Pentoxifylline as adjunct therapy to long-term clinical management of a right-to-left patent ductus arteriosus

Abstract

Management of a right-to-left (“reversed”) patent ductus arteriosus (PDA) focuses on control of clinical signs associated with hyperviscosity due to erythrocytosis. Pentoxifylline therapy is presented as an adjunct to routine phlebotomies for the long-term clinical management of reversed PDA in a 10-year-old Chihuahua.

A 10-month-old spayed female Chihuahua dog was referred to the Atlantic Veterinary College (AVC) Cardiology Service to determine a cause of her 4-month history of poly-cythemia with erythrocytosis (Hct = 74%), which was treated by the referring veterinarian with phlebotomy (15 mL of blood removed).

The patient had normal vital parameters, bilateral patellar luxation, pink oral mucous membranes, and weighed 2 kg. The owner described the patient as displaying an exercise-induced bilateral hind limb collapse at home. Upon further stress and excitement during the examination, a differential cyanosis was noted with cyanotic hind nail capillary beds and footpads, while maintaining normal pink forelimb parenchyma and pink oral mucous membranes. Radiographs were suggestive of right-sided cardiomegaly and enlargement of the main pulmonary artery. Differential diagnoses of erythrocytosis included a right-to-left shunt, reactivity to hypoxemia, orthopedic problems, and polycythemia vera. In combination with the patient’s differential cyanosis and cardiomegaly, a tentative diagnosis of reversed PDA was made. The patient was treated with phlebotomy (20 mL of blood removed) and returned at the end of the month for echo-cardiography and a contrast ultrasound study. The echocardiogram showed concentric right ventricular hypertrophy, and the contrast ultrasound was positive, revealing opacification in the right atrium, right ventricle, and abdominal aorta, confirming the diagnosis of reversed PDA. The patient’s bilateral patellar luxation was ruled out as a cause of the clinical signs due to confirmation of the reversed PDA diagnosis, and the slow onset and recovery with the patient’s hind limb collapse episodes.

The therapeutic plan consisted of routine phlebotomies based on removal of 10% of the patient’s circulating blood volume every 6 mo or earlier as needed, based on clinical signs. Pentoxifylline (Trental; Apotex, Toronto, Ontario), 25 mg/kg body weight (BW), PO, q12h, was added as adjunct therapy 5 mo after diagnosis when the patient experienced increased episodes of hind limb weakness, hunched posture, and collapse. Over the next 9 y the frequency of phlebotomies was increased, with the patient returning every 4 wk. The frequency of administration of pentoxifylline was increased to 25 mg/kg BW, PO, q8h, as clinical signs had worsened and included seizures (5 seizures over 3 y). Hyperviscosity was the suspected cause of seizures, as there were no abnormalities on blood analysis or neurologic examination.

When presenting most recently, the patient’s physical examination findings were unchanged. The patient was considered clinically stable, as there had been no seizures and no increase in intensity or severity of clinical signs since the increase in frequency of administration of pentoxifylline.

Discussion

This clinical description is similar to that of other dogs with reversed PDA reported in the literature (1–4). Patients may present with a combination of fatigue, dyspnea, seizures, and exercise-induced hind limb paralysis. The location of the ductus creates the distinguishing characteristic of this disease: a differential cyanosis, due to the branching of the brachiocephalic trunk and left subclavian artery from the aorta cranial to the ductus (3). The most common laboratory finding of erythrocytosis is due to poor perfusion of the kidneys, creating a response to the chronic hypoxemia and increased erythropoietin production (3). A hematocrit greater than 70% (4) creates hyperviscous blood with poor oxygen delivery to the capillary beds. Poor perfusion in the microcirculation may lead to clinical signs including seizures (5), hypoxemia, syncope, and intermittent hind limb paresis. A heart murmur is rarely present (3), differing from the continuous murmur ausculted in a left-to-right PDA. Diagnosis includes identifying clinical signs with a supporting erythrocytosis and a positive contrast ultrasound study. To confirm a reversed PDA with a positive contrast ultrasound study, the veterinarian injects agitated saline into the cephalic vein and uses ultrasound to detect the contrast medium in the descending aorta (6). Depending on the severity, radiographs may show right ventricular enlargement and ultrasound reveals concentric right ventricular hypertrophy in response to the persistent pulmonary hypertension.

Treatment of a right-to-left PDA is based on management of the clinical signs associated with the secondary erythrocytosis and hyperviscosity (2). In previous studies, treatment with a phlebotomy of 10% to 28% (2) of the patient’s circulating blood volume every 3 to 8 wk based on clinical signs, with or without adjunct medication, has been successful in clinical management of the disease. Although the use of pentoxifylline is not described in dogs with this disorder, it may have properties which may be beneficial to the patient, including improvement of blood flow and ability to reach microcirculation by increasing erythrocyte flexibility (7). This adjunct therapy was chosen for the patient to attempt to decrease the episodes of collapse without increasing the frequency or volume of phlebotomy, and to avoid the potential side effect of immune suppression associated with hydroxyurea (4) and cyclophosphamide adjuncts (5). Pentoxifylline has been documented in human medicine for improving blood flow in patients with circulation problems such as peripheral vascular disease and cerebrovascular diseases (8) and in veterinary medicine for treatment of dermatomyositis (7), thromboembolism, atopic dermatitis (9), contact allergy dermatitis, and erythema multiform (7).

More recent studies document surgical correction of the reversed PDA with management and treatment of pulmonary hypertension with intensive sildenafil therapy (10) to induce flow reversal, following which the PDA can be ligated or occluded with an occlusion device. Considering the patient’s age, severe pulmonary hypertension, and well-managed clinical signs with the current therapy, surgery was not a practical option.

Since beginning pentoxifylline therapy in conjunction with phlebotomy, the patient has shown decreased frequency and intensity of clinical signs and an increase in energy. Clinicians should consider pentoxifylline in addition to phlebotomy as an alternative option for clinical management of reversed PDA patients which cannot tolerate immune suppression, increases in frequencies or volume of blood removed, or surgical intervention. Dogs with reversed PDA have lifespans that range up to greater than 8 y (2), which this patient has surpassed. It is not possible to know if this patient’s longevity is due to patient variation or is a result of treatment; however, the patient’s lifespan thus far is improved compared to historical prognosis. Additional studies are needed to further evaluate the use of pentoxifylline in addition to phlebotomy for clinical treatment of reversed PDAs.