Vascular Diseases

Diseases Of Arteries

Feline Ischemic Encephalopathy

Feline ischemic encephalopathy (FIE) results in cerebral ischemic necrosis. Feline ischemic encephalopathy occurs in male and female cats of all ages and is more prevalent in the summer months. The cause of FIE is uncertain. Preliminary evidence suggests Cuterebra infection as a potential cause in some cases.

Clinical pathology is usually unremarkable. Cerebrospinal fluid (CSF) analysis may be normal or have mildly elevated protein levels and a mild to moderate pleocytosis. An increased proportion of large foamy macrophages have been observed in the CSF from 2 to 7 months after the onset of seizures. Suspected diagnosis can be made by T2 weighted MRI. In one study of six cats with FIE, MRI findings included mild to marked asymmetry of the cerebral hemispheres and bilateral asymmetric enlargement of the subarachnoid space.

Gross lesions are usually unilateral and may involve up to 75% of one cerebral or cerebellar hemisphere (or both). Hemispheres may appear atrophic and ridged with wide sulci. Histopathologic findings have included parenchymal atrophy and cystic degeneration, gliosis, and phagocytic macrophage infiltration. Perivascular lymphocytic cuffing of small capillaries and vascular occlusive lesions including thrombosis and vasculitis has been reported. Infarction of the middle cerebral artery represents the most common distribution.

Clinical signs are typically acute in onset, nonprogressive, and suggestive of unilateral cerebral or brainstem involvement. Seizures are the most common historical or presenting clinical sign. Other clinical signs may include depression, head tilt, anisocoria, circling, seizures, and behavior changes.

Treatment is limited to supportive care, and the prognosis is generally favorable. Clinical improvement typically occurs over several days to weeks. Multiple episodes can occur. Behavior changes and uncontrollable seizures can persist.

Fibrocartilcigenous Embolization

Fibrocartilaginous embolization (FCE) is associated with ischemic necrosis of the spinal cord parenchyma. The pathogenic mechanism is not resolved. Spinal cord arteries and veins become occluded with fibrocartilage originating from the nucleus pulposus of the intervertebral disc. Trauma may be a predisposing factor in a large percentage of affected cases. Fibrocartilaginous embolization can occur at any age but is most common in adult non-chondrodystrophoid breeds. Young Irish wolfhounds and miniature schnauzers are particularly prone to the disease. Fibrocartilaginous embolization has been reported less commonly in cats.

Clinical signs of myelopathy vary depending on the location and severity of the spinal cord ischemic injury. Deficits are often asymmetrical, and the clinical signs are not progressive. Affected animals do not typically show evidence of pain, although brief painful periods have been described just prior to the onset of clinical signs.

Diagnosis of FCE is based on excluding other causes of acute myelopathy. Results of plain radiographs are normal. CSF evaluation may be normal or show nonspecific abnormalities including mild protein elevations, mild pleocytosis, and xanthochromia. Myelography is typically normal, or mild spinal cord swelling is seen. MRI may reveal spinal cord edema on T2 weight images.

Treatment is primarily supportive care and physical therapy. Evidence for the use of glucocorticoid therapy is lacking, if treatment is attempted, methylprednisolone succinate (MPS) should be given within the first 6 to 8 hours after the onset of neurologic signs. Prognosis for recovery is variable depending on the location and extent of the lesion. Poor prognostic indicators include lower motor neuron (LMN) signs and size of the animal because of the inherent difficulties of performing physical therapy on large breed dogs.

Vasculitis and Angiitis

Arterial Aneurysm

An arterial aneurysm is a circumscribed dilation of an arterial wall or a blood-containing swelling connecting directly with the lumen of an artery. Arterial aneurysms are rare in dogs and cats and only isolated cases have been reported. Aneurysms can be categorized based on their shape (saccular or fusiform), cause (atherosclerotic, mycotic, inflammatory, arteritis, traumatic, congenital, dissecting), or their histologic appearance Two major histologic classes of aneurysms are (1) true aneurysms (aneurysma verum) and (2) false aneurysms (aneurysma spurium).

True Aneurysm A true aneurysm is a vascular dilatation caused by a weakened arterial or venous wall with subsequent widening of the vascular lumen. Histologically, true aneurysms involve the entire arterial wall and contain three microscopic arterial layers. Aneurysms may result from destruction of the media or the elastic fibers of large arteries (or destruction of both) by inflammatory or degenerative processes. Traumatic aneurysms can be true aneurysms or pseudoaneurysms, depending on their cause and histologic appearance. Aneurysms have been found in the aorta of dogs that were caused by migrating larvae of Spirocerca sanguinolenta (formerly S. lupi). Aneurysms can also result from turbulent blood flow with arteriovenous (AV) fistulas.

Dissecting aneurysm (aortic dissection) involves a hematoma associated with a defect in the aortic intima. Blood within the aortic lumen is forced through the intimal tear into the outer and middle layers of the aortic media, forming a second or false lumen. The dissection can then propagate proximally or distally along the aorta. A report of a dissecting aortic aneurysm was reported in a dog with clinical and histologic findings similar to that reported in humans. Dissecting aortic aneurysm has also been reported in two cats: one with CHF, severe aortic insufficiency and systemic hypertension and a second cat with signs of weakness, lethargy, and cardiogenic shock.

Peripheral aneurysms appear as soft, warm, pulsating bulges. Occasionally, a “machinery” murmur can be auscultated over these areas (see Arteriovenous Fistulas). Clinical signs are frequently absent or vague. If spontaneous vascular rupture occurs, pain, signs of anemia and shock, and pleural or mediastinal effusion may be present. Exsanguination resulting from aneurysmal rupture is possible.

Spurious (Pseudo) Aneurysm Spurious aneurysms, also known as pseudoaneurysms, are caused by localized disruption of the native artery. Their histologic appearance includes arterial wall architecture that is formed by fibrous tissue One cause of spurious aneurysms is a hematoma that communicates with an arterial lumen resulting from venipuncture.S Traumatic spurious aneurysms are probably more common than is usually realized. Clinical signs may include lameness, persistent pain, and deep muscular swelling unresponsive to local therapeutic measures, antibiotics, or glucocorticoids. Pitting peripheral edema may be present, and neither blood nor pus can be aspirated from the swelling. The diagnosis of spurious aneurysms may be suspected from physical examination. Survey radiographs may indicate soft tissue swelling. Diagnostic confirmation has classically relied on arteriography, which illustrates a nodular exudation of contrast medium at the arterial defect. Doppler echocardiography, especially color flow Doppler imaging, aids in identification by depicting blood flow and turbulence. Additional diagnostic tests include computed tomography (CT), radionuclide angiography, and surgical exploration. The differential diagnosis includes chronic infection, obstruction of a deep vein, or abscessation. With a spurious aneurysm, however, pyrexia and neutrophilia are not encountered. The prognosis is favorable if surgical vascular repair can be accomplished.


Arteriosclerosis is defined as chronic arterial wall remodeling consisting of hardening, loss of elasticity, and luminal narrowing. These changes result from proliferation of connective tissue and hyaline degeneration of media and intima. Proliferation and thickening of the intima with the deposition of ground substances leads to progressive fibrosis and vascular stenosis. Inflammation is not a feature of arteriosclerosis. Arteriosclerotic lesions are commonly detected in old dogs and cats and may comprise part of the normal aging process. These changes are typically mild and usually unimportant to health and survival. Thrombosis is rarely a complication of such microscopic lesions, and their functional significance is not known. In other instances, arteriosclerosis may be severe and associated with substantial reduction in intraluminal diameter (often referred to as small vessel disease). Lesions of this nature are also common in feline myocardial diseases, particularly hypertrophic cardiomyopathy, and may be detected in canine aortic stenosis as well. Arteriosclerotic changes may also occur in aorta and cerebral, renal, spinal, and sinoatrial node artery. Intramural coronary arterial narrowing commonly occurs in association with chronic degenerative valve disease as well. Arterial lesions may have been associated with small regions of myocardial necrosis and fibrosis. Intramural coronary arteriosclerosis was found in 26.4% of old dogs undergoing necropsy. Extensive nonthrombotic, nonatherogenic stenosis of extramural coronary arteries was described in two adult male Labrador retriever dogs with congestive heart failure. Disease of extramural arteries is less common. Endothelial aortic plaque formation associated with arteriosclerosis was detected in 77.8% of 58 dogs brought to a small animal clinic in Helsinki for euthanasia. Spontaneous arteriosclerosis, with a predilection for renal vasculature, has been demonstrated in young (<2 years old) greyhounds. The severity of the lesions was correlated with increased renal vascular tortuosity and high shear stress. Clinical consequences of these lesions have not been determined.


Diseases of the Throat

General Anatomy And Physiology

The throat is an important, but mosdy ignored, communal area of both the gastrointestinal (GI) and respiratory tracts. Anatomically it is divided into the pharynx and larynx. The pharynx is further divided into the nasopharynx, the oropharynx, and the laryngopharynx. The nasopharynx is located dorsal to the soft palate, between the choanae and the intrapharyngeal opening. It is a functional space that allows the nasal cavity to communicate with the larynx. The oropharynx is ventral to the soft palate and extends from the palatoglossal arches rostrally to the base of the epiglottis caudally. The intrapharyngeal opening and the rostral border of the esophagus create the boundaries of the laryngopharynx, the most caudal part of the pharynx. The laryngopharynx functions as an intersection to both the respiratory and digestive tracts. The larynx consists of three unpaired cartilages (epiglottis, cricoid, and thyroid) and one pair of arytenoid cartilages. The glottis (or cranial opening of the larynx) is composed of the corniculate and cuneiform process of the arytenoid cartilages and the epiglottis. Minor anatomic differences exist between feline and canine larynx. Cats lack the interarytenoid cartilage found in dogs and instead have an interarytenoid ligament in its place. Cats also lack a vestibular ligament. Due to this deficiency the feline arytenoid cartilage is connected to the ventral aspect of the larynx by the vocal ligament. Another important anatomic difference is cats lack the Iaryngeal ventricles that are found between the vestibular and vocal folds in the dog. No dramatic differences exist between feline and canine innervation and muscles of the larynx.

Swallowing, or deglutition, is a complex reflex action that coordinates many structures. Cranial nerves, the swallowing center in the reticular formation of the brain stem, the muscles of mastication, tongue, soft palate, pharynx, larynx, and esophagus are all involved in what appears to be a simple act of allowing transport of material from the mouth to the stomach. As a lesser recognized function, swallowing also allows saliva and debris to be removed from the pharynx. Deglutition begins as a voluntary act but during its execution becomes a reflex. Deglutition is traditionally described as having three phases: (1) oral, (2) pharyngeal, and (3) esophageal. The oral phase begins when mastication is complete. The tongue then moves the food bolus that is organized at the base of the tongue to a position that is on midline between the tongue and the hard palate. Motor fibers to the tongue are supplied by cranial nerve XII. Sensory fibers from the oral cavity and motor fibers to the masticatory muscles and soft palate originate from cranial nerve V. The oral phase is voluntary, but when the food bolus is pushed into the pharynx, receptors are stimulated that initiate the involuntary, or reflex, component of deglutition. Sensory receptors are found in the pharynx, palate, and epiglottis. Impulses from these receptors are transmitted along the glossopharyngeal nerve, recurrent Iaryngeal branch of the vagus nerve, and the maxillary branch of the trigeminal nerve to the swallowing center in the medulla (located in the floor of the fourth ventricle). The efferent arm of the reflex involves the motor nuclei of cranial nerves V, VII, DC, X, and XII. These nerves supply the muscles of mastication, tongue, palate, pharynx, larynx, and esophagus. During the pharyngeal phase the goal is to pass food from the oropharynx into the esophagus and to prevent food from being aspirated into the trachea or moved into the nasopharynx. This is accomplished by elevation of the soft palate and the palatopharyngeal folds moving inward as the vocal cords are pulled together and the larynx is elevated against the epiglottis. The final act during the pharyngeal stage of swallowing occurs when the cricopharyngeal muscle relaxes, the upper esophageal sphincter opens, the bolus moves into the esophagus, the sphincter closes, and the pharyngeal muscles relax. The cricopharyngeal muscle is innervated by the pharyngoesophageal nerve, which is formed by cranial nerves IX and X. The final stage of deglutition, the esophageal stage, transports the bolus from the esophagus, through the gastroesophageal sphincter, and into the stomach, The esophagus is innervated by the vagus nerve.

The larynx has three functions: (1) to act as a conduit for air, (2) to protect the lower airway from aspiration during deglutition, and (3) vocalization. The glottis remains partially open when an animal is at rest. When greater airflow is needed, the glottis is widened by abduction of the arytenoid cartilages and vocal folds (via cricoarytenoid muscles) during inspiration (and the same structures adduct during expiration). The cricoarytenoid muscles are innervated by the caudal laryngeal nerves, which are derived from the recurrent laryngeal nerves. The recurrent laryngeal nerve innervates all the muscles of the larynx except the cricothyroid muscles that are supplied by the cranial laryngeal nerves. During deglutition the larynx is pulled cranially by the geniohyoideus and mylohyoideus muscles. This allows the epiglottis to close over the larynx, protecting the lower airways. The adductor muscles close the glottis concurrently. This creates an additional defense against aspiration.

History And Physical Examination

Animals with diseases of the throat can have a variety of historical complaints. Pharyngeal diseases can be confusing because historical findings can be related to swallowing difficulties or the upper respiratory tract (URT). Historical findings secondary to laryngeal dysfunction are usually related to either inability to regulate airflow and protect the airway, or they are related to changes in vocalization. Respiratory sounds can be extremely useful in localizing the disease, whether it is pharyngeal or laryngeal, but they are not helpful if one tries to attribute a specific respiratory sound to a specific condition. Coughing, dyspnea, and nasal discharge are common clinical complaints. Stertor, a snoring sound heard on inspiration, is usually due to an intermittent obstruction such as an elongated soft palate. Stridor, an inspiratory high-pitch wheeze, is most commonly associated with laryngeal lesions. Stridor is created by air turbulence through a narrowed laryngeal opening. Any changes in vocalization would suggest a laryngeal disorder. Reverse sneezing, which is described as short periods of forceful inspiratory nasal effort with the head pulled back, indicates irritation to the dorsal nasopharyngeal mucosa. Dysphagia cases can be confusing because ineffective swallowing may not be obvious to the owner and may not be the primary historical complaint. Other signs such as coughing, gagging, regurgitation, and nasal discharge may be reported in animals with either oropharyngeal dysphagia or other diseases of the throat.

A complete physical examination (including a neurologic examination) is important when evaluating animals with pharyngeal or laryngeal disease because dysfunction may be indicative of systemic disease (i.e. myopathy, neuropathy) or there may be secondary complications from the disorder (e.g. aspiration pneumonia). If laryngeal disease is suspected, the larynx should be palpated for pain or structural abnormalities. The area over the larynx should be ausculted for abnormal sounds secondary to turbulence. Part of this complete physical examination may include exercising the patient, because occasionally manifestation of the disease only occurs after physical exertion. Many animals will have dyspnea, and a thorough physical examination may not be possible until the animal is stable. Significant airway compromise may be overlooked. It is important to assess the degree of respiratory compromise by evaluating the patient’s attitude, posture, mucous membrane color, and both respiratory rate and pattern. Precluding the emergency situation, once the general examination is complete one may concentrate on examining the oral cavity. It is extremely difficult, if not impossible, to adequately evaluate the larynx and pharyngeal areas without heavy sedation or general anesthesia. In most cases it is easier for the examiner, and safer for the animal, if tracheal intubation is performed. A standard method of evaluating the oral cavity should be established so that one does not miss an important abnormality. The larynx is evaluated both for structural problems and functional abnormalities; the pharynx is evaluated for physical abnormalities. Pharyngeal function cannot be evaluated when the patient is sedated; rather, video fluoroscopy is recommended when critically assessing pharyngeal function.

Diseases of the Throat: Diagnosis

Diseases Of The Pharynx

Soft Palate Abnormalities

Diseases Of The Larynx


Inflammatory laryngeal disease is common in both the dog and the cat. The most common cause of acute inflammation of the larynx is infectious agents such as canine infectious tra-cheobronchitis (ITB), commonly called kennel cough, or the feline upper respiratory agents (i.e. FHV-1, FCV). ITB is a result of coinfection of Bordetella bronchiseptica with either canine parainfluenza virus or canine adenovirus-2 (CAV-2). With most cases of lib, the only clinical sign is paroxysmal coughing in an otherwise healthy dog. Due to inflammation of the larynx the cough is a loud, high-pitched, “goose honk” cough. Occasionally a dog may be febrile, lethargic, and inappetent. ITB is usually self-limiting, but the severity of the cough, combined with the possibility of pneumonia complicating the disease, warrants treatment. Doxycycline at 5 to 10 mg/kg orally once daily is the antimicrobial of choice for B. bronchiseptica. Short-term administration of an anti-inflammatory dose of glucocorticoids can be effective in decreasing laryngeal edema. Antitussives, such as butorphanol tartrate or hydrocodone bitartrate, are effective in minimizing the severity of the cough but should not be used if pneumonia is suspected. Other causes of inflammatory laryngeal disease include endotracheal intubation, insect bites, foreign body penetration, or trauma from bite wounds, leash and choke chain injuries, or being hit by cars. Frequently no cause for acute laryngeal inflammation is found. Acute inflammatory laryngeal disease is usually self-limiting, and no specific treatment is indicated if the animal has only mild signs. However, if moderate to severe signs exist, a short course with an anti-inflammatory dose of glucocorticosteroids can be initiated to decrease laryngeal edema. Respiratory obstruction secondary to laryngeal inflammation is an uncommon clinical presentation but can occur in severe instances such as in laryngeal trauma. A tracheostomy is indicated if the patient is dyspneic, cyanotic, or extremely anxious due to laryngeal inflammation.

Obstructive Inflammatory Disease

An obstructive inflammatory laryngeal disease has been described in cats and dogs. Although rare, it is a disease worth noting because the gross appearance can mimic laryngeal neoplasia. The underlying cause of inflammation is unknown. Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) have not been found to be associated with this disease. In the feline reports, dyspnea secondary to upper airway obstruction was reported in all cats; retching, coughing, and dysphonia were also common. Stridor and dysphonia was reported in dogs. Direct visualization of the larynx reveals a laryngeal mass that cannot be distinguished from neoplasia or severe swelling and edema (). Histopathology is imperative to distinguish between neoplasia and obstructive inflammatory disease.

Histopathology reveals either granulomatous or nongranulomatous laryngitis (neutrophilic and lymphoplasmacytic). Most patients with obstructive inflammatory laryngeal disease need to be stabilized. This is accomplished by establishing an airway through tracheostomy tube placement. Treatment with corticosteroids (dexamethasone, prednisone, or prednisolone) has variable success, and occasionally surgical resection of the proliferative tissue is indicated. The prognosis is guarded, with a high mortality rate during the initial diagnostic and treatment period.


Aminophylline Theophylline

Phosphodiesterase Inhibitor Bronchodilator

Highlights Of Prescribing Information

Bronchodilator drug with diuretic activity; used for bronchospasm & cardiogenic pulmonary edema

Narrow therapeutic index in humans, but dogs appear to be less susceptible to toxic effects at higher plasma levels

Therapeutic drug monitoring recommended

Many drug interactions

What Is Aminophylline Theophylline Used For?

The theophyllines are used primarily for their broncho dilatory effects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity.


The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of cAMP may also inhibit the release of histamine and slow reacting substance of anaphylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllines possess maybe a result of translocating intracellular ionized calcium.

The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation (centrally-mediated).


The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sustained release products are used. One study in dogs that compared various sustained-release products (), found bioavailabilities ranging from approximately 30-76% depending on the product used.

Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses the placenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogs has been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85-1.02 L/kg. Because of the low volumes of distribution and theophylline’s low lipid solubility, obese patients should be dosed on a lean body weight basis.

Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weakbronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clearance of theophylline. The reported elimination half-lives (mean values) in various species are: dogs = 5.7 hours; cats = 7.8 hours, pigs = 11 hours; and horses = 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be expected that similar variability exists in veterinary patients, particularly those with concurrent illnesses.

Before you take Aminophylline Theophylline

Contraindications / Precautions / Warnings

The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.

The theophyllines should be administered with caution in patients with severe cardiac disease, seizure disorders, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Because it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias should receive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline.

Adverse Effects

The theophyllines can produce CNS stimulation and gastrointestinal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments.

Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.

Reproductive / Nursing Safety

In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Overdosage / Acute Toxicity

Clinical signs of toxicity (see above) are usually associated with levels greater than 20 mcg/mL in humans and become more severe as the serum level exceeds that value. Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/mL.

Treatment of theophylline toxicity is supportive. After an oral ingestion, the gut should be emptied, charcoal and a cathartic administered using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The patient should be constantly monitored for cardiac arrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol if either condition is considered life threatening.

How to use Aminophylline Theophylline

Note: Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline’s pharmacokinet-ic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed using the information found in the Chemistry section below. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route.

Aminophylline Theophylline dosage for dogs:

a) Using Theochron Extended-Release Tablets or Theo-Cap Extended-Release Capsules: Give 10 mg/kg PO every 12 hours initially, if no adverse effects are observed and the desired clinical effect is not achieved, give 15 mg/kg PO q12h while monitoring for adverse effects. ()

b) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 11 mg/kg PO, IM or IV three times daily. ()

c) For adjunctive therapy of severe, acute pulmonary edema and bronchoconstriction: Aminophylline 4-8 mg/kg IV or IM, or 6-10 mg/kg PO every 8 hours. Long-term use is not recommended. ()

d) For cough: Aminophylline: 10 mg/kg PO, IV three times daily ()

e) As a broncho dilator tor collapsing trachea: 11 mg/kg PO or IV q6- 12h ()

Aminophylline Theophylline dosage for cats:

a) Using Theo-Dur 20 mg/kg PO once daily in the PM; using Slo-Bid 25 mg/kg PO once daily in the PM (Johnson 2000) [Note: The products Theo-Dur and Slo-Bid mentioned in this reference are no longer available in the USA. Although hard data is not presently available to support their use in cats, a reasonable alternative would be to cautiously use the dog dose and products mentioned above in the reference by Bach et al — Plumb]

b) Using aminophylline tablets: 6.6. mg/kg PO twice daily; using sustained release tablets (Theo-Dur): 25-50 mg (total dose) per cat PO in the evening ()

c) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 5 mg/kg PO, two times daily. ()

d) For adjunctive therapy for bronchoconstriction associated with fulminant CHF: Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. ()

e) For cough: Aminophylline: 5 mg/kg PO twice daily ()

Aminophylline Theophylline dosage for ferrets:

a) 4.25 mg/kg PO 2-3 times a day ()

Aminophylline Theophylline dosage for horses:

(Note: ARCI UCGFS Class 3 Aminophylline Theophylline)

NOTE: Intravenous aminophylline should be diluted in at least 100 mL of D5W or normal saline and administered slowly (not >25 mg/min). For adjunctive treatment of pulmonary edema:

a) Aminophylline 2-7 mg/kg IV q6- 12h; Theophylline 5-15 mg/kg PO q12h ()

b) 11 mg/kg PO or IV q8-12h. To “load” may either double the initial dose or give both the oral and IV dose at the same time. IV infusion should be in approximately 1 liter of IV fluids and given over 20-60 minutes. Recommend monitoring serum levels. ()

For adjunctive treatment for heaves (RAO):

a) Aminophylline: 5-10 mg/kg PO or IV twice daily. ()

b) Aminophylline: 4-6 mg/kg PO three times a day. ()


■ Therapeutic efficacy and clinical signs of toxicity

■ Serum levels at steady state. The therapeutic serum levels of theophylline in humans are generally described to be between 10-20 micrograms/mL. In small animals, one recommendation for monitoring serum levels is to measure trough concentration; level should be at least above 8-10 mcg/mL (Note: Some recommend not exceeding 15 micrograms/mL in horses).

Client Information

■ Give dosage as prescribed by veterinarian to maximize the drug’s benefit

Chemistry / Synonyms

Xanthine derivatives, aminophylline and theophylline are considered to be respiratory smooth muscle relaxants but, they also have other pharmacologic actions. Aminophylline differs from theophylline only by the addition of ethylenediamine to its structure and may have different amounts of molecules of water of hydration. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous); 100 mg of aminophylline (anhydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline (anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline (hydrous).

Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slight ammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.

Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting point between 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of 7, but solubility increases with increasing pH.

Aminophylline may also be known as: aminofilina, aminophyllinum, euphyllinum, metaphyllin, theophyllaminum, theophylline and ethylenediamine, theophylline ethylenediamine compound, or theophyllinum ethylenediaminum; many trade names are available.

Theophylline may also be known as: anhydrous theophylline, teofillina, or theophyllinum; many trade names are available.

Storage / Stability/Compatibility

Unless otherwise specified by the manufacturer, store aminophylline and theophylline oral products in tight, light-resistant containers at room temperature. Do not crush or split sustained-release oral products unless label states it is permissible.

Aminophylline for injection should be stored in single-use containers in which carbon dioxide has been removed. It should also be stored at temperatures below 30°C and protected from freezing and light. Upon exposure to air (carbon dioxide), aminophylline will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline that can precipitate out of solution. Do not inject aminophylline solutions that contain either a precipitate or visible crystals.

Aminophylline for injection is reportedly compatible when mixed with all commonly used IV solutions, but may be incompatible with 10% fructose or invert sugar solutions.

Aminophylline is reportedly compatible when mixed with the following drugs: amobarbital sodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCL, erythromycin lactobionate, heparin sodium, hydro cortisone sodium succinate, lidocaine HCL, mephentermine sulfate, methicillin sodium, methyldopate HCL, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassium chloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopental sodium, and verapamil HCL

Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCL, doxorubicin HCL, epinephrine HCL, erythromycin gluceptate, hydralazine HCL, hydroxyzine HCL, insulin (regular), isoproterenol HCL, levorphanol bitartrate, meperidine HCL, methadone HCL, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCL, prochlorperazine edisylate or mesylate, promazine HCL, promethazine HCL, sulfisoxazole diolamine, tetracycline HCL, vancomycin HCL, and vitamin B complex with C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluent used and it is suggested to consult specialized references for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information.

Human-Labeled Products:

The listing below is a sampling of products and sizes available; consult specialized references for a more complete listing.

Aminophylline Tablets: 100 mg (79 mg theophylline) & 200 mg (158 mg theophylline); generic; (Rx)

Aminophylline Injection: 250 mg (equiv. to 197 mg theophylline) mL in 10 mL & 20 mL vials, amps and syringes; generic; (Rx)

Theophylline Time Released Capsules and Tablets: 100 mg, 125 mg 200 mg, 300 mg, 400 mg, 450 mg, & 600 mg. (Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; Theophylline Extended-Release (Dey); Theo-24 (UCB Pharma); Theophylline SR (various); Theochron (Forest, various); Theophylline (Able); Theocron (Inwood); Uniphyl (Purdue Frederick); generic; (Rx)

Theophylline Tablets and Capsules: 100 mg, 200 mg, & 300 mg; Bronkodyl (Winthrop); Elixophyllin (Forest); generic; (Rx)

Theophylline Elixir: 80 mg/15 mL (26.7 mg/5 mL) in pt, gal, UD 15 and 30 mL, Asmalix (Century); Elixophyllin (Forest); Lanophyllin (Lannett); generic; (Rx)

Theophylline & Dextrose Injection: 200 mg/container in 50 mL (4 mg/mL) & 100 mL (2 mg/mL); 400 mg/container in 100 mL (4 mg/ mL), 250 mL (1.6 mg/mL), 500 mL (0.8 mg/mL) & 1000 mL (0.4 mg/mL); 800 mg/container in 250 mL (3.2 mg/mL), 500 mL (1.6 mg/mL) & 1000 mL (0.8 mg/mL); Theophylline & 5% Dextrose (Abbott & Baxter); (Rx)


Treatment And Prevention of Feline Heartworm Disease

The question arises as to whether heartworm prophylaxis is warranted for cats because they are not the natural host and because the incidence is low. Necropsy studies of feline heartworm infection in the Southeast have yielded a prevalence of 2.5% to 14%, with a median of 7%. When considering the question of institution of prophylaxis, it is worth considering that this prevalence approximates or even exceeds that of feline leukemia virus (FeLV) and feline immunodeficiency virus (FTV) infections. A 1998 nationwide antibody survey of over 2000 largely asymptomatic cats revealed an exposure prevalence of nearly 12%. It is also noteworthy that, based on owners’ information, nearly one third of cats diagnosed with heartworm disease at NCSU were housed solely indoors. Lastly, the consequences of feline heartworm disease are potentially dire, with no clear therapeutic solutions. Therefore the author advocates preventative therapy in cats in endemic areas. Three drugs with FDA approval are marketed for use in cats (Table Comparison of Spectra ofMacrolides Currently in Use in Cats). Ivermectin is provided in a chewable formulation, milbemycin as a flavored tablet, and selamectin (a broad-spectrum parasiticide) comes in a topical formulation. The spectrum and the formulation of these products varies; hence the clients’ individual needs are easily met in most cases (Table Comparison of Spectra ofMacrolides Currently in Use in Cats).

Comparison of Spectra ofMacrolides Currently in Use in Cats

Drug Heartwotm prevention Hookworms Whipworms Roundworms Tapeworms Fleas & Eccs Ticks Sarcoptes Ear Mites
Ivermectin (chewable) + +              
Milbemycin (flavored tablet) + +   +          
Selamectin (topical) + +   +   +/+ + + +

Because the vast majority of cats are amicrofilaremic, microfilaricidal therapy is unnecessary in this species. The use of arsenical adulticides is problematic. Thiacetarsemide (sodium caparsolate), if available, poses risks even in normal cats. Turner, Lees, and Brown reported death due to pulmonary edema and respiratory failure in 3 of 14 normal cats given thiacetarsemide (2.2 mg/kg twice over 24 hours). Dillon and colleagues could not confirm this acute pulmonary reaction in 12 normal cats receiving thiacetarsemide, but one cat did die after the final injection. More importantly, a significant, though unquantified, percentage of cats with HW1 develop pulmonary thromboembolism (PTE) after adulticidal therapy. This occurs several days to 1 week after therapy and is often fatal. In 50 cats with HWI, seen at NCSU, 11 received thiac-etarsemide. There was no significant difference in survival between those receiving thiacetarsemide and those receiving symptomatic therapy.

Data on melarsomine in experimental (transplanted) heartworm infection in cats are limited and contradictory. Although an abstract report exists in which one injection (2.5 mg/kg; one half the recommended canine dose) of melarsomine was used in experimentally infected cats without treatment-related mortality, the worm burdens after treatment were not significantly different from those found in untreated control cats. Diarrhea and heart murmurs were frequently noted in treated cats. A second abstract report, using either the standard canine protocol (2.5 mg/kg twice over 24 hours) or the split dose (one injection, followed by two injections, 24 hours apart, in 1 month) described in posts, gave more favorable results. The standard treatment and split-dose regimens resulted in 79% and 86% reduction in worm burdens, respectively, and there were no adverse reactions. Although promising, these unpublished data need to be interpreted with caution because the transplanted worms were young (<8 months old and more susceptible), and the control cats experienced a 53% worm mortality (average worm burden was reduced by 53% by the act of transplantation). Additionally, the clinical experience in naturally infected cats has been generally unfavorable, with an unacceptable mortality. Because of the inherent risk, lack of clear benefit, and the short life expectancy of heartworms in this species, this author does not advocate adulticidal therapy in cats. Surgical removal of heartworms has been successful and is attractive because it minimizes the risk of thromboemboli. The mortality seen in the only published case series was, unfortunately, unacceptable (two of five cats). This procedure may hold promise for the future, however.

Cats with heartworm infection should be placed on a monthly preventa-tive and short-term corticosteroid therapy (prednisone at 1 to 2 mg/kg every 48 hours, three times a day) used to manage respiratory signs. If signs recur, alternate-day steroid therapy (at the lowest dose that controls signs) can be continued indefinitely. For embolic emergencies, oxygen, corticosteroids (dexamethasone at 1 mg/kg intravenously or intramuscularly, or prednisolone sodium succinate at 50 to 100 mg intravenously/cat), and bronchodilators (aminophylline at 6.6 mg/kg intramuscularly every 12 hours, theophylline sustained release at 25 mg/kg orally, or terbutaline at 0.01 mg/kg subcutaneously) may be used. Bronchodilators have logic, based on the ability of agents, such as the xanthines (aminophylline and theophylline), to improve function of fatigued respiratory muscles. In addition, the finding of hyperinflation of lung fields may indicate bronchoconstriction, a condition for which bronchodilation would be indicated. Nevertheless, this author does not routinely use bronchodilators in feline HWD.

The use of aspirin has been questioned because vascular changes associated with HW1 consume platelets, increasing their turnover rate and effectually diminishing the antithrom-botic effects of the drug. Conventional doses of aspirin did not prevent angiographically detected vascular lesions. Doses of aspirin necessary to produce even limited histologic benefit approached the toxic range. Despite this, because therapeutic options are limited, at conventional doses (80 mg orally, every 72 hours), aspirin is generally harmless, inexpensive, and convenient. Because the quoted studies were based on relatively insensitive estimates of platelet function and pulmonary arterial disease (thereby possibly missing subtle benefits), the author continues to advocate aspirin for cats with HWI. Aspirin is not prescribed with concurrent corticosteroid therapy. Management of other signs of heartworm disease in cats is largely symptomatic.


Therapy of Canine Heartworm Disease


In most cases of HWD, it is imperative to rid the patient of the offending parasite. Thiacetarsemide, for decades the only drug approved for this purpose, is no longer available. It has been replaced by melarsomine (Immiticide), an organoarsenic superior in safety and efficacy to thiacetarsemide. With two doses (2.5 mg/kg intramuscularly every 24 hours), the efficacy is over 96%. Melarsomine has a mean retention time five times longer than thiacetarsemide, and its metabolites are free in the plasma (on which heartworms feed). In a study of 382 dogs with heartworm infection receiving melarsomine, none required cessation of therapy due to hepatorenal toxicity (as compared with 15% to 30% with thiacetarsemide), and no case of severe postadulticidal thromboembolization was observed.

Despite the enhanced safety of this product, adverse reactions are still noted. In fact, successful pharmacologic adulticidal therapy, by definition, dictates thromboembolic events. The clinician can diminish the severity of this complication by restricting exercise after melarsomine administration. Perhaps the drug’s biggest asset is the possibility of flexible dosing (“split-dose” — three injections over 1 month or longer), allowing the potential for a safer 50% initial worm kill, followed by subsequent injections to approach 100% efficacy. Studies have shown that patients treated with the split-dose regimen have a higher seroconversion to a negative antigen status than patients treated with either caparsolate or the standard melarsomine dosing regimen.

Manufacturer’s Recommendations for the Use ofMelarsomine Dihydrochloride, Based on Patient Status


Heartworm Infection (Asymptomatic, Nitric Oxide Radiocraphic Lesions)

Class 2

Symptomatic Heartworm Disease (Mild To Moderate Signs)

Class 3

Symptomatic Heartworm Disease (Severe Signs)

Class 4

Caval Syndrome

Two doses melorsomine 24 hours apart (2.5 mg/kg IM) Two doses melarsomine 24 hours apart (2.5 mg/kg IM) One dose melarsomine (2.5 mg/kg IM), followed in approximately 1 month with 2 injections 24 hours apart Melarsomine not indicated for acute care

A split-dose protocol can be used in severely afflicted individuals or in those in which pulmonary thromboembolism is anticipated (Table Manufacturer’s Recommendations for the Use ofMelarsomine Dihydrochloride, Based on Patient Status). This method allows for destruction of only one half the worms initially (one intramuscular injection of 2.5 mg/kg), thereby lessening the chance for embolic complications. This single dose is followed by a two-dose regimen in 1 to 3 months, if clinical conditions permit. Although the manufacturer recommends this protocol for severely affected dogs, the author uses it for all cases unless financial constraint or underlying concern for arsenic toxicity exists (e.g., pre-existent severe renal or hepatic disease). Disadvantages to the split-dose method include additional expense, increased total arsenic dose, and the need for 2 months’ exercise restriction.

In 55 dogs with severe heartworm disease that were treated in this manner, 96% had a good or very good outcome with more than 98% negative for antigenemia 90 days post-therapy. Of the 55 severely affected dogs, 31% had “mild or moderate PTE,” but no fatalities resulted. The most common sign was fever, cough, and anorexia 5 to 7 days post-treatment. This was associated with mild perivascular caudal lobar pulmonary radiographic densities and subsided spontaneously or after corticosteroid therapy.

Microfilaricidal and Preventative Therapy in Heartworm-Positive Dogs

At the time of diagnosis (usually by a positive heartworm antigen test) a minimum data base is completed. This includes a microfilaria test, chemistry panel, complete blood count (CBC), urinalysis, and thoracic radiographic evaluation. If liver disease is suspected from clinical and laboratory findings, serum bile acid evaluation may be useful in evaluating liver function. At this time, monthly macrolide preventative is prescribed. This approach, which differs from the recommendations of the American Heartworm Society, is used to prevent further infection, to eliminate micro-filariae (chronic therapy renders the dog of no further risk to infect itself or other dogs and cats), and to destroy developing L4 (not yet susceptible to adulticidal therapy). In microfi-laremic dogs, the first macrolide dose is administered in the hospital or at home, with observation, so an adverse reaction might be recognized and treated promptly.

Corticosteroids with or without antihistamines (dexamethasone at 0.25 mg/kg intravenously and Benadryl at 2 mg/kg intramuscularly or 1 mg/kg of prednisolone orally 1 hour before +/- 6 hours after administration of the first dose of preventative) may be administered to reduce the potential for adverse reaction in highly microfilaremic patients. It is important to emphasize that adverse reactions are unusual with macrolides at preventative doses.

Depending on the time of year, up to 2 to 3 months might be allowed to lapse before adulticidal therapy is administered. Although monthly macrolide administration prevents further infection, this delay allows larval maturation to adulthood, ensuring that the only stage of the life cycle present is the adult, which is vulnerable to melarsomine therapy. This is more important if the diagnosis is made during or at the end of a mosquito exposure season. If the diagnosis is made in the spring or late winter, when infective larvae have matured, adulticidal therapy may be immediately administered.


The first injection of Melarsomine is administered by deep intramuscular injection (2.5 mg/kg) in the lumbar musculature (as described in the package insert) and the injection site recorded. Before injection, the needle is changed and care is taken to inject deep into the muscle and nowhere else. Patients are typically, but not necessarily, hospitalized for the day. The need for exercise restriction for 1 month is emphasized, and sedation is provided if necessary. Owners are also advised as to adverse reactions (fever, local inflammation, lassitude, inappetence, cough, dyspnea, collapse), to call if they have concerns, and to return for a second series of two injections in approximately 1 month.

If serious systemic reaction results, the second stage of the adulticidal treatment is delayed or, occasionally, even canceled. Typically, however, even with severe reactions, the entire treatment protocol is completed within 2 to 3 months. After a minimum of 1 month, the melarsomine injection procedure is repeated, again with a record of the injection site. If significant local reaction was noted after the first injection, subsequent injections are accompanied by dexamethasone or oral nonsteroidal anti-inflammatory drugs (NSAIDs) to minimize pain at the injection site. The next day (approximately 24 hours after the first injection) the process is repeated with melarsomine injection into the opposite lumbar area. Client instructions are similar to those previously given, with reemphasis of the need for 1 months’ strict restriction of exercise. Antigen testing is repeated 6 months after the second series of injections, with a positive test result indicating incomplete adulticidal efficacy. It is emphasized that despite the proven efficacy of melarsomine, not all worms are killed in every patient. The worm burden is typically markedly reduced, but if as few as one to three adult female worms remain, positive antigen tests are likely. Whether to repeat adulticidal therapy, under these circumstances is decided on a case-by-case basis with input from the owners.


It is now known that certain macrolides have adulticidal properties. Ivermectin, when administered monthly for 31 consecutive months, has nearly 100% adulticidal efficacy in young HWIs. Selamectin, when administered continuously for 18 months, killed approximately 40% of transplanted worms. Milbemycin and sustained release moxidectin appear to have minimal adulticidal efficacy. Although there may be a role for this therapeutic strategy in cases in which financial constraints or concurrent medical problems prohibit melarsomine therapy, the current recommendations are that macrolides not be adapted as the primary adulticidal approach (see discussion of controversies, following).

Exercise Restriction

Cage rest is an important aspect of the management of heartworm disease after adulticidal therapy, after PTE, or during therapy of heart failure. This can often be best, or only, accomplished in the veterinary clinic. If financial constraints preclude this, crating or housing in the bathroom or garage at home, tranquilization, or both, with only gende leash walks are useful alternatives. Nevertheless, some owners do not or cannot restrict exercise, resulting in or worsening thromboembolic complications.

Surgical Therapy

Sasaki, Kitagawa, and Ishihara have described a method of mechanical worm removal using a flexible alligator forceps. This method was 90% effective in 36 dogs with mild and severe HWD. Only two of the severely affected dogs (n = 9) died of heart and renal failure over 90 days postoperatively. These data suggest that, in skilled hands, the technique is safe. Subsequent studies by Morini and colleagues demonstrated superior results as compared with melarsomine, producing less postadulticidal thromboembolization and CS. It is important to note that the majority of dogs treated surgically required subsequent melarsomine administration for adequate worm destruction. Advantages to this technique include its diminished potential arsenic toxicity (subsequent adulticidal therapy would be administered to an asymptomatic dog) and relative freedom from thromboembolic complication. Disadvantages include the need for general anesthesia, a degree of operator skill, fluoroscopy, and subsequent arsenic administration. Nevertheless, it remains a potential alternative for the management of high-risk patients.


Canine Heartworm Disease: Complications And Specific Syndromes

Asymptomatic Heartworm Infection

Most dogs with heartworm infection are asymptomatic, even though many of these have heartworm disease (radiographic and pathologic lesions). Treatment is as described previously, using melarsomine in the split-dose regimen, along with a macrolide preventative.

Asymptomatic dogs may, however, become symptomatic af’er adulticidal therapy due to postadulticidal thromboembolization and lung injury (as “described elsewhere). The risk of postadulticidal thromboembolization can be imperfectly predicted by semiquantitation of the worm burden, using certain antigen tests, and by the severity of radiographic lesions. Clearly a dog with severe radiographic lesions will not tolerate thromboembolic complications well, but not all dogs with radiographic signs have heavy worm burdens. For example, a dog with moderate to severe radiographic lesions and high antigenemia may not be at high risk for postadulticidal PTE, because it is quite possible that the worms have died, explaining both the antigenemia (release from dead worms) and radio-graphic abnormalities (chronic HWD).This conclusion might also be valid in the dogs with severe radiographic lesions and negative or low antigenemia (assumes most or all worms have died, and antigen has been cleared). Alternatively, antigenic evidence of a heavy worm burden in a dog with minimal radiographic signs might still portend a severe reaction after melarsomine, because the findings suggest large worm numbers but without natural worm attrition (i.e., a relatively young infection with minimal disease). Of course, low worm burden and minimal radiographic lesions would suggest the least risk of an adverse reaction to adulticide.

It bears emphasis that with each scenario, guesswork is involved and precautions should be taken. When the risk is greatest, aspirin (5 to 7 mg/kg daily — begun 3 weeks prior to and continued until 3 weeks after adulticide) or even heparin may be used, and cage confinement is most important. The owners should be educated as to the risk, the suggestive signs, and the importance of prompt veterinary assistance in case of an adverse reaction.


The majority of dogs suffering from chronic HWI have glomerulonephritis, which can be severe. Therefore when a dog demonstrates glomerular disease, heartworm infection should be considered as a differential diagnosis. Although it is generally felt that the glomerular lesions produced by heartworm infection are unlikely to produce renal failure, a therapeutic dilemma results when one is found in a dog with proteinuria, azotemia, and HWI. Logic suggests that adulticidal therapy is indicated because heartworm infection contributes to glomerular disease, but it likewise carries risks. The approach embraced by this author is to hospitalize the patient and to administer intravenous fluids (lactated Ringer’s solution at 2 to 3 mL/kg/hr) for 48 hours (beginning 12 hours prior to the first melarsomine dose). The patient is then released, and a recheck appointment for blood urea nitrogen (BUN) and creatinine determination after 48 hours is advised. The second and third injections are tentatively scheduled for 1 to 3 months, with the treatment decision based on renal function and the overall response to initial adulticidal therapy.

Allergic Pneumonitis

Allergic pneumonitis, which is reported to affect 14% of dogs with HWD, is a relatively early development in the disease course. In fact, the pathogenesis probably involves immunologic reaction to dying microfilariae in the pulmonary capillaries. Clinical signs include cough and sometimes dyspnea and other typical signs of HWD, such as weight loss and exercise intolerance. Specific physical examination findings may be absent or may include dyspnea and audible crackles in more severe cases. Radiographic findings include those typical of heartworm disease but with an infiltrate, usually interstitial, but occasionally with an alveolar component, often worse in the caudal lung lobes. Eosinophils and basophils may be found in excess in peripheral blood and in airway samples. Corticosteroid therapy (prednisone or prednisolone at 1 to 2 mg/kg per day) results in rapid attenuation of clinical signs, with radiographic clearing in less than a week. The dose can then be stopped in 3 to 5 days if clinical signs subside. Although microfilaricidal therapy is typically not indicated because infections are often occult, macrolide prophylaxis is indicated to avoid further infection. Adulticidal therapy can be used after clinical improvement.

Eosinophilic Granulomatosis

A more serious, but rare, manifestation, pulmonary eosinophilic granulomatosis, responds less favorably. This syndrome is characterized by a more organized, nodular inflammatory process, associated with bronchial lymphadenopathy and, occasionally, pleural effusion. With pulmonary granulomatosis, cough, wheezes, and pulmonary crackles are often audible; when very severe, lung sounds may be muffled and associated with dyspnea and cyanosis. Treatment with prednisone at twice the dose for allergic pneumonitis is reported to induce partial or complete remission in 1 to 2 weeks. The prognosis remains guarded because recurrence within several weeks is common. Prednisone may be combined with cyclophosphamide or azathioprine in an effort to heighten the immunosuppressive effect. The latter combination appears to be the most effective Adulticide therapy should be delayed until remission is attained. As the prognosis for medical success is guarded; surgical excision of lobar lesions has been advocated.

Pulmonary Embolization

Spontaneous thrombosis or postadulticidal thromboembolization associated with dead and dying worms — the most important heartworm complication — may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, hemoptysis and pulmonary infarction. Acute fatalities may result from fulminant respiratory failure, exsanguination, DIC, or may be unexplained and sudden (arrhythmia or massive pulmonary embolism). The most common presentation, however, is a sudden onset of lethargy, anorexia, and cough 7 to 10 days after adulticidal therapy — often after failure to restrict exercise. Dyspnea, fever, mucous membrane pallor, and adventitial lung sounds (crackles) may be noted on physical examination. Thoracic radiographs reveal significant pulmonary infiltrates, most severe in the caudal lung lobes.

The degree of worsening, as compared with pretreatment radiographs, is typically dramatic. The infiltrate, typically alveolar, is most severe in the caudal lobes, and occasionally areas of consolidation are noted. Laboratory abnormalities vary with the severity of signs but may include leukocytosis, left shift, monocytosis, eosinophilia, and thrombocytopenia. The degree thrombocytopenia may provide prognostic information.

Medical management of thromboembolic lung disease is largely empiric and somewhat controversial. It is generally agreed that strict cage confinement, oxygen administration via oxygen cage or nasal insufflation (50 to 100 mL/kg), and prednisone (1 mg/kg/day for 3 to 7 days) are indicated in the most severe cases. KMW Some advocate careful fluid therapy (see recommendations for CS), measuring CVP to avoid precipitation of heart failure, to maximize tissue perfusion and combat dehydration. The use of heparin (75 IU/kg subcutaneously three times a day until platelet count has normalized [5 to 7 days]) and aspirin (5 to 7 mg/kg/day) has been advocated y some but remains controversial.

Other therapeutic strategies might include cough suppressants, antibiotics (if fever is unresponsive), and, although speculative at this time, vasodilators (amlodipine, hydralazine, diltiazem). If vasodilatory therapy is used, one must monitor blood pressure because hypotension is a potential side effect. Clinical improvement may be rapid and release from the hospital considered after several days’ treatment. For less severely affected dogs, careful confinement and prednisone at home are often adequate.

Congestive Heart Failure

Right heart failure results from increased right ventricular afterload (secondary to chronic pulmonary arterial disease and thromboemboli with resultant PHT). When severe and chronic, pulmonary hypertension may be complicated by secondary tricuspid regur-gitation and right heart failure. Congestive signs (ascites) are worsened in the face of hypoproteinemia. Calvert suggests that up to 50% of dogs with severe pulmonary vascular complication to heartworm disease will develop heart failure. Clinical signs variably include weight loss, exercise intolerance, ashen mucous membranes with prolonged capillary refill time, ascites, dyspnea, jugular venous distension and pulsation, arrhythmias with pulse deficits, and adventitial lung sounds (crackles and possibly wheezes). Dyspnea may be due to pulmonary infiltrates (PIE or PTE, but not cardiogenic pulmonary edema), abdominal distension, or pleural effusion.

Treatment aims include reduction of signs of congestion, reducing PHT, and increasing cardiac output. This involves dietary, pharmacologic, and procedural interventions. Moderate salt restriction is logical and probably useful in diminishing diuretic needs. This author chooses a diet designed for senior patients or early heart disease, because salt restriction should only be moderate. Diuretics may be useful in preventing recurrence of ascites but are typically not able to mobilize large fluid accumulations effectively. This then requires periodic abdominal or thoracic paracentesis (or both) when discomfort is apparent. Furosemide is typically used at 1 to 4 mg/kg daily, depending on severity and patient response Additional diuretics, which provide a supplemental effect by using differing parts of the nephron, include spironolactone (1 to 2 mg/kg orally twice a day) and chlorothiazide (2 mg/kg orally daily to every other day). The ACE-inhibitors (eg., enalapril, benazepril, lisino-pril, ramipril), by their effect on the renin-angiotensin-aldosterone system, may be of use as mixed vasodilators, in blunting pathologic cardiac remodeling, and in reducing fluid retention, particularly cases of refractory ascites. Adulticide therapy is delayed until clinical improvement is noted. No evidence indicates that digoxin improves survival in HWD. Because of the risk of toxicity and pulmonary vasoconstriction associated with its use, it is not routinely used by is author in the management of HWD-induced heart failure However, digoxin may be beneficial in the presence of supraventricular tachycardia or refractory heart failure Aspirin, theoretically useful because of its ability to ameliorate some pulmonary vascular lesions and vasoconstriction, may be used 5 mg/kg/day orally.

The arterial vasodilator, hydralazine, has been shown by Lombard to improve cardiac output in a small number of dogs with heartworm disease and heart failure. It has also been demonstrated to reduce pulmonary artery pressure and vascular resistance right ventricular work, and aortic pressure without changing cardiac output or heart rate in dogs with experimental heartworm disease (but without heart failure). Clinical experience has shown perceived improvement with the vasodilators diltiazem and amlodipine as well. Research and clinical experience suggest that hydralazine, amlodipine, and diltiazem might have a role in this setting, but further studies are necessary to define their role, if any. In heart failure the author uses hydralazine at 0.5 to 2 mg/kg orally twice a day, diltiazem at 0.5 to 1.5 mg/kg orally three times a day, or amlodipine at 0.1 to 0.25 mg/kg/day orally. The risk of hypotension with these therapies must be realized and blood pressure monitored.

Often heart failure follows adulticidal therapy, but if it is present prior to adulticidal therapy, the difficult question arises as when (or whether) to administer melarsomine. If clinical response to heart failure management is good, adulticidal therapy may be offered in 4 to 12 weeks, as conditions allow. Melarsomine is generally avoided if heart failure is refractory. Antiarrhythmic therapy is seldom necessary, although slowing the ventricular response to atrial fibrillation with digoxin, Diltiazem, or both () may be necessary in some cases.

Caval Syndrome

Heartworm CS is a relatively uncommon but severe variant or complication of HWD. Most studies have shown a marked sex predilection, with 75% to 90% of CS dogs being male. It is characterized by heavy worm burden (usually >60, with the majority of the worms residing in the right atrium and venae cavae) and a poor prognosis.

Studies performed in the author’s laboratory indicate that retrograde migration of adult heartworms to the cavae and right atrium, from 5 to 17 months after infection, produces partial inflow obstruction to the right heart and, by interfering with the valve apparatus, tricuspid insufficiency (with resultant systolic murmur, jugular pulse, and CVP increase). Affected dogs also exhibit pre-existent heartworm-induced PHT, which markedly increases the adverse hemodynamic effects of tricuspid regurgitation. These combined effects substantially reduce left ventricular preload and hence cardiac output. Cardiac arrhythmias may further compromise cardiac function.

This constellation of events precipitates a sudden onset of clinical signs, including hemolytic anemia caused by trauma to red blood cells (RBCs) as they pass through a sieve of heart-worms occupying the right atrium and venae cavae, as well as through fibrin strands in capillaries if disseminated intravascular coagulation has developed. Intravascular hemolysis, metabolic acidosis, and diminished hepatic function with impaired removal of circulating pro-coagulants contribute to the development of DIC. The effect of this traumatic insult to the erythron is magnified by increased RBC fragility, due to alterations in the RBC membrane in dogs with HWD. Hemoglobinemia, hemoglobinuria, and hepatic and renal dysfunction also are observed in many dogs. The cause of hepatorenal dysfunction is not clear, but it probably results from the combined effects of passive congestion, diminished perfusion, and the deleterious effects of the products of hemolysis. Without treatment, death frequently ensues within 24 to 72 hours due to cardiogenic shock, complicated by anemia, metabolic acidosis, and DIC.

A sudden onset of anorexia, depression, weakness, and occasionally coughing are accompanied in most dogs by dyspnea and hemoglobinuria. Hemoglobinuria has been considered pathognomonic for this syndrome. Physical examination reveals mucous membrane pallor, prolonged capillary refill time, weak pulses, jugular distension and pulsation, hepatosplenomegaly, and dyspnea. Thoracic auscultation may disclose adventitial lung sounds; a systolic heart murmur of tricuspid insufficiency (87% of cases); loud, split S2 (67%); and cardiac gallop (20%). Other reported findings include ascites (29%), jaundice (19%), and hemoptysis (6%). Body temperature varies from subnormal to mildly elevated.

Hemoglobinemia and microfilaremia are present in 85% of dogs suffering from CS. Moderate (mean PCV, 28%) regenerative anemia characterized by the presence of reticulocytes, nucleated RBC, and increased mean corpuscular volume (MCV) is seen in the majority of cases. This normochromic, macrocytic anemia has been associated with the presence of target cells, schistocytes, spur cells, and spherocytes. Leukocytosis (mean white blood cell (WBC] count, approximately 20,000 cells/cm) with neutrophilia, eosinophilia, and left shift has been described. Dogs affected with disseminated intravascular coagulation are characterized by the presence of thrombocytopenia and hypofibrinoginemia, as well as prolonged one stage prothrombin time (PT), partial thromboplastin time (PTT), activated coagulation time (ACT), and high fibrin degradation product concentrations. Serum chemistry analysis reveals increases in liver enzymes, bilirubin, and indices of renal function. Urine analysis reveals high bilirubin and protein concentrations in 50% of cases and more frequently, hemoglobinuria.

CVP is high in 80% to 90% of cases (mean, 11.4 cm H20). Electrocardiographic abnormalities include sinus tachycardia in 33% of cases and atrial and ventricular premature complexes in 28% and 6%, respectively. The mean electrical axis tends to rotate rightward (mean, +129 degrees), with an S1,2,3 pattern evident in 38% of cases. The S wave depth in CV6LU (V<) is the most reliable indicator of right ventricular enlargement (>0.8 mv) in 56% of cases. Thoracic radiography reveals signs of severe heartworm disease with cardiomegaly, main pulmonary arterial enlargement, increased pulmonary vascularity, and pulmonary arterial tortuousity recognized in descending order of frequency (). Massive worm inhabitation of the right atrium with movement into the right ventricle during diastole is evident echocardiographically. This finding on M-mode and two-dimensional echocardiograms is nearly pathognomonic for CS in the appropriate clinical setting. The right ventricular lumen is enlarged and the left diminished in size, suggesting pulmonary hypertension accompanied by reduced left ventricular loading. Paradoxical septal motion, caused by high right ventricular pressure, is commonly observed. No echocardiographic evidence of left ventricular dysfunction exists. Cardiac catheterization documents pulmonary, right atrial, and right ventricular hypertension and reduced cardiac output.

Prognosis is poor unless the cause of the crisis — the right atrial and caval heartworms — is removed. Even with this treatment, mortality can approximate 40%.

Fluid therapy is needed to improve cardiac output and tissue perfusion, to prevent or help to reverse DIC, to prevent hemoglobin nephropathy, and to aid in the correction of metabolic acidosis. Overexuberant fluid therapy, however, may worsen or precipitate signs of congestive heart failure. In the author’s clinic, a left jugular catheter is placed and intravenous fluid therapy instituted with 5% dextrose in water or one-half strength saline and 2.5% dextrose. The catheter should not enter the anterior vena cava because it will interfere with worm embolectomy. A cephalic catheter may be substituted for the somewhat inconvenient jugular catheter, but this does not allow monitoring of CVP. The intravenous infusion rate for fluids is dependent on the condition of the animal. A useful guideline is to infuse as rapidly as possible (up to 1 cardiovascular volume during the first hour) without raising the CVP or without raising it above 10 cm H20 if it was normal or near normal at the outset. Initial therapy should be aggressive (10 to 20 mL/kg/hr for the first hour) if shock is accompanied by a normal CVP (<5 cm HzO), and it should be curtailed to approximately 1 to 2 mL/kg/hr if CVP is 10 to 20 cm HzO. Whole blood transfusion is not indicated in most cases because anemia usually is not severe, and transfused coagulation factors may worsen DIG Sodium bicarbonate is not indicated unless metabolic acidosis is severe (pH, 7.15 to 7.20). Broad-spectrum antibiotics and aspirin (5 mg/kg daily) should be administered. Treatment for disseminated intravascular coagulation is described elsewhere in this text.

The technique for surgical removal of caval and atria] heartworms was developed by Jackson and colleagues. This procedure should be undertaken as early in the course of therapy as is practical. Often, sedation is unnecessary, and the procedure can be accomplished with only local anesthesia. The dog is restrained in left lateral recumbency after surgical clipping and preparation. The jugular vein is isolated distally. A ligature is placed loosely around the cranial aspect of the vein until it is incised, after which the ligature is tied. Alligator forceps (20 to 40 cm, preferably of small diameter) are guided gently down the vein while being held loosely between the thumb and forefinger. The jugular vein can be temporarily occluded with umbilical tape. If difficulty is encountered in passage of the forceps, gentle manipulation of the dog by assistants to further extend the neck will assist in passage of the forceps past the thoracic inlet; medial direction of the forceps may be necessary at the base of the heart. Once the forceps have been placed, the jaws are opened, the forceps are advanced slightly, the jaws are closed, and the worms are removed. One to four worms are usually removed with each pass. This process is repeated until five to six successive attempts are unsuccessful. An effort should be made to remove 35 to 50 worms. Care should be taken not to fracture heartworm during extraction. After worm removal, the jugular vein is ligated distally, and subcutaneous and skin sutures are placed routinely. Other catheters, such as urethral stone basket catheters, horsehair brushes, snares and flexible alligator forceps have also been used. Fluoroscopic guidance, when available, is useful in this procedure.

Successful worm retrieval is associated with a reduction in the intensity of the cardiac murmur and jugular pulsations, rapid clearing of hemoglobinemia and hemoglobinuria, and normalization of serum enzymatic aberrations. Immediate and latent improvement in cardiac function occurs over the next 24 hours. It is important to realize that removal of worms does nothing to reduce right ventricular afterload (PHT), and hence fluid therapy must be monitored carefully before and after surgery to avoid precipitation or worsening of right heart failure. Cage rest should be enforced for a period of time suitable for individual care.

Worm embolectomy through a jugular venotomy is frequently successful in stabilizing the animal, allowing adulticide therapy to be instituted to destroy remaining heartworms in a minimum of 1 month. Careful scrutiny of BUN and serum liver enzyme concentrations should precede the latter treatment. Aspirin therapy is continued for 3 to 4 weeks after adulticide therapy. Substantial improvement in anemia should not be expected for 2 to 4 weeks after worm embolectomy. Macrolide preventative therapy, as described previously, is administered at the time of release from the hospital.

Aberrant Migration

Although heartworms in the dog typically inhabit the pulmonary arteries of the caudal lung lobes, they may find their way to the right ventricle, and rarely (see Caval Syndrome) the right atria and venae cavae. Much less frequently, immature L5 may aberrantly migrate to other sites, including the brain, spinal cord, epidural space, anterior chamber of the eye, the vitreous, the subcutis, and the peritoneal cavity. In addition, the worms may inhabit the systemic circulation, producing systemic thromboembolic disease. Treatment of aberrantly migrating heartworms requires either nothing (e.g., peritoneal cavity), surgical excision of the offending parasite, adulticidal therapy, or symptomatic treatment (e.g., seizure control with brain migration). The method for surgical removal from internal iliac and femoral arteries has been described.


Sample Treatment Regimens

Case 1

The typical horse with moderate recurrent airway obstruction may have 30% to 70% neutrophils in the bronchoalveolar lavage fluid, resting airway resistance that is elevated twice to three times normal, and visible signs of increased breathing effort. This horse would show a 30% to 50% reduction in airway resistance after receiving 450 meg of albuterol via metered-dose inhaler. This horse would have recommendations for radical environmental modifications and would be treated with a four-week (weeks 1-4) decreasing course of systemic corticosteroids (e.g., prednisolone), with inhaled therapy beginning in the second to third week of treatment (week 3).

Week 3

  • • salmeterol 210 μg (10 puffs) twice daily
  • • fluticasone 2200 μg (10 puffs) twice daily

Week 4

  • • salmeterol 210 μg (10 puffs) once daily
  • • fluticasone 2200 μg (10 puffs) once daily
  • • Lung function recheck at end of 4 weeks; if good response:
  • salmeterol 210 μg once daily
    fluticasone 2200 μg every other day

This client should contact the veterinarians monthly, and the horse should have twice-yearly to yearly lung function rechecks to fine-tune inhaled drug therapy and keep the disease in remission. During periods of remission, lung function tests are aimed at measuring baseline airway resistance and airway reactivity. Heightened airway reactivity suggests the need for intensive long-term treatment.

Case 2

The horse with inflammatory airway disease is usually younger (2-7 years), although older horses can manifest inflammatory airway disease without heaves. Typical findings include declining performance, cough, and persistent mucoid discharge visible mostly upon endoscopy. Exercise intolerance commonly is observed in horses with inflammatory airway disease, and in these cases, lower airway inflammation is present. Bronchoalveolar lavage reveals elevated neutrophils, mast cells, or eosinophils, and increased airway reactivity to histamine is also present.

Examples of Treatments

Weeks 1 and 2

  • • fluticasone 2200 μg (10 puffs) twice daily or beclomethasone hydrofluoroalkane-134a, 1000 nig (5 puffs)
  • • albuterol 450 μg (5 puffs) before steroid inhaler and at least 30 minutes before exercise

Week 3

  • • fluticasone 2200 μg (10 puffs) once daily or beclomethasone HFA, 1000 mg (5 puffs)
  • • albuterol 450 μg as needed, not to exceed 3 times/week

Week 4

  • • fluticasone 2200 μg once daily or beclomethasone HFA, 1000 mg (5 puffs)
  • • albuterol should no longer be necessary
  • • Rechecking at the end of the week to determine further course of treatment

Heaves (Recurrent Airway Obstruction)

Practical Management of Acute Episodes and Prevention of Exacerbations

Heaves, also known as recurrent airway obstruction (RAO) and chronic obstructive pulmonary disease (COPD), is an inflammatory condition in horses that results from the inhalation of dust in moldy hay and bedding. The condition affects primarily the small airways of horses and causes bronchospasm, bronchial hyperresponsiveness, mucus plugs, and pathologic changes of the bronchiolar walls, leading to obstruction of terminal airways. The mechanisms by which dust inhalation causes lower airway inflammation remains ill-defined, although evidence exists that a hypersensitivity reaction to specific antigens present in hay may be implicated. However, a wide range of particles is present in the horse’s environment that also could be implicated in the development of heaves.

The treatment of heaves aims at (1) preventing further inhalation of offending dust in hay, (2) decreasing inflammation of the lower airways, and (3) providing symptomatic relief of airway obstruction. Although environmental dust control is pivotal to prevent the exacerbation of heaves, medications often are required for immediate improvement of airway function.

It is currently unknown whether a mechanistic relationship exists between heaves and inflammatory airway disease (inflammatory airway disease) in young performing horses and therefore findings regarding the treatment of heaves may not necessarily be appropriate for inflammatory airway disease.

Acute Episodes

The primary goal of therapy during acute exacerbation of heaves is to relieve airway obstruction primarily by the administration of antiinflammatory agents and bronchodilators.

Table Medications Recommended for the Treatment of Heaves

Medication Dosage*
dexamethasone 20-50 mg** IV, IM, or PO q24h
dexamethasone 21-isonicotinate 0.04 mg/kg IM q3d
prednisolone 2.2 mg/kg PO q24h
isoflupredone acetate 10-14 mg** IM q24h
triamcinolone acetonide 20-40 mg** IM
beclomethasone dipropionate 3500 μg/horse q12h in MDI (Equine AeroMask)
1320 μg/horse q12h in MDI (3M Equine Aerosol Delivery System)
fluticasone propionate 2000 μg/horse q12h in MDI (Equine AeroMask)
clenbuterol 0.8-3.2 μg/kg orally twice daily
0.8 μg/kg IV
aminophylline 5-10 mg/kg orally or IV twice daily
fenoterol 1-2 mg/horse in MDI (Equine AeroMask)
albuterol 0.8-2 μg/kg in MDI
ipratropium bromide 2-3 μg/kg q6h with mechanical nebulizer
90-180 μg/horse q6h in MDI (Equine AeroMask)
1200 μg/horse q6h with DPI
salmetreol 63-210 μg q8h (Equine AeroMask)
sodium cromoglycate 80 mg/horse q24h for 4 days with a mechanical nebulizer
200 mg/horse q12h in MDI (Equine AeroMask)
nedocromil sodium 10-20 mg q8h in MDI (Equine AeroMask)

IV, Intravenous; IM, intramuscular; MDI, metered-dose inhaler; q12h, every 12 hours; DPI, dry powder inhaler.

* Suggestive dosages are indicative only.

** The usual dose for a horse that weighs 450 to 500 kg.

Corticosteroids Recommended for the Treatment of Heaves

Bronchodilators Recommended for the Treatment of Heaves

Expectorant, Mucolytic, and Mucokinetic Agents

Expectorants are drugs that increase pulmonary secretion, whereas mucolytic agents loosen secretions. The term mucokinetic agent may be preferred because it indicates that the therapy is aimed at increasing the clearance of the respiratory tract secretions. Although the administration of mucokinetic agents may help loosen the secretions in the large airways, evidence of their efficacy in improving the clinical signs of heaves is sparse. Clenbuterol, because of its bronchodilator and mucokinetic properties, may be preferred to clear mucus from the airways. Dembrexine (Sputolysin) and potassium iodide also improve clearance of bronchial secretions. Potassium iodide should be administered with caution to heavey horses because it is irritating for the respiratory tract and can induce or worsen bronchospasm. Nebulization with N-acetylcysteine (1 g/horse q12h via mechanical nebulizer) depolymerizes mucus by breaking disulfide bridges between macromolecules and has been advocated in the treatment of horses.

Overhydration by the massive administration of isotonic saline solution combined with bronchodilators or mucokinetic agents has been used to treat airway obstruction of horses with heaves. Although in a controlled laboratory setting this author failed to find an improvement in the pulmonary mechanics of heaves-affected horses with overhydration alone, it occasionally was associated with improved airway function of some clinical cases particularly when heaves-affected horses were refractory to other modes of therapy including potent corticosteroids. The proposed beneficial effects of this treatment are improved mucus transport and removal of mucus plugs related to the liquefaction of excessively viscous mucus. This treatment should be administered with caution as a number of side effects, including dyspnea and colic, have been observed with its use.

Antitussive agents are rarely indicated in the treatment of equine heaves because cough is a mechanism essential for the clearance of respiratory secretions.

Prevention Of Exacerbation

Environmental Changes

Clinical exacerbation of heaves occurs when susceptible horses are exposed to environmental dust particles. Drugs administered to heaves-affected horses will have only transitory effects if concurrent strict dust control measures are not applied. A wide diversity of particles may be found in a barn, including molds, noxious gases, endotoxins, and other irritants. The greatest exposure to particles small enough to be inhaled deep into the lungs of horses occurs when they are eating hay. For this reason, long-term management of heaves depends primarily on the replacement of hay in the diet by non-dusty hay alternatives. The airways of heaves-affected horses are hyperreactive, and therefore any inhaled irritants also potentially could contribute to the airway obstruction in susceptible horses.

The reversal of clinical signs of heaves with strict environmental changes may take up to 3 to 4 weeks. The remission time correlates with age and the duration and severity of illness. Horses kept permanently outdoors and fed grass or other hay substitutes usually remain free of clinical signs. Horses do well when kept outdoors even in very cold conditions, as long as they have access to enough food, fresh water (heated water tub), and shelter. The replacement of hay by less dusty feed can induce clinical remission in stabled horses. Pelleted hay, hay silage, and hydroponic hay are well tolerated and free of dust. Hay soaked in water for 2 to 4 hours before feeding may control heaves in some horses, whereas in others only partial improvement often is noted. Wood shavings, shredded paper, peanut kernels, and peat moss are good substitutes for straw, although a recent study failed to find differences in airway function in heaves-susceptible horses fed silage that were bedded on good quality straw or shavings. Other commonly made recommendations include removing the horse from the stable when cleaning the box stalls and watering the aisles before sweeping to decrease the amount of dust particles suspended in air. Proper ventilation is also important, although identifying the proper ventilation system, which would minimize dust, is problematic.

Aerosol Medications

Aerosol medications, in particular steroids such as BDP and FDP, are quite effective to prevent relapses, if given long term (see “Aerosolized Drug Delivery Devices” and “Use of Aerosolized Bronchodilators and Corticosteroids”). These drugs prevent the cascade of inflammation that is the hallmark of the allergic process and may reduce the previous remodeling of the airway (airway wall thickening via epithelial hyperplasia and goblet cell metaplasia). Although little information exists in the literature, the use of 10 puffs of BDP (84 meg/puff) or FDP (220 μg/puff) given daily or every other day has been reported to be an effective means to prevent exacerbations during periods of susceptibility but does not replace the need for environmental changes.

Alternatively, the prophylactic administration of sodium cromoglycate (Intal, 80 mg q24h for 4 days) by inhalation in heaves-susceptible horses in clinical remission prevented the appearance of clinical signs for up to 3 weeks after they were introduced to a dusty environment. The administration of sodium cromoglycate using a dose metered inhaler and a treatment mask facilitated drug administration and therefore decreased treatment failure resulting from inadequate drug administration. A similar mast cell blocker is nedocromil sodium (Tilade) that is given at a dose of 10 to 20 puffs (1 mg/puff) three times per day. These two mast cell blockers may be effective in preventing exacerbations in horses that do not respond to inhaled steroids, or as supplements to reduce the need for steroids. The problem with mast cell blockers is the need for large and frequent dosing.


Corticosteroids Recommended for the Treatment of Heaves

Corticosteroids are the most potent drugs currently available for the treatment of heaves (Table Medications Recommended for the Treatment of Heaves). The mechanisms of action of corticosteroids include decreasing smooth muscle contraction and epithelial damage by inhibiting the effects of inflammatory cells and their mediators, potentiation of the bronchodilating effects of catecholamines and reduction of mucus production. Corticosteroids with potent antiinflammatory effects are also more likely to result in detrimental effects. Corticosteroids have been commonly administered systemically, and more recently, by inhalation. An advantage of inhaled medication is achievement of a high local concentration of drug in the lungs while minimizing systemic effects. A number of corticosteroid drugs have been proposed for the treatment of heaves but objective information concerning their comparative efficacy and toxicity is sparse. Drug selection depends on the severity of the clinical signs and the ability to improve the environment. The minimal effective dose should be used, and the prolonged systemic administration of corticosteroids usually is avoided to prevent side effects.

Systemic Corticosteroids

Systemic corticosteroid administration for a minimum of 2 weeks usually is recommended for the control of heaves. A delay of a week can be expected between the initiation of therapy and the maximal clinical response, although some improvement may be observed within a few days of drug administration. Therefore in horses with severe respiratory dysfunction, corticosteroids should be combined with drugs such as bronchodilators, which can provide symptomatic relief more rapidly. If concurrent environmental control is not performed, the respiratory signs are likely to recur soon after cessation of drug administration. For a severe attack, dexamethasone (initial dose 0.05-0.1 mg/kg, IV, followed by decremental doses and alternate day dosing) has proven efficacious to control clinical signs.

Isoflupredone acetate has the advantage that it can be administered by the intramuscular route and is as effective as dexamethasone in improving the airway function of horses with heaves. The dose used is 10 to 14 mg intramuscularly daily for 5 days; the drug is then administered on alternate days and tapered to a low dose over a period of 10 to 20 days. Although hypokalemia may occur after the administration of isoflupredone acetate to horses, the severe hypokalemic myopathy reported in cattle and in people apparently does not occur when this drug is used in horses.

Triamcinolone acetonide (20-40 mg IM) also reverses clinical signs of airway obstruction in horses with severely impaired airway function. Because long-acting corticosteroids are more likely to be associated with detrimental side effects, triamcinolone administration is recommended when short-acting corticosteroids cannot be administered. Even in severe cases when no improvement has been made in the horse’s environment, the clinical improvement lasts up to 5 weeks.

Prednisone and prednisolone are less potent and less toxic than the above corticosteroids and have been used for the treatment of mildly affected horses. Recent studies have shown that oral prednisone is absorbed poorly in horses and, when administered in conjunction with environmental changes, provides no additional benefit over management alone.

Inhaled Corticosteroids

Inhalation therapy is well-suited to corticosteroid administration because of the large number of glucocorticoid receptors at the level of bronchial epithelial cells and vascular endothelial cells. Inhalation therapy allows a maximal concentration of drug at the effector sites and minimizes side effects. Inhaled corticosteroids may therefore be preferable when prolonged therapy would be required.

Beclomethasone dipropionate (BDP) in metered-dose inhalers (MDIs) improves respiratory mechanics parameters within 3 to 4 treatment days. The maximal beneficial effects usually are observed during the first week of therapy. Fluticasone propionate (FDP) administered from a MDI and a mask also results in a decrease in airway obstruction, in neutrophil counts, in bronchoalveolar lavage fluid, and in bronchial hyperresponsiveness.

The information available to date in horses suggests that the short-term administration of inhaled corticosteroids is both efficacious and well tolerated but has little residual effect when the treatment is discontinued. Because a delay in response is expected with inhaled corticosteroids, they should be combined with faster acting drugs, such as bronchodilators or systemic corticosteroids in horses with respiratory distress. Bronchodilator administration also may improve pulmonary distribution of aerosolized surface-active antiinflammatory preparations. Masks used in combination with MDIs or dry powder inhalers (DPIs) increase the resistance to airflow and therefore may not be suitable and well tolerated for the initial treatment of horses with labored breathing. This author has treated a few horses that became reluctant to inhale the medication after a few days. Replacing the poorly tolerated drug with another of the same class often corrects this problem.

Chronic airway inflammation in heaves results in airway remodeling. The dosages and duration of corticosteroid administration required to restore the normal lung morphology in heaves are unknown but are likely to exceed, by far, the usually recommended posology.

Side effects of corticosteroids are uncommon based on the available literature. Detrimental findings that have been reported after systemic corticosteroid administration to heaves-affected horses include laminitis, suppression of the hypothalamo-pituitary-adrenal axis, altered bone metabolism, and bacterial pneumonia. To date, the only side effect attributed to inhaled corticosteroids is a decrease in serum cortisol.


Medical Therapy For Upper Airway Disease

Because of the possibility that regional inflammation of the upper airway may be responsible for some obstructive upper airway diseases, enteral, parenteral, and topical antiinflammatory therapy may prove useful in their treatment. Although a proven correlation between airway inflammation and upper airway obstructive diseases remains to be established, an association exists between the presence of upper airway inflammation and the occurrence of obstructive upper airway disease. This premise finds support in numerous anecdotal accounts of improved upper airway function in horses after antiinflammatory treatment.

Systemic and inhaled corticosteroids have been used successfully to treat upper airway inflammation and neuromuscular dysfunction that results in dorsal and lateral nasopharyngeal collapse and dorsal displacement of the soft palate. After a thorough physical examination and complete blood cell count and fibrinogen have been performed to rule out active bacterial infection, systemic corticosteroid therapy can be initiated. Dexamethasone can be administered in a tapering dose, orally, at 0.02 to 0.04 mg/kg twice daily for 10 days to 2 weeks, followed by 0.02 to 0.04 mg/kg, once daily for 10 days to 2 weeks, then 0.02 to 0.04 mg/kg every other day for 2 weeks. The horse should be rested during this time, and either turned out in a pasture or worked lightly for 6 to 8 weeks. The airway inflammation typically resolves within 7 to 10 days, however, upper airway function may not improve for as long as 4 months, thus patience is important. Oral prednisolone can also be given at 1 to 2 mg/kg with the same dosing regimen as dexamethasone. It is important to note that oral prednisone therapy in horses is ineffective. Prednisone is poorly absorbed by the equine gastrointestinal tract and is not converted to the active antiinflammatory form, prednisolone.

Inhaled and topical medications have also been used to decrease airway inflammation in horses. Dexamethasone and prednisolone can be nebulized for distribution in the nasopharynx. Antiinflammatory topical throat sprays, composed of nitrofurazone, dimethyl sulfoxide, glycerin, and prednisolone or dexamethasone, can be administered into the nasopharynx by passing a uterine infusion pipette or narrowing tubing of sufficient length into the nasopharynx and spraying 10 to 20 ml of the solution into the nasopharynx. Application of throat spray may be performed twice daily for 2 weeks and then daily for 2 weeks.

Interferons are a family of proteins that have antiviral and immunomodulatory activity. Oral administration of a low dose (0.1 IU/kg) of human interferon-α (HuIFNα) reduces tracheal and nasopharyngeal exudate in racehorses with inflammatory airway disease. Horses are generally treated daily for 5 to 7 days. Oral administration of HuIFNα likely is effective because it stimulates lymphoid tissue in the oropharynx. At Michigan State University the following procedure is used to prepare interferon:

1. Add 1 ml of interferon α-2a (3 million U/ml, Roferon-A) to 99 ml of 0.9% saline and mix well but do not shake. This makes 100 ml of 30,000 U/ml interferon α-2a.

2. Remove 143 ml of 0.9% saline from a 1-L container and add 3 ml of the 30,000 U/ml interferon α-2a solution. The final volume of 900 ml will contain 100 U/ml interferon α-2a.

3. Divide the 100 U/ml solution into aliquots of 30 ml each, place in 1 oz bottles, and refrigerate.

4. Label each aliquot with the following information:

  • • Interferon α-2a 100 U/ml.
  • • Store in refrigerator.
  • • Prepared on date _____.
  • • Discard after 30 days.

Discard any solution remaining from step 1. Interferon tends to bind to surfaces and any long-term storage must be in a – 70° C freezer.