Transvenous Heartworm Extractionin a Ferret With Caval Syndrome

Introduction

Dirofilaria (D.) immitis has been reported to cause natural and experimental infection in the domestic ferret,^1–8 and susceptibility of ferrets to D. immitis in an experimental setting appears to be high. Ferrets experimentally inoculated with D. immitis larvae were found to have an overall infection rate of 100%, with average worm recovery rates of up to 54%.¹ These findings are similar to canine susceptibility to D. immitis.^9,10 As with feline heartworm disease, the ferret’s small size can result in significant clinical disease and death, despite the presence of very few heartworms. Though several case reports of heartworm disease in ferrets have been published,^2,5,6,11 the prevalence of natural dirofilariasis in the domestic ferret remains unknown.

Caval syndrome is a life-threatening complication of chronic heartworm disease and has been described in dogs, cats, and ferrets.^{1,2,10,12–15} The syndrome frequently results in hemoglobinemia, hemoglobinuria, and hemolytic anemia, as well as renal and hepatic dysfunction.^4,13,15 Caval syndrome occurs when adult heartworms migrate from the pulmonary arteries to the right atrium, right ventricle, and vena cava. Heartworms frequently become entrapped within the tricuspid valve, resulting in tricuspid regurgitation and hemolysis.¹⁰ Pulmonary hypertension may develop in chronic heartworm disease, leading to right-sided heart failure and reduced cardiac output.¹⁰ The principal therapy for dogs and cats with caval syndrome is transvenous heartworm extraction; however, even with intervention, prognosis is guarded. Mortality rates are as high as 42% in dogs.¹⁰

The purposes of this report are to describe successful transvenous heartworm extraction in a ferret with caval syndrome and to discuss the clinical and diagnostic abnormalities associated with heartworm disease in ferrets.

Case Report

A 10-month-old, spayed female, fitch ferret was admitted to the Texas A&M University Veterinary Medical Teaching Hospital for evaluation of an acute onset of lethargy, trembling, and collapse. The ferret was purchased from a pet store several months prior to presentation. She was fed an adult maintenance ferret diet and was not on a heartworm preventative. On the morning of presentation, she had been eating and drinking normally and was energetic; however, when the owner returned home in the afternoon, the ferret was lying at the bottom of her cage and appeared reluctant to move. When removed from her cage, she began shaking and was unable to ambulate.

On initial physical examination, the ferret was obtunded and 5% to 8% dehydrated. Body weight was 1.72 lbs (0.78 kg), and body condition score was 3/5. Mucous membranes were pale pink with a capillary refill time of <2 seconds. Cardiac rhythm was irregular, with a rate ranging from 120 to 220 beats per minute. Femoral pulses were fair with notable deficits. Respiratory rate was 40 breaths per minute, and lungs were clear in all fields on auscultation. The abdomen was slightly distended and appeared painful on palpation. Posterior paresis, loss of normal dorsal spinal curvature, and ataxia were obvious in the ferret’s gait. Primary differential diagnoses considered for an obtunded, ataxic ferret included hypoglycemia secondary to an insulinoma or sepsis, cardiovascular disease, lymphoma, and gastrointestinal foreign body.

Blood was drawn from the cranial vena cava and analyzed to rule out hypoglycemia, electrolyte abnormalities, and renal disease. The ferret was mildly anemic with a packed cell volume of 42% (reference range 47% to 51%), and total solids were low normal at 5.4 g/dL (reference range 5.3 to 7.2 g/dL).¹⁶ No other abnormalities were noted. An intravenous catheter was placed in the right cephalic vein, and lactated Ringer’s solution^a was administered at a rate of 48 mL/kg per day to support the cardiovascular system. The ferret was placed in a temperature-controlled environment^b (85°F [29.4°C], 70% humidity) overnight. The following morning, a complete blood count (CBC) was evaluated and found to be unremarkable aside from the mild anemia (41%; reference range 47% to 51%) and a mild mature neutrophilia (4131/μL; reference range 725 to 2409/μL).¹⁶ Repeat serum biochemical analysis was within normal limits.

Whole-body radiographs showed decreased detail in the cranial abdomen, suggestive of effusion or mesenteric lymphadenopathy. The pulmonary arteries were large and tortuous, and the vertebral heart score was normal at 5.4 (reference range 5.23 to 5.47).¹⁷ Abdominal ultrasonography was performed, and abnormal findings included renal cysts present bilaterally, a small amount of free fluid in the abdomen, and enlarged jejunal lymph nodes. An ultrasound- guided cystocentesis was performed, and the urine collected was bright green in color. Urinalysis results included a specific gravity of 1.042, large quantities of bilirubin, trace blood, three to five granular casts per low-powered field (LPF), one to three white blood cells per high-powered field (HPF), three to five red blood cells per HPF, two to four squamous epithelial cells per LPF, and moderate crystalluria. In the light of multiple findings suggestive of heartworm disease, including pulmonary artery enlargement and bilirubinuria, a heartworm antigen enzyme-linked immunosorbent assay^c (ELISA) was performed. Results of the ELISA were strongly positive.

Echocardiographic findings included the presence of parallel hyperechoic “equal signs” present in the right atrium and ventricle and main pulmonary artery that were consistent with the presence of heartworms [Figure 1]. A mild amount of tricuspid regurgitation was documented, and the tricuspid regurgitation velocities were mildly elevated (2.96 meters per second), suggesting mild pulmonary hypertension. The main pulmonary artery was not enlarged, and both atria were normal in size. Left ventricle systolic function was normal based on a fractional shortening of 52%¹⁸ (i.e., the percentage of change in the left ventricular cavity dimension with systole). A sinus tachycardia with a heart rate of 250 beats per minute and occasional premature beats were noted during the echocardiographic examination. The premature beats were only identified during the echocardiogram and not during a subsequent electrocardiogram, so the origin of the premature beats could not be identified. The ferret was diagnosed with caval syndrome based on the echocardiographic presence of heartworms within the heart, in combination with mild anemia and biliverdinuria.

Because of the poor prognosis associated with medical treatment alone,^2,4 transvenous heartworm retrieval was recommended. Anesthesia was induced and maintained with isoflurane.^d The ferret was placed in left lateral recumbency, and the right side of the neck was sterilized. An incision was made over the right jugular vein, and careful dissection was performed to isolate the vein. Following a venotomy, a basket endoscopic retrieval device^e was inserted into the vein and advanced into the cranial vena cava with fluoroscopic guidance. Initially, the device would not advance into the right atrium because of the presence of heartworms in the cranial vena cava.

With careful manipulation, three heartworms (two females, one male) were manually extracted from the cranial vena cava and right atrium. Worms had been identified in the right ventricle during transthoracic echocardiography; however, the retrieval device could not be fully extended into the right ventricle because of the small size of the animal. Since successful removal of the heartworms from the cranial vena cava and right atrium alone was anticipated to result in an improved clinical status, continued attempts at retrieving the worms in the right ventricle were not pursued. The jugular vein was permanently ligated both proximally and distally, and the incision was closed in a routine manner.

A transthoracic echocardiogram performed following the procedure documented the persistent presence of heartworms in the right ventricle and no worms present in the right atrium. The ferret recovered without complication and was discharged the following day with prednisolone^f (0.5 mg/kg per os [PO] q 12 hours) and ivermectin^g (55 mcg PO monthly). The urine returned to a yellow color within 48 hours of heartworm extraction.

The ferret was returned for reevaluation at 19 days and again 5 months following heartworm extraction. At 19 days, she was presented with a 2-day history of coughing and a blue hue to the abdomen. The owner reported the ferret was energetic and had a good appetite since being discharged. On physical examination, the heart rate was 160 beats per minute, respiratory rate was 80 breaths per minute, and mucous membranes were pink and moist. No murmurs or arrhythmias were auscultated, and all lung fields were clear. Hair on the abdomen, which had been shaved for abdominal ultrasound during the previous visit, was growing back and creating the bluish hue. Thoracic and abdominal radiographs were repeated; these showed increased opacity in the caudodorsal lung fields and decreased detail in the cranial abdomen, consistent with free fluid. The ferret was treated with furosemide^h (1 mg/kg PO q 12 hours for 14 days) and prednisolone (0.3 mg/kg PO q 12 hours for 7 days, then tapered to q 24 hours thereafter for a total of 2 months).

Five months following heartworm retrieval, the ferret was presented for a scheduled reevaluation. The owner reported the ferret had a good appetite and energy level, with no coughing, sneezing, or diarrhea. Occasionally the owner observed green-colored urine. As directed, the owner had discontinued the prednisolone 2 months after initial diagnosis and the furosemide approximately 2 weeks after the second visit. The ferret was bright, alert, and responsive. Heart rate was 180 beats per minute, respiratory rate was 40 breaths per minute, and mucous membranes were pink and moist. Femoral pulses were strong and synchronous. The remainder of the physical examination was unremarkable.

Thoracic radiographs were repeated, and vertebral heart score remained static at 5.4. An echocardiogram was repeated that documented the continued presence of heartworms in the right ventricle only. Urine was collected via cystocentesis, and the color was a pale green. Abnormal CBC findings included a mild anemia (41%; reference range 47% to 51%) and an eosinophilia (3192/μL; reference range 50 to 516/μL); the eosinophilia differed from the initial CBC, which showed only a mature neutrophilia.¹⁶ A serum biochemical panel was unremarkable, and a heartworm antigen test^c remained positive, suggesting persistent infection with at least one female worm. The ferret was discharged with owner instructions to continue monthly heartworm prevention.

Discussion

Clinical signs of heartworm disease reported in the ferret include coughing, dyspnea, lethargy, pulmonary congestion, and ascites.^1,2,4–6 The ferret in this report was obtunded on initial presentation and had weak femoral pulses with deficits, pale mucous membranes, posterior paresis, and abdominal discomfort. Posterior paresis is a nonspecific sign of weakness in ferrets.⁷ These findings differ from those of previous reports^4–6 and may be reflective of this particular ferret’s signs of caval syndrome upon presentation. Previously reported radiographic abnormalities in heartworm-infected ferrets include pleural effusion and right-sided cardiomegaly without enlargement of the pulmonary arteries.^4,6,8

Commonly identified abnormalities in cats and dogs with heartworm disease typically include enlarged, tortuous pulmonary arteries; a prominent pulmonary trunk; right-sided cardiomegaly; and an interstitial pulmonary pattern.¹⁹ The ferret of this report had enlarged, tortuous pulmonary arteries and right-sided cardiomegaly. Eosinophilia is not reported as a common finding in ferrets with heartworm disease^2,4–6 and was not reported initially in this ferret, but it was recorded at the 5-month recheck examination.

Anecdotally, green-colored urine has been described in heartworm-positive ferrets.^1,4 The ferret of this report had green-colored urine on initial presentation and a green hue to the urine at the 5-month recheck. We hypothesized the green color was due to the presence of biliverdin in the urine. Biliverdin, a product of heme degradation, was confirmed. Briefly, commercially available biliverdin dihydrochlorideⁱ was dissolved in 100% dimethyl sulfoxide to a concentration of 100 mg/dL. Standard concentrations of 0.5, 1.0, 5.0, 10.0, 15.0, and 20.0 mg/dL of biliverdin were made in diluent. Samples were composed of 100 μL of ferret urine added to 190 μL of reduction buffer. The initial absorbance was measured at a predetermined wavelength. Subsequently, 10 μL of activator was added to each sample. The samples were gently mixed and then incubated at room temperature for approximately 1 hour in a humidified, light-protected (dark) chamber. After incubation, the final absorbance was determined at the same predetermined wavelength. A standard curve was plotted, and a “best fit” regression curve and equation were determined. Subsequent biliverdin concentrations were calculated using the standard curve.

Hemoglobinuria is considered a hallmark of caval syndrome in dogs. It occurs secondary to mechanical damage to fragile red blood cells, which leads to lysis and liberation of the heme molecules.¹⁰ The first step of heme degradation involves the production of biliverdin, which is further degraded into bilirubin by biliverdin reductase. One possible reason for the observed green color of the urine is that ferrets have either less total biliverdin reductase or less biliverdin reductase activity than dogs and cats. If such is the case, hemolysis in ferrets would cause an excess of biliverdin in both the blood (biliverdinemia) and urine (biliverdinuria).

The development of caval syndrome in domestic animals is thought to be associated with the migration of heartworms from the pulmonary arteries into the right side of the heart in response to hemodynamic changes, such as acute worsening of pulmonary arterial hypertension.¹⁰ Though cats have an overall lower worm burden than dogs, one study found that 35% and 41% of heartworm-infested cats had echocardiographic evidence of worms in the right atrium and right ventricle, respectively.²⁰ In ferrets, heartworms have been identified in the right atrium and ventricle via echocardiography;¹¹ in both natural and experimental dirofilariasis, ferrets were found at necropsy to harbor D. immitis within the heart.^1,3–6,9,11

Heartworm extraction can be challenging to perform in an extremely small animal, such as the ferret of this report. However, extraction was considered a reasonable therapeutic option based on the severity of clinical signs at presentation, evidence of anemia and hemolysis, and the presence of heartworms in the right atrium and ventricle. Transvenous heartworm extraction has been successfully performed in dogs and cats and was performed in this case in a similar manner as previously described.²¹ Adulticide therapy using melarsomine has been described in ferrets, with up to 50% of reported cases developing anaphylaxis following administration.² Because of the relatively high percentage of adverse reactions, melarsomine injections were not administered to this ferret. Symptomatic therapy with corticosteroids and diuretics can facilitate management of clinical signs of heartworm disease. Routine heartworm prevention is recommended, and low-dose ivermectin PO once monthly has been shown to be both safe and effective in preventing heartworm infection in ferrets and shortening the life span of adult worms in dogs.^3,9,22

Conclusion

Caval syndrome was diagnosed in a 10-month-old ferret. Successful transvenous heartworm extraction was performed, and although at least one female worm remained in the right ventricle, the majority of clinical signs related to the presence of the heartworms resolved. Diagnostic tests indicative of caval syndrome included echocardiographic evidence of heartworms within the right atrium and ventricle, as well as a mild anemia and green-colored urine that was subsequently identified as biliverdinuria. Eosinophilia is not a routine finding in ferrets with heartworm disease, and it was not noted in this ferret until 5 months following the procedure. Further studies to determine the prevalence of heartworm disease in ferrets and the mechanism for biliverdinuria development in heartworm-infected ferrets may be of value.