding to 50–5000 ng/g in serum). The r² value for the calibration curve was 0.998. Recoveries of lamotrigine in fortified negative control serum at 100 ng/g (n = 5) and at 500 ng/g (n = 3) were within the 80–120% range, indicating good quantitative performance for the method.

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Lamotrigine concentrations were found to rapidly decrease within the initial 30 min of ILE administration and continued to reduce throughout the patient’s stay in the hospital. No lamotrigine was detected in a serum sample collected immediately prior to discharge at 38 hr after treatment.

Discussion

This case report documents a severe case of lamotrigine toxicosis in a dog, highlighting the speed with which symptoms can develop and the apparent benefit of ILE in the treatment of this intoxication.

Lamotrigine has an oral bioavailability in humans of 98% with minimal first-pass effect, typically resulting in a rapid onset of action; maximum plasma levels are reached 1–3 hr after ingestion. However, extended-release preparations can delay this up to 11 hr.^6,7 Lamotrigine is reported to have a good margin of safety in humans but a much narrower one in companion and laboratory animals. The average oral lethal dose is 245 mg/kg in mice and 205 mg/kg in rats, yet potentially fatal signs can be seen at lower doses in dogs (40 mg/kg) and cats (5 mg/kg).¹ This is likely due to the species variation in metabolism of lamotrigine. In humans, lamotrigine is metabolized by the liver to an inactive form, lamotrigine-2-N-glucuronide.⁶ Although the same process of glucuronidation has been documented in dogs, a larger proportion of the drug is metabolized to a lamotrigine-2-N-methyl metabolite, which is known to have cardiotoxic effects, such as widening of the QRST complexes or even atrioventricular conduction block.⁷ This case report is the first in the veterinary literature to temporally document serum levels following lamotrigine toxicosis in a dog.

Human literature identifies mostly mild to moderate signs such as drowsiness, ataxia, vomiting, and nausea, with no deaths in the majority of accidental overdoses.² These clinical signs were similar to findings reported by the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center, in which 128 cases of canine lamotrigine toxicosis over an 8 yr period were reviewed. Vomiting, ataxia, lethargy, tachycardia, and tremors were the most common signs. However, more severe findings included seizures, arrhythmias, collapse, and extensor rigidity. When considering only the dogs for whom follow-up was available, this case series reports a 27% mortality rate, with sudden cardiac arrest occurring in the majority of these dogs. The details of each case were not discussed and no specific treatment was highlighted as having an association with outcome.¹ It should be noted that the true course of a toxicosis cannot always be ascertained in veterinary medicine because of the option of elective euthanasia.

Despite a low prevalence of severe side effects of lamotrigine overdose in people, there are several isolated case studies presenting evidence of marked cardiotoxicity identified via changes on ECG, with prolongation of the QT interval being a frequent occurrence.^8,9 Lamotrigine is known to block voltage-gated sodium channels in neural tissue; however, this inhibition may also impact cardiac sodium channels, delaying intraventricular cardiac conduction and resulting in the aforementioned cardiotoxicity.¹⁰ Prolonged QT interval is an indication of delayed cardiac repolarization, which is a documented risk factor for sudden cardiac death in multiple species and has been reported in dogs with familial long QT syndrome.¹¹ Such an abnormality is concerning, and clinicians should be aware of its potential occurrence in lamotrigine toxicosis.

Cardiac signs are considered more likely in canine patients owing to the species variation in the metabolism of lamotrigine, with the predisposition in dogs to forming the toxic lamotrigine-2-N-methyl metabolite.⁷ It is unfortunate that a metabolite standard is unavailable and that we were therefore unable to assay for this toxin; however, our clinical findings support its existence. It is thought that cardiac effects are unlikely to be seen in dogs with ingestion of lamotrigine below 20 mg/kg.¹ In this case report, the presence of ventricular premature complexes and an elevated cardiac troponin I are suggestive of toxic effects to the myocardium. Without an echocardiogram or documentation that the patient’s cardiac troponin I level returned to normal, we cannot fully ascertain that this was a transient myocardial insult resulting from lamotrigine toxicosis. Regrettably, images of the presenting arrhythmia are not available but are completely described above.

Evaluation of QTc in dogs is incompletely studied in clinical canine patients. Although many formulas exist for the application of QT correction, the most appropriate formula in awake, clinical canine patients is not known. One clinical study of conscious dogs with congestive heart failure proposed the use of Fredericia’s formula.¹² Several studies aiming to improve QT correction in canine toxicology and pharmacology research have suggested that the most commonly applied formulas (Bazett and Fredericia) result in variable overcorrection of the QT interval in research beagles. Here we reported four possible formulae, two of which have been validated in awake research dogs to appropriately correct for variation in heart rate—the Todt and Van de Water methods.^4,13 Three of four QT correction methods we report documented QTc prolongation with return to normal over 18–36 hr. One validated method of QT correction (Van de Water) did not document QT prolongation and questions the effects of lamotrigine on cardiac repolarization in this case. In cardiac toxicology research on canine subjects, a QTc alteration of >10% is largely considered significant across a survey of research centers.¹⁴ In this case, regardless of the QTc method applied, we observed a QTc reduction of 11–26%, suggesting that true alterations of cardiac repolarization were observed.

Several therapeutic recommendations have been provided, including routine gastric decontamination, specific antiarrhythmic medications, and electrolyte supplementation.¹⁵ Extracorporeal blood purification was initially considered, as it has been evaluated in human case reports.^10,16 However, there is poor evidence in the literature to support its success in lamotrigine overdose, with each hemodialysis treatment providing only a 17–20% extraction rate.^10,16 Significant individual variation is also documented, making the predictable efficacy of hemodialysis unknown; given the high cost of treatments, it is unlikely to be of feasible benefit in cases of lamotrigine toxicosis in veterinary medicine.

Lamotrigine has a pKa of 5.7, making it a weak base, and has been shown to be lipophilic with a logP of 2.4; as such, there is rationale behind alkalinization and lipid administration as treatment options.^6,7,17 Based on this rationale, ILE was implemented as a form of treatment in several isolated cases of lamotrigine overdose in people, with encouraging outcomes.^10,17,18 With these promising findings recognized on an initial literature search, it was felt prudent to commence ILE in this dog. The apparent benefit in this case report supports the use of 20% intralipid emulsion administered IV as treatment for lethal doses of lamotrigine ingestion in veterinary medicine pending further research.

Despite evidence demonstrating the success of ILE in many drug overdoses, especially those with cardiotoxic insult, the mechanism of action remains unclear. Three theories exist: the first is the concept of a separate compartment within the intravascular space into which the lipophilic drug can diffuse, thereby reducing the amount of free drug, in the plasma and ultimately the tissues, that is able to exert toxic effects. This is known as the “lipid sink” theory. A second hypothesis suggests enhancement of myocardial membrane ion channels such as calcium and potassium to overcome reduced inotropy and delayed conduction. The third is simply the provision of a substrate to energy-depleted myocardial cells.^10,17,19

This case report documents a steady reduction in lamotrigine serum levels over time, with a rapid decrease noted immediately following ILE therapy. In healthy humans, the elimination half-life is reported to vary from 22 to 36 hr.⁷ The reduction noted in this patient exceeds the expected decrease from metabolism, suggesting an alternate form of clearance from the serum. This corroborates the lipid sink theory and further supports the use of lipid emulsion in cases of lamotrigine toxicosis.

Serum concentrations of lamotrigine increase in direct proportion to the amount ingested given its linear pharmacokinetic nature.⁷ However, the human literature reports diverse clinical signs despite similar serum levels and thus an unpredictable clinical correlation to serum concentrations. Death and stupor were commonly reported at equivalent serum levels to this case.²⁰

The strength of this report is that we were able to document inappropriately high serum levels of lamotrigine on presentation and measure these levels throughout the course of the patient’s treatment, showing a marked improvement following instigation of intravenous lipid emulsion therapy. However, one limitation that should be considered is our inability to assay for lamotrigine metabolites to enable correlation of clinical signs with increases in those metabolites known to exert toxic effects. Additionally, the lack of echocardiogram or follow-up cardiac troponin I value prohibits confirmation of lamotrigine-induced cardiotoxicity.

Conclusion

This case report is the first in the veterinary literature to temporally document drug serum concentration following an overdose of lamotrigine, with successful treatment using ILE therapy. Lamotrigine is a poorly studied human medication that has potentially fatal consequences with rapid onset when ingested by domestic animals. Cardiotoxicity is confirmed in large overdoses and often requires urgent therapy. Careful evaluation of the ECG, particularly relative to generation of cardiac arrhythmias and QT interval prolongation, is warranted in patients with suspected toxicity. ILE administration is shown to rapidly reduce the serum concentration of lamotrigine and has an apparent benefit on corresponding clinical signs.