Clinical Signs of Cardiovascular Effects Secondary to Suspected Pimobendan Toxicosis in Five Dogs
The purpose of this study was to review the medical records of dogs that were either suspected or known to have ingested large doses of pimobendan and to describe the clinical signs associated with pimobendan toxicosis. The database of Pet Poison Helpline, an animal poison control center located in Minneapolis, MN, was searched for cases involving pimobendan toxicosis from Nov 2004 to Apr 2010. In total, 98 cases were identified. Of those, seven dogs that ingested between 2.6 mg/kg and 21.3 mg/kg were selected for further evaluation. Clinical signs consisted of cardiovascular abnormalities, including severe tachycardia (4/7), hypotension (2/7), and hypertension (2/7). In two dogs, no clinical signs were seen. Despite a wide safety profile, large overdoses of pimobendan may present risks for individual pets. Prompt decontamination, including emesis induction and the administration of activated charcoal, is advised in the asymptomatic patient. Symptomatic and supportive care should include the use of IV fluid therapy to treat hypotension and address hydration requirements and blood pressure and electrocardiogram monitoring with high-dose toxicosis. Practitioners should be aware of the clinical signs associated with high-dose pimobendan toxicosis. Of the dogs reported herein, all were hospitalized, responded to supportive care, and survived to discharge within 24 hr of exposure.
Introduction
Pimobendana is a benzimidazole-pyridazinone calcium sensitizer and phosphodiesterase III inhibitor that functions as an inodilator. In veterinary medicine, pimobendan is prescribed for the treatment of congestive heart failure (CHF), usually in combination with diuretics and/or angiotensin-converting enzyme inhibitors.1–3 In 2007, pimobendan received Food and Drug Administration approval in the United States as a treatment of CHF in dogs and is currently being marketed and widely used in both general practices and specialty clinics.
Pimobendan is available in the United States as a flavored, chewable tablet in 1.25 mg, 2.5 mg and 5 mg sizes. In Canada, Europe, and Australia, pimobendan is available in a capsular formulation in 1.25 mg, 2.5 mg, and 5 mg sizes. The recommended dose range is 0.2–0.6 mg/kg per os (PO) q 12 hr.4 Pimobendan appears to have a wide safety margin.5,6 Due to the flavored nature of the tablet, there is potential for accidental ingestion of large quantities. To the authors’ knowledge, there are no previous published case reports of pimobendan toxicosis in either large or small animal veterinary medicine. In this report, the authors describe seven dogs that presented for either suspected or confirmed ingestion of large doses of pimobendan and the clinical signs associated with pimobendan toxicosis.
Materials and Methods
The database of Pet Poison Helpline, an animal poison control center located in Minneapolis, MN, was searched for cases involving pimobendan toxicosis from Nov 2004 to Apr 2010. Seventy-four calls were analyzed involving 88 dogs and 10 cats. Patients ingesting multiple medications were excluded from this case series to prevent unrelated clinical signs from being reported. In addition, those patients ingesting only a therapeutic dose of pimobendan were excluded from this case series. A total of seven dogs were ultimately identified as having ingested presumptive toxic amounts of pimobendan (ranging from 2.6 mg/kg to 21.3 mg/kg). A toxic amount of pimobendan was considered to be an amount that was greater than 0.6 mg/kg q 12 hr if clinical signs were observed, or doses that exceeded 2 mg/kg, regardless of the presence of clinical signs.
Results
Cases 1–3
Three dogs from the same household were presented to their local emergency veterinarian after having ingested a bottle containing 30 tablets of 5 mg pimobendan approximately 1 hr prior to pre-sentation. Based on owner history, it was unknown which dog, or how many of the dogs, ingested what amount. The pimobendan prescription was intended for a fourth dog that was not presented to the veterinarian. The fourth dog may also have been exposed to the product, but due to the dog’s age, the owner declined evaluation of this particular pet.
The first dog in the household was a 14 mo old male whippet weighing 14 kg that was otherwise in good health. If it had in-gested the entire bottle, the maximum toxic ingestion would have been 10.7 mg/kg. Approximately 1 hr after ingestion, at the time of presentation to the veterinary clinic, the dog was bright, alert, hydrated, had a normal body condition, was normothermic (body temperature was 39°C; reference range, 37.5–39.2°C), and had a respiratory rate of 30 breaths/min (reference range, 15–30 breaths/min). The dog’s capillary refill time (CRT) was profoundly prolonged (approximately 7 sec) and he was tachycardic (estimated heart rate was 360 beats/min; reference range, 80–120 beats/min). There was no printed record of the electrocardiogram (ECG) performed by the attending veterinarian at the time of presentation. Emesis was induced with apomorphine (0.03 mg/kg), which produced a large amount of food, brown gastric liquid, flecks of blue plastic foreign material, and several pimobendan tablets. The dog was then treated with a single dose of activated charcoalb (15 mL/kg PO). An abbreviated cage-side chemistryc revealed hypernatremia (155 mmol/L; reference range, 139–150 mmol/L) and a packed cell volume of 60% (reference range, 37.0–55.0%). Potassium, chloride, ionized calcium, glucose, blood urea nitrogen, total protein, and creatinine were within normal limits. The dog was hypotensive (Dopplerd systolic blood pressure [SBP] was 78 mm Hg; reference range, 100–120 mm Hg), and the dog was administered a 300 mL (21.4 mg/kg) IV bolus of crystalloids over an unknown duration of time. Two hours later, the heart rate had decreased to 110 beats/min and SBP had increased to 130 mm Hg. This first patient was hospitalized for further monitoring and supportive care and was maintained on IV crystalloids (5 mL/kg/hr) with 20 mEq/L potassium chloride supplementation. Six hours later, the heart rate and SBP remained within clinically accepted limits (80 beats/min and 140 mm Hg, respectively). Twelve hours later, the dog was discharged.
The second dog in the household was a 14 mo old female whippet weighing 11.9 kg that was in good health prior to the presumptive ingestion of pimobendan. The maximum possible toxic ingestion was estimated to be 12.6 mg/kg. Approximately 1 hr after ingestion, at the time of presentation to the veterinary clinic, the dog was bright, alert, hydrated, had a good body condition, was normothermic (38.8°C), and had a respiratory rate of 30 breaths/min. The mucous membranes were pink with a normal CRT; however, the dog was tachycardic with an estimated heart rate of 336 beats/min. An ECG was not performed. Emesis was induced with apomorphine (0.03 mg/kg IV), which resulted in the production of a large amount of brown gastric liquid. No pimobendan pills were noted in the vomitus. At the time of presentation, an abbreviated cage-side chemistry panelc was performed, including glucose, blood urea nitrogen, creatinine, ionized calcium, and electrolytes. All were within reference intervals. The dog had a packed cell volume of 54% and a total protein of 6.8 g/dL (reference range, 5.8–7.9 g/dL). A Dopplerd SBP was also within normal limits (120 mm Hg). The dog was administered activated charcoalb (15 mL/kg PO) and hospitalized for 4 hr for monitoring, but was not placed on IV fluid therapy due to financial constraints. During the first 4 hr of hospitalization, the dog’s heart rate decreased to 136 beats/min. Electrolytes were re-evaluatede 2 hr after presentation and remained within the reference ranges. Shortly thereafter, 3 hr after initial presentation, re-evaluation of the SBP revealed that the dog had become hypotensive (88 mm Hg), but the dog appeared clinically normal. The owner declined hospitalization for IV fluid therapy and monitoring, and the dog was discharged within 4–5 hr of initial presumptive ingestion of the pimobendan. Approximately 8 hr later, this dog presented to the emergency clinic because she vomited at home. At that time, the SBP was normal (100 mm Hg), and no further diagnostics were performed. The dog was not administered any form of treatment, but was instead discharged for home monitoring. She developed no further clinical signs of pimobendan toxicosis.
The third dog in the household was an 8 yr old male whippet weighing 16 kg that had been previously diagnosed with a soft right-sided systolic murmur. Had he ingested the entire bottle of pimobendan, the maximum toxic ingestion would have been 9.4 mg/kg. Approximately 1 hr after ingestion, at the time of presentation to the veterinarian, the dog was alert, mildly dehydrated, and had a body condition score of 2/5. Physical examination findings revealed a normal body temperature (38.8°C), respiratory rate (36 breaths/min), and CRT. The heart rate was mildly elevated (160 beats/min). The initial SBP revealed hypertension (200 mm Hg). Due to financial constraints, no other diagnostics were performed. Emesis was induced with apomorphine (0.03 mg/kg IV), which produced a large amount of food and brown fluid. There was no evidence of pimobendan pills in the vomitus. The dog was administered one dose of activated charcoalb (17.5 mL/kg PO), but spontaneously vomited the charcoal approximately 3 hr after administration. Further hospitalization was declined, and the dog recovered uneventfully.
Case 4
Case 4 was a previously healthy 13 mo old male Boston terrier weighing 14.6 kg. The dog had consumed 30 tablets of 1.25 mg pimobendan, resulting in a toxic ingestion of 2.6 mg/kg. On presentation to the veterinary hospital, several hours after the calculated ingestion of the tablets, the dog was nervous, but alert and responsive. The dog’s temperature was mildly elevated (39.4°C), and the dog was both tachypneic (50 breaths/min) and tachycardic (210 beats/min). Mucous membranes were injected, and the CRT was <2 sec. A grade 3/6 heart murmur was auscultated at that time, which had not been reported by the veterinarian on previous examinations. Diagnostics performed on presentation included a complete blood countf, routine serum biochemistryg, and Dopplerd blood pressure monitoring. A mild decrease in globulin (2.4 g/dL; reference range, 2.5–4.5 g/dL), a mild increase in γ-glutamyltransferase (8 U/L; reference range, 0–7 U/L), and a mild hypokalemia (3.3 mmol/L; reference range, 3.5–5.8 mmol/L) were noted. The dog was mildly hypertensive (SBP was 160 mm Hg), and a lead II ECG revealed a sinus tachycardia. The dog was referred to a tertiary facility for further diagnostics and monitoring.
On admission to the tertiary facility, the heart rate had decreased to 160 beats/min; however, the murmur was still present and unchanged. Due to the dog’s anxiety and hypertension, butorphanol (0.2 mg/kg IV) was administered. The heart rate decreased to 120 beats/min. The dog was monitored overnight with continuous blood pressure and ECG monitoring. Overnight, the dog maintained a normal sinus rhythm. The heart rate remained within normal limits (80–100 beats/min); however, the dog had periodic bursts of supraventricular tachycardia (between 180 and 200 beats/min) for short periods of time, even while at rest. In addition, the dog had episodes of hypertension (SBP was 180–190 mm Hg), but these episodes were thought to be due, at least in part, to the dog’s agitation. Throughout the night, electrolytesh remained within the reference ranges. Twenty-four hours after initial ingestion, the heart murmur had decreased to a barely audible intensity. The dog was discharged and recovered uneventfully. On subsequent veterinary visits, the heart murmur was no longer identified.
Case 5
A 12.5 yr old spayed female mixed-breed dog weighing 27.7 kg presented to an emergency veterinary clinic for coughing, respiratory distress, and collapse. Pertinent physical exam findings included a mildly elevated heart rate (136 beats/min), poor femoral pulse quality, a grade 3/6 systolic murmur, and increased bronchovesicular sounds over all of the lung fields. Thoracic radiography revealed enlargement of the left atrium with areas of interstitial infiltrates in both the caudal and cranioventral fields. Echocardiography demonstrated a fractional shortening of 21%, intermittent ventricular premature contractions, and asynchronous contractions. The ratio of the left atrium: aorta was 2.73. The dog was presumptively diagnosed with CHF secondary to dilated cardiomyopathy (DCM). The dog was treated with furosemide (100 mg intramuscularly) and prescribed oral pimobendan (10 mg in the morning and 5 mg in the evening), furosemide (75 mg PO q 12 hr), and enalapril (15 mg PO q 24 hr) during hospitalization. Thirty minutes prior to discharge, it was discovered that the dog had accidentally chewed through the pimobendan bottle and ingested 105 mg, resulting in a toxic exposure of 3.8 mg/kg. Emesis was induced with apomorphine (0.036 mg/kg IV), which produced brown gastric fluid. No pills were noted in the vomitus. A single dose of activated charcoali (2.2 mL/kg) was administered, and the dog was hospitalized for an additional 24 hr. Continuous ECG and blood pressure monitoring were performed. Throughout the night, the dog was tachycardic (150–180 beats/min). In addition, occasional ventricular premature contractions, which had been observed prior to ingestion of the pimobendan, were noted. The dog remained normotensive throughout the observation period, and no other clinical signs developed. The dog was discharged the following day.
Cases 6 and 7
The last two dogs were from the same household. The first was a 1 yr old spayed female Belgian shepherd weighing 28.2 kg that was in good health (case 6) and the second was a 7 yr old castrated male Doberman pinscher weighing 44 kg that was previously diagnosed with DCM (case 7) 4 mo prior to presentation and was being treated with pimobendan at 0.2–0.3 mg/kg q 12 hr. Both dogs were presented to their veterinarian after ingesting 120 pimobendan (5 mg) tablets. The time of ingestion was unknown. The owner suspected that case 6 was the most likely to have ingested the pimobendan. The presumptive maximum ingestion was 21.3 mg/kg. At the time of presentation, case 6 was bright, alert, and had a normal heart rate (100–145 beats/min). Baseline SBP was 150 mm Hg, and an ECG revealed no significant findings. Case 6 was hospitalized overnight and remained subclinical. After being discharged the following day, case 6 vomited pieces of plastic resembling the bottle that had contained the pimobendan.
Prior to the possible pimobendan toxicosis, case 7 was already receiving pimobendan, digoxin, enalapril, and furosemide for management of DCM. The presumptive toxic ingestion for case 7 was 13.6 mg/kg. On presentation to the emergency clinic, a grade 2/6 systolic murmur was detected, the heart rate was normal (100 beats/min), and no arrhythmias were noted. At the time of potential toxicosis, baseline SBP was normal (120 mm Hg), and an ECG revealed a heart rate ranging from 134 beats/min to 156 beats/min with periodic ventricular trigeminy present. A second ECG 4 hr later revealed an idioventricular rhythm and a heart rate of 126 beats/min, which resolved shortly thereafter. Case 7 remained stable overnight, but none of his cardiac medications were administered while hospitalized. He was discharged after 24 hr. A routine follow-up phone call by the veterinarian revealed that the dog died 3 days after initial possible pimobendan overdose, and it is unknown whether this was due to toxicosis or due to complications from the underlying cardiac disease.
Discussion
This case series is the first report of suspected pimobendan toxicosis in dogs and describes the potential clinical signs associated with pimobendan overdose. In this case series, the potential ingested doses involved ranged from 2.6 mg/kg to 21.3 mg/kg (approximately 10–70 times the recommended therapeutic dose). The clinical signs observed with suspected pimobendan toxicosis included severe tachycardia, mild hypotension or hypertension, and identification of a new (transient) heart murmur. These signs were consistent with either the pharmacodynamic effects of phosphodiesterase inhibition (resulting in peripheral vasodilation with a reflex tachycardia) or direct effects on the myocar-dium (resulting in either sinus tachycardia or supraventricular tachycardia).7 Although dose-dependent effects are expected with pimobendan toxicosis, this series also illustrates a potential range of individual responses to overdoses of pimobendan.8,9 For example, some dogs remained subclinical whereas some developed clinically relevant adverse effects.
There are several inherent limitations to this retrospective case series. As with almost all cases of animal poisonings, the exact dose ingested of a toxicant and time of ingestion are often unknown. Animal poison control centers must err on the most conservative dose (i.e., the estimated maximum dose ingested) on which to base their treatment recommendations. In this case series, it was possible to estimate a maximum dose in five of the seven cases, but the exact dose could not be confirmed. General methods for confirming ingestion of a toxicant include presence of the pills after inducing emesis and/or measuring systemic blood levels (the latter of which is not currently available for pimobendan). Furthermore, the quality or detail of information collected retrospectively from medical records was dependent on the attending veterinarian. It is also important to note that accurate blood pressure monitoring systems were either not always available or blood pressure monitoring was declined by the owners due to financial reasons.
Ingestions of large quantities of pimobendan appear to occur with some frequency. The database of Pet Poison Helpline was searched for cases involving pimobendan from Nov 2004 to April 2010. During that time period, 98 cases were identified. The majority of the animals (84/98, 86%) were considered subclinical by the owner when the initial call to Pet Poison Helpline was made. However, pets with mild cases of hypotension and/or tachycardia may not have clinical signs that were apparent to their owners. Of the 98 potential intoxications, 34% (33/98) reported ingesting doses within the therapeutic dose range recommended by the manufacturer for dogs.3,6 Sixty-three percent of the callers (62/98) reported ingested doses ranging from 0.6 mg/kg to ≤8 mg/kg. In the remaining three cases, the dose was either not recorded or available. For all calls made to Pet Poison Helpline, the maximum dose ingested was 27.5 mg/kg. Fifty-four ingestions were either witnessed or confirmed (e.g., by observing pills in emesis, identification of a chewed or empty pill vial, a single pet household). Twenty-four of those were considered nontoxic doses (<0.6 mg/kg). The median dose for the 54 confirmed ingestions was 0.6 mg/kg (range, 0.1–23.4 mg/kg). Forty-one ingestions were considered unconfirmed ingestions (e.g., owners did not witness the ingestion, no chewed or empty pill vial was found, no pills were found in emesis, the household contained multiple pets that had access to the medication). In those 41 cases, the median calculated dose for potential exposure was 6.9 mg/kg (range, 0.15–27.5 mg/kg). The majority of the 98 cases did not develop signs, and few owners ultimately sought veterinary attention.
There are few studies on the use of pimobendan in cats.10–12 Anecdotally, pimobendan has been prescribed without adverse effects in feline cases involving poor systolic dysfunction.10–12 To date, no formal safety or pharmacokinetic studies have been performed in cats. Ten cases reported to Pet Poison Helpline involved potential ingestion by cats. Prognosis in cats affected by pimobendan toxicosis is likely similar to dogs, and intoxications should be treated with close observation, decontamination, and symptomatic and supportive care as needed.
Overall, pimobendan appears to have a wide safety margin.1,5,6,13 In one toxicity study performed by the manufacturer of pimobendan, healthy beagle dogs administered either 0 mg/kg, 0.5 mg/kg, 2.0 mg/kg, or 8.0 mg/kg IV pimobendan daily for either 4 wk or 7 wk showed dose-dependent increases in heart rate at doses >0.5 mg/kg. In the 8 mg/kg group, 30 min after dosing in the fourth week of treatment, the mean heart rate was 174 beats/min versus 125 beats/min at baseline. Blood pressure monitoring was not evaluated in that study. In addition, dogs developed a dose-dependent increase in cardiac histopathologic lesions at doses ≥2 mg/kg, including myxomatous thickening of the mitral valve, endocardial thickening in the left ventricular outflow tracts, and small foci of subendocardial necrosis with scarring.6 Other adverse effects included mild increases in serum alkaline phosphatase in the 0.5 mg/kg (n=1/6), 2.0 mg/kg (n=2/6), and 8.0 mg/kg (n=3/6) groups. Concomitant histopathologic hepatic lesions were not observed. One dog in the 8 mg/kg group had decreased hemoglobin and erythrocyte counts.6
In a separate safety study performed in 24 healthy dogs receiving 0 mg/kg/day, 0.5 mg/kg/day (1×), 1.5 mg/kg/day (3×), or 2.5 mg/kg/day (5×) divided and administered q 12 hr PO, heart murmurs (grades 2–3/6) were detected in one dog in the 3× group (on Day 65) and two dogs in the 5× group (on Days 135 and 163, respectively).6 Mild decreases in diastolic blood pressure and SBP were seen in the 3× and 5× groups, respectively, 2 hr after oral dosing. At necropsy, the dogs had similar cardiac histopathologic lesions to those seen in the previous safety evaluations.6,13,14
To the authors’ knowledge, no safety studies have been performed using higher than recommended doses in dogs with concurrent CHF. One could speculate that overdoses of pimobendan may exacerbate signs already present in dogs with advanced CHF, making it difficult to differentiate between the effects of pimobendan overdose and the primary cardiac disease. Presumably, dogs with CHF (similar to the dogs in the toxicity studies) would also be at increased risk for long-term effects due to valvular or myocardial damage, depending on the dose ingested. Currently, no evidence exists regarding the potential for either cardiac histopathologic lesions or long-term effects with acute toxic ingestion. That said, with the wide margin of safety generally seen with pimobendan, it is not expected.
Pimobendan is converted to the active metabolite UD-CG 212 Cl by oxidative demethylation in first-pass hepatic metabolism.15 Pimobendan and the active metabolite are >90% protein-bound, and the metabolite is considered to be more potent than pimobendan. Pimobendan is excreted mainly in the bile and feces, but a small amount is excreted in the urine of human patients. In previously reported studies, peak plasma concentrations of pimobendan were obtained within 1 hr of ingestion.13 In dogs, the maximum plasma concentrations were observed 1–4 hr postdosing; however, maximum inotropic effects were delayed.10,16 In humans, even when the plasma concentrations were undetectable, significant hemodynamic effects were observed, suggesting strong tissue binding and slow myocardial washout.15 Therefore, clinical signs in severe intoxications may be either delayed or prolonged. Due to its highly protein-bound nature, higher plasma concentrations may contribute to the toxic effects in hypoalbuminemic dogs, those who are taking other highly protein-bound drugs, or dogs with pre-existing hepatic disease.
Conclusion
Due to the chewable, flavored formulation of pimobendan, there is a potential for increased risk of toxicosis to dogs (and to a lesser extent, cats). Pimobendan overdoses through inadvertent ingestion of large quantities of drug are likely more common than reported here, but the consequences of such ingestions are relatively benign. However, in patients with underlying disease (e.g., cardiac disease, hyperthyroidism), appropriate compensatory responses to hypotension (e.g., reflex tachycardia) may not occur, worsening the potential for clinical signs. In addition, patients with underlying metabolic disease (e.g., hepatic, renal) may have altered metabolism of the drug, resulting in prolonged elimination and potential for exacerbation of clinical signs.
As with all potential intoxications in veterinary medicine, prompt decontamination is imperative. In several cases reported to Pet Poison Helpline and in the cases described herein, some of the ingested tablets were obtained after emesis induction. Because of rapid gastrointestinal absorption, monitoring is recommended even if it appears that the tablets were retrieved, particularly in pets with underlying cardiac disease that may be unable to compensate appropriately. Following decontamination, the administration of a single dose of activated charcoal might have some benefit. Treatment generally consists of fluid therapy to address the hypotension, but should be used judiciously in pets with known cardiac disease/heart failure. Appropriate blood pressure and ECG monitoring are recommended, particularly in animals with pre-existing cardiovascular disease. With appropriate and rapid decontamination, supportive care, and monitoring, the prognosis for pimobendan toxicosis is excellent in healthy patients without cardiac disease. In patients with underlying cardiac disease, more aggressive therapy and monitoring is likely warranted. Nevertheless, the prognosis is generally fair to good.
Contributor Notes
L. Reinker's present affiliation is Loomis Basin Veterinary Clinic, Loomis, CA.
