Use of pimobendan in feline congenital heart failure

Abstract

A 6-month-old domestic shorthair cat was referred for evaluation of sudden lethargy and tachypnea following ovariohysterectomy. Upon failure of improvement with supportive care, a cardiologist identified congenital tricuspid dysplasia with signs of heart failure. Furosemide, enalapril, and pimobendan were used to reduce clinical signs and improve length and quality of life.

Case description

On April 7, 2011, a 6-month-old domestic shorthair cat that had been spayed 2 days earlier by animal control was referred to an emergency clinic in downtown Toronto. The patient had been adopted from animal control 10 days previous. There had been no significant findings on presurgical physical examination. The patient was discharged the same day the ovariohysterectomy was performed, at which time the owners noticed lethargy and tachypnea. The owners monitored the patient throughout the day and no change was noted. The owners brought her to their veterinarian’s clinic where the patient was placed on subcutaneous fluids and sent home with buprenorphine hydrochloride (Vetergesic; Champion Alstoe, Whitby, Ontario), 0.17 mL, PO, q12h and amoxicillin plus clavulanic potassium (Clavamox drops; Zoetis, Kirkland Quebec), 1 mL, PO, q12h.

When there was no improvement the following day the owners brought the cat back to their veterinarian for assessment. Blood work revealed mild leukopenia, anemia, hypokalemia, increased total bilirubin, and negative tests for feline immunodeficiency virus antibodies and feline leukemia virus antigen. Treatments included fluids at a rate of 20 mL/h, ampicillin sodium (Novo-ampicillin; Novopharm, Toronto, Ontario), 20 mg/kg body weight (BW), IV, famotidine (Famotidine Omega; Omega Laboratories, Montreal, Quebec), 0.5 mg/kg BW, IV, and hydromorphone (Hydromorphone HP; Sandoz, Boucherville, Quebec), 0.05 mg/kg BW, IV. The patient was transferred to the emergency clinic that evening (April 7th) after no improvement was noted post-treatment.

Upon presentation to the emergency hospital, the patient was tachypnic, dyspneic, and bradycardic. Auscultation revealed harsh lung sounds but no murmur, arrhythmia, wheezes, or crackles. The remainder of the physical examination was within normal limits. Initial diagnostics revealed a packed cell volume (PCV) of 32% [reference interval (RI): 29% to 45%], a blood urea nitrogen (BUN) within 50 to 80 mmol/L (RI: 5 to 12.9 mmol/L), and normal acid base status with mild hyponatremia, hypocalcemia, and hyperglycemia. No free abdominal fluid was detected using an abdominal focused assessment with sonography for trauma (AFAST) and a small amount of pleural fluid was present on a thoracic focused assessment with sonography for trauma (TFAST). Lateral radiographs revealed a tall cardiac silhouette, increased opacity in cranial lung fields, and mild pleural effusion. Ventral-dorsal radiographs revealed severe consolidation of the left cranial lung lobe, pleural effusion on the left side, and increased pulmonary infiltrates in both the right middle lung lobes and all left lung lobes.

Treatment included oxygen support at 1 L/min, intravenous fluids, ampicillin (Novo-ampicillin; Novopharm), 22 mg/kg BW, IV, q12h, azithromycin (Zithromax; Pfizer, Saint-Laurent, Quebec), 10 mg/kg BW, PO, q24h, and buprenorphine (Vetergesic; Champion Alstoe), 0.01 mg/kg BW, IV, q12h. Mild improvement was noted the following day but tachypnea and dyspnea were still present and bronchiovesicular sounds were auscultated bilaterally. Oxygen was gradually reduced throughout the day with continued supportive care, analgesia, and antibiotics. No improvement was noted throughout the day or overnight.

A thoracocentesis yielded 34 mL and 30 mL of fluid from the left and right sides of the chest, respectively. The fluid was serous and yellow. Cytology revealed a low number of inflammatory cells, mainly neutrophils and monocytes, with no evidence of bacteria or degeneration. Post-thoracocentesis, lateral thoracic radiographs revealed a tall cardiac silhouette, increased cranial opacity, and retraced lung lobes consistent with pleural effusion. Severe air bronchograms were noted in the cranial lung lobes, consistent with lung consolidation. Post-thoracocentesis, ventral-dorsal thoracic radiographs confirmed the presence of pleural effusion and pulmonary infiltrates. The patient appeared significantly more comfortable after the thoracocentesis, but her respiratory rate significantly increased throughout the night.

With the increased suspicion of cardiac disease, intravenous fluids were discontinued and furosemide (Salix; Merck Animal Health, Kirkland, Quebec), 1 mg/kg BW, IV, was administered. Antibiotic therapy was continued as previously described. A cardiac consultation resulted in a diagnosis of marked tricuspid dysplasia. Improvement was noted after the administration of furosemide, demonstrated by an increase in appetite and an improvement in respiratory rate and rhythm. The cat was then weaned off oxygen but subsequently became more depressed. She improved when placed back on 0.5 L/min oxygen overnight.

Re-evaluation 1 day later revealed minimal pleural effusion around the heart and a normal physical examination. Elevated total bilirubin was resolving, the cat was no longer dependent on oxygen, and mild improvement in respiratory rate and rhythm was noted. Furosemide (Apo-furosemide; Apotex, Toronto, Ontario) was given at a maintenance dose of 1 mg/kg BW, PO, q24h and the patient was started on pimobendan (compounded by Habers Pharmacy, Toronto, Ontario), 0.3125 mg, q12h, and enalapril (Enacard; Mérial Canada, Baie d’Urfé, Quebec), 0.5 mg, PO. The cat was given buprenorphine (Vetergesic), 0.015 mg/kg BW, IV, and was continued on amoxicillin and clavulanic acid (Clavaseptin; Vétoquinol, Lavaltrie, Quebec), 50 mg, PO, q12h and azithyromycin (Zithromax, Pfizer), 0.6 mL, PO, q12h for 2 wk.

For the past 2 y, the cat has been maintained on enalapril (Enacard; Mérial Canada), 2.5 mg, PO, q24 h, furosemide (Apo-furosemide; Apotex), 20 mg, PO, q24h, and pimobendan (compounded by Habers pharmacy) 0.3125 mg, PO, q12h. No signs of cardiac disease or congestive heart failure were evident on a recent physical examination.

Discussion

Congenital malformations and valvular heart disease, such as tricuspid dysplasia, are rare in cats (1). Tricuspid dysplasia can be due to focal or diffuse thickening of the valve leaflets, underdevelopment of chordae tendinae and papillary muscles, incomplete separation of valvular components of the ventricular wall, or focal agenesis of valvular tissue (2). These anomalies result in the back-flow of blood from the right ventricle into the right atrium, and back into the circulation, leading to leakage of blood outside of vessels and into spaces such as the thoracic cavity. Such abnormal flow ultimately results in clinical signs such as dyspnea, lethargy, and possibly death. Cats with cardiac disease do not always present with an audible murmur (1). This makes diagnosing cardiac disease very challenging, especially in young apparently healthy cats. An echocardiogram should be an important diagnostic test to consider in future cases of healthy young cats that do not recover well from anesthesia and are showing signs of unthriftiness and respiratory changes on physical examination and diagnostic imaging.

Typical home therapy for cats with congestive heart failure includes a diuretic (e.g., furosemide) at a starting dose of 1 to 2 mg/kg BW, IM or PO, q12h, and an ACE-inhibitor (e.g., enalapril) at a starting dose of 0.25 mg/kg BW, PO, which is later increased to 0.5 mg/kg BW, PO, q12h at the 5- to 7-day re-check (1). The use of pimobendan is off-label in cats as there are no scientific studies on pharmacokinetics or pharmacodynamics in this species. It has been hypothesized that a dosage regimen comparable to that in dogs (0.25 mg/kg BW, PO, q12h) is well-tolerated in cats (1). Pimobendan works by inhibiting phosphodiesterase III and by calcium sensitization. Inhibition of phosphodiesterase III reduces the breakdown of cyclic adenosine monophosphate (cAMP), an important secondary messenger in cardiac myocytes (3). The result is an increase in the stimulation of cells and thus an increase in inotropy. Calcium sensitization is the predominant inotropic effect pimobendan has in patients with heart failure. Pimobendan increases the affinity of cardiac troponin C, a regulatory site for calcium, resulting in increased binding of calcium to troponin C and myofilament interaction (4–6). The end result is an increase in the strength of contraction without an increase in myocardial oxygen demand (7).

The use of pimobendan in feline congenital heart conditions has not been thoroughly examined or reported. The limited number of studies examining pimobendan in cats has looked mainly at dilated, hypertrophic, and restrictive cardiomyopathy (8,9). One study examined the use of pimobendan in 170 cats with other various forms of heart disease (8). The median pimobendan dose was 0.24 mg/kg BW, PO, q12 h. Cats (98%) were concurrently receiving furosemide as part of the treatment regimen. Sixty-two percent of cats had documented rechecks and of these patients, 66% had resolution of congestive heart failure. Some cats had resolution of pleural effusion (55%) and pericardial effusion (43%) at the time of the recheck examination. Survival analyses revealed that 26% of cats were still alive at last contact and median survival time from initial examination was 151 d (range: 1 to 870 d). This study revealed that pimobendan is well-tolerated in a large population of cats with advanced heart disease. Although none of these cases had congenital heart disease, the use of pimobendan in cats with systolic dysfunction is well-assessed and appears to be well-tolerated.

Another study evaluated the use of pimobendan in cats with heart failure, characterized by ventricular systolic dysfunction (9). Twenty-seven cats were included in the study and 3 cats (11%) had congenital heart failure resulting in ventricular systolic dysfunction. One of the cats with congenital heart failure had tricuspid valve dysplasia with pulmonary hypertension and a right to left shunting patent ductus arteriosus. In this study pimobendan was administered at a dose of 0.26 +/− 0.08 mg/kg BW, PO, q12h (9). Follow-up revealed marked decreases in dyspnea and other signs of congestive heart failure. Survival analyses revealed that all cats died; median survival time was 167 d (range: 32 to 339 d). According to this study, mean survival time was longer compared with cats in heart failure not receiving treatment with pimobendan.

The dosage of pimobendan in these studies was determined based on the presently acceptable dosage established for dogs. Although these dosages appear to be well-tolerated and beneficial in managing heart failure, limited studies on the pharmacokinetics and pharmacodynamics of pimobendan in cats complicates determination of correct dosages in other species. One study considered the use of a single dose of pimobendan in healthy cats, and determined that compared with dogs, the agent reaches a concentration more than 4 times the recorded level in dogs. Further, the elimination half-life is 3 times longer than previously recorded in dogs (10). This may need to be considered in future studies assessing the most effective dosage regimen for use of pimobendan in feline patients with heart disease. CVJ