Categories
Diseases

Diseases of the Ear: General Principles Of Management

The therapeutic plan for otitis externa requires identification of the primary disease process and perpetuating factors. Ideally management is aimed at thoroughly cleaning and drying the ear canal, removing or managing the primary factors, controlling perpetuating factors, administering appropriate topical or systemic therapy (or both), and evaluating response to therapy.

Ear Cleaning

Ear cleaning serves several functions: (1) it removes material that supports or perpetuates infection; (2) it removes bacterial toxins, white blood cells (WBCs), and free fatty acids that stimulate inflammation; (3) it allows complete evaluation of the external ear canal and tympanum; (4) it allows topical therapy to contact all portions of the ear canal; and (5) it removes material that may inactivate topical medications. Significandy painful ears may benefit from initial anti-inflammatory therapy to decrease pain and swelling of the ear canal prior to cleaning. Severe cases of otitis externa often require general anesthesia to facilitate complete cleaning and evaluation of the external and middle ear.

Many different solutions are available for removing cerumen, exudate, and debris from the ear canal (Table Otic Cleaning Solutions). If the tympanic membrane cannot be visualized, only physiologic saline solution or water should be used, because many topical cleaning agents are ototoxic or incite inflammation of the middle ear. An operating otoscope, ear loops, and alligator forceps facilitate manual removal of large amounts of cerumen or debris. Debris is carefully removed under direct visualization, and care is taken deeper in the ear canal (close to the tympanic membrane). Aggressive hair removal is not advised, because inflammation and damage to the epithelium can result in secondary bacterial colonization and infection. Flushing may be performed after large accumulations of cerumen and debris are mechanically removed from the ear canal.

Otic Cleaning Solutions

Trade Name Acetic Acid Boric Acid Salicylic Acid Isopropyl Alcohol Propylene Clycol Dss Other
Ace-Otic Cleanser 2%   0.1%       Lactic acid 2.7%
Adams Pan-Otic         X X Parachlorometaxylenol, tris EDTA, methylparaben, diazolidinyl urea, popylparaben, octoxynol
Alocetic Ear Rinse X     X     Nonoxynol-12, methylparaben, alovera gel
Cerulytic Ear Ceruminolytic         X   Benzyl alcohol, butylated hydroxytoluene
Cerumene             25% Isopropyl myristate
DermaPet Ear/Skin Cleanser for Pets X X          
Docusate Solution         X X  
Earmed Boracetic Flush X X         Aloe
Earmed Cleansing Solution & Wash         X   50A 40B alcohol, cocamidopropyl phosphatidyl and PE dimonium chloride
Earoxide Ear Cleanser             Carbamide peroxide 6.5%
Epi-Otic Ear Cleanser     X   X X Lactic acid, chitosanide
Fresh-Ear X X X X X   Lidocaine hydrochloride, glycerin, sodium docusate, lanolin oil
OtiCalm     X       Benzoic acid, malic acid, oil of eucalyptus
Otic Clear X X X X X   Glycerin, lidocaine hydrochloride
Oticlean-A Ear Cleaning Lotion X X X 35% X   Lanolin oil, glycerin
Oti-Clens     X   X   Malic acid, benzoic acid
Otipan Cleansing Solution         X   Hydroxypropyl cellulose, octoxynol
Otocetic Solution 2% 2%          
Wax-O-Sol 25%             Hexamethyltetracosane

Flushing and evacuation of solution is done under direct visualization through an operating otoscope. A bulb syringe and red rubber catheter system may be used to both flush and evacuate solutions and accumulations from the ear canal. The operator, avoiding drastic pressure changes within the external ear canal that could damage the tympanum, should carefully control suction and manual evacuation of the contents of the bulb syringe from the ear canal. Other alternatives include tomcat catheters (3.5 F) or flexible, intravenous catheters (14 gauge, Teflon); stiff, narrow catheters should be used cautiously and under direct visualization deep in the external ear canal. Other reservoir systems for delivery or evacuation of solutions include a 12 mL syringe or suction tubing attached to in-house vacuum systems. In-house vacuum systems should be used cautiously and under direct visualization. Care should be taken to avoid trauma to the tympanic membrane until its integrity can be assessed. Initial flushes should be done with physiologic saline solution or water until the integrity of the tympanic membrane is established.

Other solutions may aid in the removal of wax in the ear canal. Ceruminolytics are emulsifiers and surfactants that break down ceruminocellular aggregates by causing lysis of squamous cells. A ceruminolytic agent in an alkaline pH may more effectively lyse squamous cells via cell surface protein disruption. Oil-based products soften and loosen debris to aid in their removal but do not cause cell lysis. Water-based ceruminolytics are easier to remove and dry more quickly than oil-based solutions, which are occlusive if they remain in the ear canal. Water-based products include dioctyl sodium sulfosuccinate, calcium sulfosuccinate, and carbamate peroxide, which has a foaming action with the release of urea and oxygen. Oil-based products include squalene, triethanolamine polypeptide, hexamethyltetracosane, oleate condensate, propylene glycol, glycerin, and mineral oil. In a recent study only the combination of squalene and isopropyl myristate in a liquid petrolatum base had no adverse effects on hearing, the vestibular system, and histopathologic examination. Other agents tested contained glycerin, dioctyl sodium sulfosuccinate (2% or 6.5%), parachlorometaxylenol, carbamide peroxide (6%), propylene glycol, triethanolamine polypeptide oleate condensate (10%), and chlorobutanol (0.5%).

Alcohol-based drying agents added to ceruminolytics include boric acid, benzoic acid, and salicylic acid, which decrease the pH of the ear canal, cause keratolysis, and have a mild antimicrobial effect. Drying the ear canal is important to combat increased humidity, which potentiates infection.

If the tympanum is intact, the ear canal is filled with a ceruminolytic agent for at least 2 minutes and the pinna is cleaned at the same time. The solution is flushed twice with warm water, and the canal inspected. The procedure is repeated until cleaning is complete. Other solutions commonly advocated for ear flushing include dilute chlorhexidine solution (0.05%), dilute povidone-iodine, and acetic acid (2.5%). The first two agents are potentially ototoxic or induce inflammation and should not be used if the tympanum is ruptured. A combination of propylene glycol malic, benzoic, or salicylic acid; 2% acetic acid; or dilute povidone-iodine have been suggested for use in dogs with a ruptured tympanum.

Owners may clean the ears at home with mild preparations of ceruminolytics and drying agents if mild otitis is present without severe accumulation of cerumen or exudate. Aqueous solutions are usually recommended because they are less occlusive and easier to clean from the ear, dog, and home environment.

The ear should be filled with the solution, then massaged for 40 to 60 seconds. The pet should be allowed to shake its head to remove the majority of the solution, and the excess should be wiped from the ear canal and pinna with a tissue. Daily flushing is usually recommended, followed by every other day, weekly, then as needed, depending on the solution. Ear swabs are not recommended for home use, because cerumen and debris may be forced into the horizontal ear canal and impact against the tympanic membrane

Topical Therapy

Erythematous ceruminous otitis externa is diagnosed 2.7 times more often than acute suppurative otitis according to one report. Yeast ± cocci were identified in those cases, with cocci or rods identified in suppurative otitis. Topical therapy should be based on the cytologic examination to diminish the incidence of inappropriate treatment (Table Topical Medications Used in the Treatment of Ear Disease). Many preparations combine anti-inflammatories and antimicrobials in an attempt to decrease the inflammation and combat bacterial or yeast overgrowth. All topical medications should be considered supportive, and specific treatment should be aimed at controlling the primary disease process.

Topical Medications Used in the Treatment of Ear Disease

Generic Name Trade Name Dose Frequency Description
Fluocinolone 0.01% DMSO 60% Synotic 4-6 drops; total dose<17mL q12h initially. q48-72h maintenance Potent corticosteroid anti-inflammatory
Hydrocortisone 1.0% HB101,

Burrows H,

2-12 drops, depending on ear size q12h initially. q24-48h maintenance Mild corticosteroid anti-inflammatory
Hydrocortisone 1.0%, lactic acid Epiotic HC 5-10 drops q12h for 5 days Mild corticosteroid anti-inflammatory, drying agent
Hydrocortisone 0.5%, sulfur 2%. acetic acid 2.5% Clear X Ear Treatment 2-12 drops, depending on ear size q12-24h initially. q24-48h maintenance Mild corticosteroid anti-inflammatory, astringent, germicidal
DSS 6.5%. urea (carbamide peroxide 6%) Clear X Ear Cleansing Solution 1-2 mL per ear Once per week to as necessary Ceruminolytic, lubricating agent
Chlorhexidine 2% Nolvasan Dilute 1:40 in water As necessary Antibacterial & antifungal activity
Chlorhexidine 1.5% Nolvasan Dilute 2% in

propylene glycol

q12h Antibacterial & antifungal activity
Povidone-iodine 10% Betadine solution Dilute 1:10-1:50 in water As necessary Antibacterial activity
Polyhydroxidine iodine 0.5% Xenodyne Dilute 1:1-1:5 in water As necessary, q12h, once weekly Antibacterial activity
Acetic acid 5% White vinegar Dilute 1:1-1:3 in water As necessary; q12-24h for Pseudomonas Antibacterial activity, lowers ear canal pH
Neomycin 0.25%, triamcinolone 0.1%, thiabendazole 4% Tresaderm 2-12 drops depending on ear size q12h up to 7 days Antibacterial & antifungal activity, parasiticide (mites), moderate corticosteroid anti-inflammatory
Neomycin 0.25%, triamcinolone 0.1%, nystatin 100,000 U/mL Panalog 2-12 drops depending on ear size q12h to once weekly Antibacterial & antifungal activity, moderate corticosteroid anti-inflammatory
Chloramphenicol 0.42%. prednisone 0.17%, tetracaine 2%, squalene Liquachlor, Chlora-Otic 2-12 drops depending on ear size q12h up to 7 days Antibacterial activity, mild corticosteroid anti-inflammatory
Neomycin 1.75 & polymyxin B 5000 lU/mL, penicillin C procaine 10,000 lU/mL Forte Topical 2-12 drops depending on ear size q12h Antibacterial activity
Centamicin 0.3%, betamethasone valerate 0.1% Centocin Otic Solution, Betagen Otic Solution 2-12 drops depending on ear size q12h for 7 to 14 days Antibacterial activity, potent corticosteroid anti-inflammatory
Centamicin 0.3%, betamethasone 0.1%, clotrimazole 0.1% Otomax, Obibiotic Ointment 2-12 drops depending on ear size q12h for 7 days Antibacterial & antifungal activity, potent corticosteroid anti-inflammatory
Centamicin 0.3%, betamethasone valerate 0.1%, acetic acid 2.5% Centaved Otic Solution 2-12 drops, depending on ear size q12h for 7 to 14 days Antibacterial activity, potent corticosteroid anti-inflammatory
Polymixin B 10,000 lU/mL, hydrocortisone 0.5% Otobiotic 2-12 drops, depending on ear size q12h Antibacterial activity, mild corticosteroid anti-inflammatory
Enrofloxacin 0.5%, silver sulfadiazine 1% Baytril Otic 2-12 drops, depending on ear size q12h for up to 14 days Antibacterial activity
Carbaryl 0.5%, neomycin 0.5%, tetracaine Mitox Liquid 2-12 drops, depending on ear size   Antibacterial activity, parasiticide (mites)
Pyrethrins 0.06%, piperonyl butoxide 0.6% Ear Mite and Tick Control 5 drops q12h Parasiticide (mites)
Pyrethrins 0.05%, squalene 25% Cerumite 2-12 drops, depending on ear size q24h for 7 to 10 days Parasiticide (mites), ceruminolytic
Isopropyl alcohol 90%, boric acid 2% Panodry Fill ear canal As necessary Drying agent
Acetic acid 2%, aluminum acetate Otic Domeboro Fill ear canal q12-48h Drying agent, antibacterial activity, lowers ear canal pH
Silver sulfadiazine Silvadene Dilute 1:1 with water, 1 g powder in 100 mL water q12h for 14 days Antibacterial & antifungal activity
Tris EDTA±

gentamicin 0.03%

  2-12 drops, depending on ear size q12h for 14 days 1 L distilled water, 1.2g Tris EDTA, 1 mL glacial acetic acid; antibacterial activity
Silver nitrate   Use sparingly As necessary Cauterization of

ulcerative otitis externa

Miconazole 1%; ± topical glucocorticoid (7.5 mL of dexamethasone phosphate (4 mg/mL] to10mLof1% miconazole) Conofite 2-12 drops, depending on ear size q12-24h Antifungal activity
Ivermectin 0.01% Acarexx 0.5 mL per ear Once Parasiticide (mites)
Pyrethrins 0.15%, piperonyl butoxide 1.5% Many 2-12 drops, depending on ear size Twice at 7-day interval Parasiticide (mites)
Pyrethrins 0.05%, piperonyl butoxide 0.5%, squalene 25% Cerumite 2-12 drops, depending on ear size q24h for 7 days Parasiticide (mites), ceruminolytic
Pyrethrins 0.04%, piperonyl butoxide 0.49%, DSS 1.952%, benzocaine 1.952% Aurimite 10 drops q12h  
Rotenone 0.12%, cube resins 0.16% Many 2-12 drops, depending on ear size Every other day Parasiticide (mites)

Topical glucocorticoids benefit most cases of otitis externa by decreasing pruritus, exudation, swelling, and proliferative changes of the ear canal. The most potent glucocorticoids available in topical preparations are betamethasone valerate and fluocinolone acetonide. Less potent corticosteroids include triamcinolone acetonide and dexamethasone; the least potent is hydrocortisone. Most dogs benefit from short-term therapy with topical corticosteroids at the initiation of therapy, with concurrent therapy aimed at the primary and other perpetuating factors. Long-term therapy with topical corticosteroids can be deleterious because of systemic absorption of drug. Increased serum liver enzymes and depressed adrenal responsiveness may occur; with prolonged use iatrogenic hyperadreno-corticism is possible. Glucocorticoids alone may be of benefit for short-term therapy in cases of allergic or erythematous ceruminous otitis.

Antimicrobials are important for controlling secondary bacterial or yeast overgrowth or infection. Antimicrobials are indicated in any case with cytologic evidence of bacterial overgrowth or infection, with attention paid to the morphology and gram-staining characteristics of the bacteria. Otic preparations commonly contain aminoglycoside antibiotics. Neomycin is effective against typical otitis bacteria such as Staphylococcus intermedium. Gentamicin and polymyxin B are also appropriate initial topical treatments for gram-negative bacterial otitis externa.The significant risk of bone marrow toxicity in people limits the use of chloramphenicol for treating otitis in dogs and cats despite its antibacterial spectrum and availability.

Due to the frequency of resistant gram-negative bacteria such as Pseudomonas, other topical preparations have been developed. Enrofloxacin, ophthalmic tobramycin, and topical application of injectable ticarcillin have been used to treat otitis in dogs.< Their use should be limited to cases of resistant bacteria, and culture and susceptibility testing should be performed prior to application. Other topical agents may be used to supplement treatment of resistant Pseudomonas, such as silver sulfadiazine solution and tris EDTA. Tris EDTA can render Pseudomonas susceptible to enrofloxacin or cephalosporins by enhancing membrane permeability and altering ribosome stability. Frequent ear cleaning may also assist in the treatment of resistant bacterial otitis; ceruminolytics have antimicrobial properties, and their use in clinical cases has been evaluated. Acetic acid in combination with boric acid is effective against both Pseudomonas and Staphylococcus, depending on concentration and duration of exposure. Ear cleaning removes proinflammatory products, cells, and substances that diminish the effectiveness of topical antibiotics.

Many topical preparations control yeast organisms, which may complicate erythematous ceruminous otitis and suppurative otitis. Common active ingredients include miconazole, clotrimazole, nystatin, and thiabendazole. Preparations containing climbazole, econazole, and ketoconazole have also been evaluated. Eighty percent of yeast were susceptible to miconazole and econazole, intermediately resistant to ketoconazole, and 90% were resistant to nystatin and amphotericin B in one in vitro study. Topical ear cleaning agents have some efficacy against Malassezia organisms. Other preparations (e.g. chlorhexidine, povidone-iodine, acetic acid) are also effective in the treatment of secondary yeast overgrowth.

Response to topical therapy should be gauged by re-evaluation of physical, cytologic, and otoscopic examinations every 10 to 14 days after the initiation of therapy. Any changes in the results of these examinations should be recorded. Most cases of otitis can be managed topically; failure to respond to therapy should prompt re-evaluation of the diagnosis and treatment.

Systemic Therapy

Systemic glucocorticoid administration may be beneficial in cases of severe, acute inflammation of the ear canal, chronic proliferative changes of the ear canal, and allergic otitis. Anti-inflammatory doses should be limited to 7 to 10 days. Cases of significant thickening or proliferative changes in the external ear canal benefit from systemic antimicrobial therapy. Systemic therapy should be considered if concurrent dermatologic changes of the surrounding skin, pinna, or other regions of the body are present. Long-term administration of appropriate antimicrobials based on culture and susceptibility is required in all cases of otitis media. Systemic therapy for yeast is rarely recommended in animals with otitis alone. One study evaluated oral itraconazole therapy, and in ear samples evaluated on cytology and culture, no change in cytology score was found.

 

Categories
Diseases

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

Laryngitis

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.

Categories
Drugs

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.

Pharmacology/Actions

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).

Pharmacokinetics

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. ()

Monitoring

■ 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)

Categories
Diseases

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.

Categories
Diseases

The Medical Management Of Heartworm Infection

The medical management of heartworm infection is complex because of the complicated parasite life cycle, the marked variability in clinical manifestations and severity of HWD, prophylactic considerations, adulticidal and microfilaricidal considerations, and the relative toxicity and complications associated with adulticidal therapy. For these reasons, the diagnosis, prevention, and treatment of heartworm infection remains a challenge

Prophylaxis

Prevention of heartworm infection is an obvious and attainable goal for the veterinary profession. Prevention failure results from ignorance on the part of owners as to the presence or potential severity of HWI, lack of owner compliance, or from inadequate instruction on preventative measures by the attending veterinarian. Studies of owner compliance have revealed that approximately 55% of dog owners that use veterinary care purchase heartworm preventative, and enough medication is dispensed only to meet the needs of approximately 56% of those dogs. Hence the proportion of “cared for” dogs in the population that receive adequate heartworm prophylaxis is less than one third. If one takes into consideration doses purchased but not administered and dogs that are never taken to a veterinarian, the percentage of protected dogs falls drastically. This was emphasized in North Carolina in 1999, when Hurricane Floyd caused extensive flooding and disruption in the poorest part of the state. Of dogs rescued from the floodwaters, 67% were infected with heartworms (personal communication, Dr. Kelli Ferris, North Carolina State University, 2003). In addition, evidence suggests that the veterinary profession is failing in its education of clients. New and colleagues, upon questioning veterinary clients purchasing macrolide preventatives, found that 38% did not realize that their prescribed drug’s spectrum was broader than solely preventing HWI.

Diethylcarbamazine

Diethylcarbamazine (DEC), which long enjoyed popularity as the preventative of choice, has now been largely replaced by the safer and more convenient macrolide preventatives. This product is safe (only in amicrofilaremic dogs) and effective; however, it must be given daily, making owner compliance problematic. Diethylcarbamazine is thought to kill L3 and early L4 tissue migrating larvae but only has a small temporal window of therapeutic efficacy, thus explaining the need for frequent administration. Preventative should be administered daily from the onset of mosquito season, continuously until 1 to 2 months after a killing frost. In some geographic regions, the persistence of mosquitoes dictates yearlong prophylaxis, although this is controversial for much of the United States (see discussion of controversies, following).

Diethylcarbamazine must only be administered to dogs free of microfilariae, thus dictating a yearly heartworm test prior to reinstitution of preventative therapy. Inadvertent administration of diethylcarbamazine to microfilaremic dogs produces an adverse, possibly immune-mediated reaction in approximately 30%. Signs associated with this adverse drug reaction usually occur within 1 hour of medication and include depression, ptyalism, vomiting, diarrhea, weak pulse, pale mucous membranes with poor capillary refill time, and bradycardia. Subsequently some dogs may become recumbent, dyspneic, and tachycardic, and 18% of reactors succumb. Restated, 6% of microfilaremic dogs to which diethylcarbamazine is administered will die due an adverse reaction.

Not infrequently, owners inadvertently miss one or more doses of Diethylcarbamazine preventative. If 1 day of therapy is omitted, no problem exists and drug administration should continue. In the event of a more prolonged lapse in diethylcarbamazine treatment, reinstitution of medication should be advised, with the realization that infection may have occurred during the prophylactic hiatus.

These dogs should be reevaluated in 6 to 7 months to determine if infection has resulted. If a dog is found to be microfilaremic when receiving diethylcarbamazine, prophylaxis should be continued; however, if inadvertently stopped, reinstitution may result in the aforementioned adverse reaction.

Macrolide Antibiotics

The introduction of the macrolide agents (macrocyclic lactones) ivermectin (Heartgard ®), milbemycin oxime (Interceptor ®), moxidectin (ProHeart ® and ProHeart ® 6), and selamectin (Revolution ™) has provided the veterinary profession with effective heartworm preventatives in a variety of formulations. These agents, because they interrupt larval development during the first 2 months after infection, have a large window of efficacy and are administered monthly or less frequently. Macrolide agents are superior to Diethylcarbamazine in convenience. They produce less severe reactions when inadvertently given to microfilaremic dogs, allow a grace period for inadvertent lapses in administration, are more effective with treatment lapses of up to 2 to 3 months when used continuously for the next 12 months, and have a dual role as microfilaricides. Recently it has been shown that some macrolides have adulticidal activity, if used continuously for prolonged periods. (NOTE: ProHeart ® 6 is no longer oh the market.)

Ivermectin

Ivermectin, a chemical derivative of avermectin B1 that is obtained from Streptomyces spp., is effective against a range of endo- and ectoparasites and is marketed as a once-monthly heartworm preventative. It is also marketed in a form with pyrantel pamoate to improve efficacy against intestinal parasites (). Macrolides provide a wide window of efficacy and provide some protection when lapses in therapy occur. Ivermectin is effective as a prophylactic with lapses of up to 2 months. Protection is extended, with continuous 12-month administration postexposure, with lapses of 3 months (98% efficacy) and of 4 months (95% efficacy). As stated previously, ivermectin is microfilaricidal at preventative doses (6 to 12 µg/kg/month), resulting in a gradual decline in microfilarial numbers. Despite this gradual microfilarial destruction, generally mild, adverse reactions (transient diarrhea) can occur if administered to microfilaremic dogs. Some breeds (collies and Shedand sheep dogs) are susceptible to ivermectin (and other macrolide) toxicosis at high doses, suffering neurologic signs. This has typically resulted with the use of concentrated livestock preparations, with clinical signs recognized with doses greater than 16 times the recommended dose. For this reason, only preparations designed for pet use should be administered to dogs. When used appropriately, ivermectin is virtually 100% effective in preventing HWI. Additionally, recent studies have shown ivermectin to have partial adulticidal properties when used continuously for 16 months and virtually 100% effective with continuous administration for 30 months. (See discussion of controversies, following.)

Milbemycin

Milbemycin oxime is a member of a family of milbemycin macrolide antibiotics derived from a species of Streptomyces. At 500 to 999 Hg/kg, it has efficacy against developing filarial larvae, arresting development in the first 6 weeks. It can therefore be given at monthly intervals with a reachback effect of 2 months when doses are inadvertently delayed. With 12 months’ continuous treatment postexposure, this “safety net” can be extended to 3 months (97% efficacy), falling to 41% with lapses of 4 months. At the preventative dose, milbemycin is a broad-spectrum parasiticide, being also effective against certain hookworms, roundworms, and whipworms (). In microfilaremic dogs, milbemycin has greater potential for adverse reactions than do other macrolides, because it is a potent microfilaricide at preventative doses. Adverse reactions, similar to those observed with ivermectin at microfilaricidal doses, may be observed in microfilaremic dogs receiving milbemycin at preventative doses. As with microfilaricidal doses (50 ug/kg) of ivermectin, Benadryl (2 mg/kg intramuscularly) and dexamethasone (0.25 mg/kg intravenously) may be administered prior to milbemycin to prevent adverse reactions, particularly in dogs with high micro-filarial counts. Milbemycin is also safe for use in collies at the preventative dose. With appropriate use, milbemycin is virtually 100% efficacious as a heartworm prophylactic.

Moxidectin

The macrolide preventative, moxidectin, has been more recently marketed as a narrow-spectrum heartworm preventative () and shown to be safe and virtually 100% effective at 3 ug/kg orally, given monthly or bimonthly up to 2 months postinfection. Moxidectin, at this dose, is gradually microfilaricidal and did not produce adverse reactions in a small number of microfilaremic dogs treated with the prophylactic dose. At 15 ug/kg, 98% reduction in micro-filarial numbers was documented 2 months post-treatment. Lastly, moxidectin appears to be safe in collies. A new liposomal formulation of moxidectin, which provides the potential to improve owner compliance, gives 6 months’ protection with one subcutaneous injection. With 12 months’ (two injections) continuous treatment, injectable moxidectin is 97% effective at preventing infection after a 4-month lapse in preventative therapy. (This product was removed from the market in late 2004 pending further study.)

Selamectin

Selamectin is a semisynthetic macrolide. It is unique in its broad spectrum and in the fact that it is applied topically once monthly (). Its efficacy is similar to that of other macrolides (virtually 100%, when used as directed). At 6 to 12 mg/kg topically, this preventative is effective at preventing heartworms infection and kills fleas and flea eggs, sarcoptic mange mites, ticks, and ear mites. Bathing and swimming, as soon as 2 hours after application, does not alter efficacy. Safety has been shown at tenfold topical doses, with oral consumption of single doses and, in ivermectin-sensitive collies, at recommended doses and fivefold overdoses for 3 months. Like other macrolides, selamectin has at least a 2-month reach-back effect and with 12 months’ continuous administration is 99% protective after 3-month lapses in prophylaxis. Selamectin has microfilaricidal activity similar to other macrolides. Chronic, continuous selamectin administration has adulticidal efficacy, although no published data indicate it is as effective in this role as ivermectin.

In summary, the macrolides offer a convenient, effective, and safe method of heartworm prophylaxis with varying spectra and methods of administration (). They each have microfilaricidal efficacy and render female heartworms sterile. Hence microfilarial tests for heartworm infection cannot be reliably used in dogs receiving these products. Prophylaxis should be commenced at 6 to 8 weeks of age in endemic areas or as soon thereafter as climatic conditions dictate. Although safer than Diethylcarbamazine in microfilaremic dogs, before first-time administration any dog over 6 months of age and at risk of infection should be tested (antigen test, followed by a microfilaria test, if antigen positive). Additionally, even though protective for at least 8 weeks postexposure, macrolides should be administered precisely as indicated by the manufacturer. If accidental lapses of more than 10 weeks occur, the preventative should be reinstituted at recommended doses and maintained for 12 consecutive months. Macrolides can also be used to “rescue” dogs that have lapsed in their Diethylcarbamazine daily therapy for up to 60 to 90 days. In the event of a lapse in preventative administration during a time of known exposure risk, an antigen heartworm test should be performed 7 months after the last possible exposure to determine if infection has occurred.

The necessary duration of protection is controversial. The American Heartworm Society indicates that in colder climates, yearlong prevention is not necessary, advocating beginning macrolides within 1 month of the anticipation of transmission season and continuing 1 month beyond the transmission season. On the other hand, some experts believe that yearlong prevention should be embraced, regardless of geographic location. This author advocates yearlong prevention, at least below the Mason-Dixon line in North America.

Categories
Diseases

Therapy of Canine Heartworm Disease

Melarsomine

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

Class1

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.

Procedure

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.

Macrolides

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.

Categories
Diseases

Canine Heartworm Disease: Ancillary Therapy

Corticosteroids

The anti-inflammatory and immunosuppressive effects inherent to corticosteroids are useful for treatment of some aspects of HWD. Prednisone, the steroid most often advocated, reduces pulmonary arteritis but actually worsens the proliferative vascular lesions of HWD, diminishes pulmonary arterial flow, and reduces the effectiveness of thiacetarsemide. For these reasons, corticosteroids are indicated in heartworm disease only in the face of pulmonary parenchymal complications (eosinophilic pneumonitis, eosinophilic granulomas, and PTE), to treat or prevent adverse reactions to microfilaricides, and possibly to minimize tissue reaction to melarsomine. For allergic pneumonias, prednisone (1 mg/kg/day) is administered for 3 to 5 days and discontinued or tapered as indicated. The response is generally favorable. Prednisone has also been advocated, along with cage rest, for the management of postadulticidal thromboembolization at 1 to 2 mg/kg per day, continued until radiographic and clinical improvement is noted. Because of the potential for steroid-induced fluid retention, such therapy should be used cautiously in the face of heart failure. In addition, caution is warranted because early studies demonstrated that postadulticidal corticosteroid therapy reduced pulmonary blood flow and worsened intimal disease in a model of HWI; corticosteroids are also procoagulant As mentioned with adulucidal (previously discussed) and microfilaricidal (discussed following) therapies, corticosteroids may be used to minimize potential adverse reactions to melarsomine and to macrolides given to rapidly kill microfilariae.

Aspirin

Antithrombotic agents have received a good deal of attention in the management of HWD. Potential benefits include reduction in severity of vascular lesions, reduction in thromboxane-induced pulmonary arterial vasoconstriction and PHT, and minimization of postadulticidal PTE. Aspirin has shown success in diminishing the vascular damage caused by segments of dead worms, reduced the extent and severity of myointimal proliferation caused by implanted living worms, and improved pulmonary parenchymal disease and intimal proliferation in dogs receiving thiacetarsemide after previous living heartworm implantation. More recent studies, however, have produced controversial results. Four dogs with implanted heartworms, receiving adulticide and administered aspirin, showed no improvement in pulmonary angio-graphic lesions, and treated dogs had more severe tortuousity than did controls and dogs receiving heparin. Boudreau and colleagues demonstrated that the aspirin dose required to decrease platelet reactivity by at least 50% was increased by nearly 70% with heartworm infection (implantation model) and by nearly 200% with a model (dead worm implantation) of PTE. There were not significant differences in severity of pulmonary vascular lesions in aspirin-treated versus control dogs. For these reasons, the American Heartworm Society does not endorse antithrombotic therapy for routine treatment of HWD. Calvert and colleagues have, however, successfully used the combination of aspirin and strict cage confinement with adul-ticidal therapy for severe HWD.

If used, aspirin is administered daily beginning 1 to 3 weeks prior to and continued for 4 to 6 weeks after adulticide administration. With protracted aspirin therapy, packed cell volume (PCV) and serum total protein, should be monitored periodically. Aspirin is avoided or discontinued in the face of gastrointestinal (GI) bleeding (melena or falling PCV), persistent emesis, thrombocytopenia (50,000/mm), and hemoptysis.

Heparin Therapy

Low-dose calcium heparin has been studied in canine heartworm disease and shown to reduce the adverse reactions associated with thiacetarsemide in dogs with severe clinical signs, including heart failure. In this study, calcium heparin administered at 50 to 100 IU/kg subcutaneously every 8 to 12 hours for 1 to 2 weeks before and 3 to 6 weeks after adulticidal therapy, reduced thromboembolic complications and improved survival, as compared with aspirin and indobufen. Dogs in both groups also received prednisone at 1 mg/kg/day. It is emphasized that this therapy has not been studied with melarsomine adulticidal therapy. Calvert and colleagues advocate sodium heparin (50 to 70 U/kg) in dogs with thrombocytopenia, DIC, or both, continuing until the platelet count is greater than 150,000/mm, for at least 7 days, and possibly for weeks.

Microfilaricidal Therapy

Despite the fact that no agent is approved by the Food and Drug Administration for the elimination of microfilaria, microfilaricidal therapy is traditionally instituted 4 to 6 weeks after adulticide administration. The macrolides offer a safe and effective alternative to levamisole and dithiazanine. Microfilariae are rapidly cleared with ivermectin at 50 ug/kg (approximately eight times preventative dose) or milbemycin at 500 mg/kg (preventative dose), although this represents an extra-label use of ivermectin. Adverse reactions, the severity of which is likely related to microfilarial numbers, were observed in 6% of 126 dogs receiving ivermectin at the microfilaricidal dose. Signs included shock, depression, hypothermia, and vomiting. With fluid and corticosteroid (dexamethasone at 2 to 4 mg/kg intravenously) therapy, all dogs recovered within 12 hours. One fatality, however, was observed 4 days after microfilaricidal therapy. Similar findings and frequency have been reported with milbemycin at the preventative dose. Dogs so treated should be hospitalized and carefully observed for the day. Dogs less than 16 kg, harboring more than 10,000 microfilaria per milliliter of blood, are more apt to suffer adverse reactions. Benadryl (2 mg/kg intramuscularly) and dexamethasone (0.25 mg/kg intravenously) can be administered prophylactically to prevent adverse reactions to microfilaricidal doses of macrolides.

A slower microfilarial kill rate can also be achieved with ivermectin, moxidectin, and selamectin at preventative doses. Using either the rapid or “slow kill” approach rids the patient of microfilariae and sterilizes the female heartworm.

The American Heartworm Society recommends that macrolide therapy, at preventative doses, be instituted 3 to 4 weeks after adulticidal therapy. Accelerated microfilaria] destruction can be achieved using recommended doses of milbemycin or by reducing the dosing interval for the other topical or oral formulations to every 2 weeks. Filter or modified Knott tests are rechecked in 5 months when using a slow kill or after 2 to 3 macrolide doses when using a accelerated dose. This interval for testing can be reduced if milbemycin or high-dose ivermectin (50 ug/kg) is chosen.

This author chooses an alternative approach (), beginning the administration of a macrolide preventative at the time of diagnosis, often days to weeks prior to adulticidal therapy. With the slow kill microfilaricides (ivermectin, moxidectin, or selamectin at preventative doses), little chance exists of an adverse reaction; however, the owner is warned of the possibility and advised to administer the medication on a day when he or she will be at home. If milbemycin is used, it is usually administered in the hospital and may be preceded by administration of dexamethasone and Benadryl (as described previously in adulticidal therapy).

Categories
Drugs

Amikacin Sulfate (Amikin, Amiglyde-V)

Aminoglycoside Antibiotic

Highlights Of Prescribing Information

Parenteral aminoglycoside antibiotic that has good activity against a variety of bacteria, predominantly gram-negative aerobic bacilli

Adverse Effects: Nephrotoxicity, ototoxicity, neuromuscu-lar blockade

Cats may be more sensitive to toxic effects

Risk factors for toxicity: Preexisting renal disease, age (both neonatal & geriatric), fever, sepsis & dehydration

Now usually dosed once daily when used systemically

What Is Amikacin Sulfate Used For?

While parenteral use is only approved in dogs, amikacin is used clinically to treat serious gram-negative infections in most species. It is often used in settings where gentamicin-resistant bacteria are a clinical problem. The inherent toxicity of the aminoglycosides limit their systemic use to serious infections when there is either a documented lack of susceptibility to other, less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram-negative infection before culture and susceptibility results are reported.

Amikacin is also approved for intrauterine infusion in mares. It is used with intra-articular injection in foals to treat gram-negative septic arthritis.

Pharmacology/Actions

Amikacin, like the other aminoglycoside antibiotics, act on susceptible bacteria presumably by irreversibly binding to the 30S ribosomal subunit thereby inhibiting protein synthesis. It is considered a bactericidal concentration-dependent antibiotic.

Amikacin’s spectrum of activity includes: coverage against many aerobic gram-negative and some aerobic gram-positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strains of Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still be killed by amikacin.

Antimicrobial activity of the aminoglycosides is enhanced in an alkaline environment.

The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria.

Pharmacokinetics

Amikacin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration, but is absorbed from topical administration (not from skin or the urinary bladder) when used in irrigations during surgical procedures. Patients receiving oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM administration to dogs and cats, peak levels occur from ½1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bio availability from extravascular injection (IM or SC) is greater than 90%.

After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids; high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner ear and kidneys, which may help explain their toxicity. Volumes of distribution have been reported to be 0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may be significantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta; fetal concentrations range from 15-50% of those found in maternal serum.

Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The approximate elimination half-lives for amikacin have been reported to be 5 hours in foals, 1.14-2.3 hours in adult horses, 2.2-2.7 hours in calves, 1-3 hours in cows, 1.5 hours in sheep, and 0.5-2 hours in dogs and cats. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibiotics.

Before you take Amikacin Sulfate

Contraindications / Precautions / Warnings

Aminoglycosides are contraindicated in patients who are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative infections, there are no other absolute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration.

Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e.g., “seeing-eye,” herding, dogs for the hearing impaired, etc.).

Aminoglycosides should be used with caution in patients with neuromuscular disorders (e.g., myasthenia gravis) due to their neuromuscular blocking activity.

Because aminoglycosides are eliminated primarily through renal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals.

Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affect the GI flora balance in these animals.

Adverse Effects

The aminoglycosides are infamous for their nephrotoxic and ototox-ic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely understood, but are probably related to interference with phospholipid metabolism in the lysosomes of proximal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by: increases in BUN, creatinine, nonprotein nitrogen in the serum, and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring.

Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can manifest by either auditory and/or vestibular clinical signs and may be irreversible. Vestibular clinical signs are more frequent with streptomycin, gentamicin, or tobramycin. Auditory clinical signs are more frequent with amikacin, neomycin, or kanamycin, but either form can occur with any of these drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides.

The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI clinical signs, hematologic and hepatic effects have been reported.

Reproductive / Nursing Safety

Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of therapy may exceed the potential risks. 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.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should he used cautiously as a last resort when the benefit of therapy clearly outweighs the risks.)

Aminoglycosides are excreted in milk. While potentially, amikacin ingested with milk could alter GI flora and cause diarrhea, amikacin in milk is unlikely to be of significant concern after the first few days of life (colostrum period).

Overdosage / Acute Toxicity

Should an inadvertent overdosage be administered, three treatments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug but is not a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/day in humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by this effect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also be minimized using this procedure.

How to use Amikacin Sulfate

Note: Most infectious disease clinicians now agree that aminoglycosides should be dosed once a day in most patients (mammals). This dosing regimen yields higher peak levels with resultant greater bacterial kill, and as aminoglycosides exhibit a “post-antibiotic effect”, surviving susceptible bacteria generally do not replicate as rapidly even when antibiotic concentrations are below MIC. Periods where levels are low may also decrease the “adaptive resistance” (bacteria take up less drug in the presence of continuous exposure) that can occur. Once daily dosing may decrease the toxicity of aminoglycosides as lower urinary concentrations may mean less uptake into renal tubular cells. However, patients who are neutropenic (or otherwise immunosuppressed) may benefit from more frequent dosing (q8h). Patients with significantly diminished renal function who must receive aminoglycosides may need to be dosed at longer intervals than once daily. Clinical drug monitoring is strongly suggested for these patients.

Amikacin Sulfate dosage for dogs:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 15-30 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for cats:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 10-15 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for ferrets:

For susceptible infections:

a) 8-16 mg/kg IM or IV once daily ()

b) 8-16 mg/kg/day SC, IM, IV divided q8-24h ()

Amikacin Sulfate dosage for rabbits, rodents, and small mammals:

a) Rabbits: 8-16 mg/kg daily dose (may divide into q8h-q24h) SC, IM or IV Increased efficacy and decreased toxicity if given once daily. If given IV, dilute into 4 mL/kg of saline and give over 20 minutes. ()

b) Rabbits: 5-10 mg/kg SC, IM, IV divided q8-24h Guinea pigs: 10-15 mg/kg SC, IM, IV divided q8-24h Chinchillas: 10-15 mg/kg SC, IM, IV divided q8-24h Hamster, rats, mice: 10 mg/kg SC, IM q12h Prairie Dogs: 5 mg/kg SC, IM q12h ()

c) Chinchillas: 2-5 mg/kg SC, IM q8- 12h ()

Amikacin Sulfate dosage for cattle:

For susceptible infections:

a) 10 mg/kg IM q8h or 25 mg/kg q12h ()

b) 22 mg/kg/day IM divided three times daily ()

Amikacin Sulfate dosage for horses:

For susceptible infections:

a) 21 mg/kg IV or IM once daily (q24h) ()

b) In neonatal foals: 21 mg/kg IV once daily ()

c) In neonatal foals: Initial dose of 25 mg/kg IV once daily; strongly recommend to individualize dosage based upon therapeutic drug monitoring. ()

d) Adults: 10 mg/kg IM or IV once daily (q24h)

Foals (<30 days old): 20-25 mg/kg IV or IM once daily (q24h).

For uterine infusion:

a) 2 grams mixed with 200 mL sterile normal saline (0.9% sodium chloride for injection) and aseptically infused into uterus daily for 3 consecutive days (Package insert; Amiglyde-V — Fort Dodge)

b) 1-2 grams IU ()

For intra-articular injection as adjunctive treatment of septic arthritis in foals:

a) If a single joint is involved, inject 250 mg daily or 500 mg every other day; frequency is dependent upon how often joint lavage is performed. Use cautiously in multiple joints as toxicity may result (particularly if systemic therapy is also given). ()

For regional intravenous limb perfusion (RILP) administration in standing horses:

a) Usual dosages range from 500 mg-2 grams; dosage must be greater than 250 mg when a cephalic vein is used for perfusion and careful placement of tourniquets must be performed. ()

Amikacin Sulfate dosage for birds:

For susceptible infections:

a) For sunken eyes/sinusitis in macaws caused by susceptible bacteria: 40 mg/kg IM once or twice daily. Must also flush sinuses with saline mixed with appropriate antibiotic (10-30 mL per nostril). May require 2 weeks of treatment. ()

b) 15 mg/kg IM or SC q12h ()

c) For gram-negative infections resistant to gentamicin: Dilute commercial solution and administer 15-20 mg/kg (0.015 mg/g) IM once a day or twice a day ()

d) Ratites: 7.6-11 mg/kg IM twice daily; air cell: 10-25 mg/egg; egg dip: 2000 mg/gallon of distilled water pH of 6 ()

Amikacin Sulfate dosage for reptiles:

For susceptible infections:

a) For snakes: 5 mg/kg IM (forebody) loading dose, then 2.5 mg/kg q72h for 7-9 treatments. Commonly used in respiratory infections. Use a lower dose for Python curtus. ()

b) Study done in gopher snakes: 5 mg/kg IM loading dose, then 2.5 mg/kg q72h. House snakes at high end of their preferred optimum ambient temperature. ()

c) For bacterial shell diseases in turtles: 10 mg/kg daily in water turtles, every other day in land turtles and tortoises for 7-10 days. Used commonly with a beta-lactam antibiotic. Recommended to begin therapy with 20 mL/kg fluid injection. Maintain hydration and monitor uric acid levels when possible. ()

d) For Crocodilians: 2.25 mg/kg IM q 72-96h ()

e) For gram-negative respiratory disease: 3.5 mg/kg IM, SC or via lung catheter every 3-10 days for 30 days. ()

Amikacin Sulfate dosage for fish:

For susceptible infections:

a) 5 mg/kg IM loading dose, then 2.5 mg/kg every 72 hours for 5 treatments. ()

Monitoring

■ Efficacy (cultures, clinical signs, WBC’s and clinical signs associated with infection). Therapeutic drug monitoring is highly recommended when using this drug systemically. Attempt to draw samples at 1,2, and 4 hours post dose. Peak level should be at least 40 mcg/mL and the 4-hour sample less than 10 mcg/mL.

■ Adverse effect monitoring is essential. Pre-therapy renal function tests and urinalysis (repeated during therapy) are recommended. Casts in the urine are often the initial sign of impending nephrotoxicity.

■ Gross monitoring of vestibular or auditory toxicity is recommended.

Client Information

■ With appropriate training, owners may give subcutaneous injections at home, but routine monitoring of therapy for efficacy and toxicity must still be done

■ Clients should also understand that the potential exists for severe toxicity (nephrotoxicity, ototoxicity) developing from this medication

■ Use in food producing animals is controversial as drug residues may persist for long periods

Chemistry / Synonyms

A semi-synthetic aminoglycoside derived from kanamycin, amikacin occurs as a white, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during the manufacturing process. 1.3 grams of amikacin sulfate is equivalent to 1 gram of amikacin. Amikacin may also be expressed in terms of units. 50,600 Units are equal to 50.9 mg of base. The commercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5-5.5 with sulfuric acid.

Amikacin sulfate may also be known as: amikacin sulphate, amikacini sulfas, or BB-K8; many trade names are available.

Storage / Stability/Compatibility

Amikacin sulfate for injection should be stored at room temperature (15 – 30°C); freezing or temperatures above 40°C should be avoided. Solutions may become very pale yellow with time but this does not indicate a loss of potency.

Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially available solutions at 15 pounds of pressure at 120°C for 60 minutes did not result in any loss of potency.

Note: When given intravenously, amikacin should be diluted into suitable IV diluent etc. normal saline, D5W or LRS) and administered over at least 30 minutes.

Amikacin sulfate is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniramine maleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodium phosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with or without sodium bicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCL, secobarbital sodium, sodium bicarbonate, succinylcholine chloride, vancomycin HCL and verapamil HCL.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasone sodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoin sodium, oxacillin sodium, oxytetracycline HCL, penicillin G potassium, phenytoin sodium, potassium chloride (in dextran 6% in sodium chloride 0.9%; stable with potassium chloride in “standard” solutions), tetracycline HCL, thiopental sodium, vitamin B-complex with C and warfarin sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

In vitro inactivation of aminoglycoside antibiotics by beta-lac-tam antibiotics is well documented. While amikacin is less susceptible to this effect, it is usually recommended to avoid mixing these compounds together in the same syringe or IV bag unless administration occurs promptly. See also the information in the Amikacin Sulfate Interaction and Amikacin Sulfate/Lab Interaction sections.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Amikacin Sulfate Injection: 50 mg (of amikacin base) per mL in 50 mL vials; Amiglyde-V (Fort Dodge), AmijectD (Butler), Amikacin K-9 (RXV), Amikacin C (Phoenix), Amtech Amimax C (IVX), Caniglide (Vedco); generic (VetTek); (Rx); Approved for use in dogs.

Amikacin Sulfate Intrauterine Solution: 250 mg (of amikacin base) per mL in 48 mL vials; Amifuse E (Butler), Amiglyde-V (Fort Dodge), Amikacin E (Phoenix), Amikacin E (RXV), Amtech Amimax E (IVX), Equi-phar Equiglide (Vedco); (Rx); Approved for use in horses not intended for food.

WARNING: Amikacin is not approved for use in cattle or other food-producing animals in the USA. Amikacin Sulfate residues may persist for long periods, particularly in renal tissue. For guidance with determining use and withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix for contact information).

Human-Labeled Products:

Amikacin Injection: 50 mg/mL and 250 mg/mL in 2 mL and 4 mL vials and 2 mL syringes; Amikin (Apothecon); generic; (Rx)

Categories
Horses

Interstitial Pneumonia

Interstitial pneumonia is an uncommon cause of acute or chronic disorders of the lower respiratory tract of horses. However, because of the severity of the process, recognition and definitive diagnosis of this entity are important as early as possible in its clinical course.

The term interstitial pneumonia defines a number of diseases that are chronic and progress to pulmonary fibrosis. The course is insidious and morphologically characterized by alveolar structural derangements that lead to loss of functional gas exchange units of the lung and altered mechanical properties of the lung, characterizing the pneumonia as a restrictive lung problem.

Etiology of Interstitial Pneumonia

Pathophysiology of Interstitial Pneumonia

Interstitial pneumonia progresses through four phases. During the first, the initial insult causes parenchymal injury and alveolitis. This is followed by a proliferative phase characterized by cellular and parenchymal alterations in tissues of the lung. Chronic cases progress to the development of interstitial fibrosis, whereas the final stage results in end-stage irreparable fibrosis of the lung.

The structural changes that occur in the lung reduce the number of functional alveoli, adversely affecting ventilatory function of the lung and altering ventilation/per-fusion relationships. Reduced lung compliance is associated with the loss of distensible alveoli and presence of pulmonary edema and fibrosis. Total and vital lung capacities are decreased in association with the loss of functional gas exchange units and reduced lung compliance. The work of breathing is increased, resulting in exercise intolerance and difficulty in breathing. Pulmonary hypertension and cor pulmonale may present as complications of interstitial pneumonia and fibrosis. Although the origin of pulmonary hypertension is unclear, hypoxic vasoconstriction and generation of vasoactive compounds (such as endothelin-1) that alter pulmonary vascular resistance acutely, and vessel anatomy chronically, may play a role.

Interstitial Pneumonia: Clinical Signs

Horses affected with interstitial pneumonia frequently present with fever, cough, weight loss, nasal discharge, exercise intolerance, severe dyspnea, cyanosis, and a restrictive breathing pattern. A “heave line” is frequently present; nostril flare and an anxious expression are usual. The history can be acute or chronic. Although affected foals are frequently depressed and anorectic, adults may be bright and alert with a variable appetite. The disease proceeds toward death in many cases, with progressive respiratory compromise, although some also may improve slowly with time. More than one foal at a farm may be affected.

Diagnosis of Interstitial Pneumonia

In older horses, the primary differential diagnosis of heaves may be excluded by the leukocytosis and hyperfibrinogenemia that commonly occur in horses with interstitial pneumonia and fibrosis but do not occur in horses with heaves. However, these abnormal features are common in horses with infectious bronchopneumonia and thoracic radiography is paramount in the establishment of a definitive diagnosis. Typically, thoracic radiographs reveal extensive interstitial and bronchointerstitial pulmonary patterns (). Nodular infiltrates may be present, either large or miliary, but always diffusely distributed.

Culture of transtracheal or bronchoalveolar lavage (bronchoalveolar lavage) aspirates often yields no significant growth of bacterial or fungal pathogens. This is particularly useful in foals and, in combination with negative results of a Gram-stained tracheal aspirate, reinforces the clinical diagnosis of interstitial pneumonia. Cytologic evaluation of tracheal or bronchoalveolar lavage fluid shows increased numbers of neutrophils and macrophages. If P. carinii is involved, bronchoalveolar lavage fluid may reveal trophozoites or intracystic bodies with special stains, such as toluidine blue or methenamine silver.

Histologic examination of a transthoracic lung biopsy specimen is the definitive diagnostic test for chronic interstitial pneumonia and fibrosis (). Care must be taken to ensure the biopsy is obtained from a representative area and ultrasound guidance has been useful in the hands of the author. Complications from this technique are uncommon but can occur. Biopsy rarely defines the causative agent but confirms the clinical diagnosis.

Additional diagnostics could include arterial blood gas analysis, abdominocentesis, and thoracocentesis to rule out metastatic neoplastic disease, pulmonary function testing, viral isolation, serologic testing for antibody to fungi and chicken serum if hypersensitivity pneumonitis is suspected, and immunohistochemical evaluation of lung tissue for suspected infectious agents. A complete cardiac evaluation also should be conducted to screen for pulmonary hypertension and cor pulmonale.

Treatment of Interstitial Pneumonia

Treatment of these cases is often unrewarding. Therapeutic goals are treatment of any underlying or secondary infection; suppression of inflammation; maintenance of tissue oxygen delivery within appropriate limits; relief of any associated bronchoconstriction; and prevention or treatment of complications. Environmental control, with appropriate temperature and humidity control and good ventilation, is beneficial.

Parenteral corticosteroid therapy is the mainstay of treatment, with early and aggressive therapy providing the best long-term outcome, particularly in foals. In one report of 23 foals affected with acute bronchointerstitial pneumonia, 9 of 10 treated with corticosteroids survived, whereas none of those not receiving steroid treatment lived. Dexamethasone (0.1 mg/kg q24h) is suggested initially. Inhaled beclomethasone (8 μg/kg q12h) may be considered. Additional antiinflammatory therapy includes, but is not limited to, dimethyl sulfoxide (DMSO; 1 g/kg as a 10% solution IV q24h), flunixin meglumine (Banamine; 1 mg/kg IV q12h) and methyl sulfonyl methane (15-20 mg/kg PO q24h).

Broad-spectrum antimicrobial treatment should be instituted initially, particularly in foals, as described for the treatment of infectious bronchopneumonia (see “Pleuropneumonia”). The choice of antimicrobial and duration of therapy should be dictated finally by the culture and sensitivity results from the transtracheal aspirate and by the patient’s clinical course.

Foals, in particular, and adults with severe respiratory distress may benefit from nasal insufflation of humidified oxygen, with flow rates of 10 L/min for foals and 15 L/min in adults. If necessary, as determined by persistent hypoxemia in the face of intranasal insufflation at the rates given, a second nasal canula can be placed in the opposite nostril to increase the Fio2. Care must be taken to avoid obstruction of the nasal passages. Alternatively, intratracheal or transtracheal insufflation can be considered to further increase Fio2 and improve oxygenation.

Systemic bronchodilator therapy may or may not be indicated in these cases. If utilized, bronchodilators may worsen ventilation-perfusion inequalities. Thus bronchodilator therapy should be accompanied by supplemental oxygen and the effects should be monitored with serial blood gas measurements and discontinued if hypoxemia worsens. Nebulized or aerosolized bronchodilator therapy may be more judicious, and beneficial effects are evident in some foals with respiratory distress. Examples include albuterol (180-360 μg) or ipratropium bromide (40-80 p.g) or two to four puffs of either, or in combination. Aminophylline and theophylline should not be used because of their narrow therapeutic range. Furosemide (0.5 mg/kg q12h) may be appropriate for its bronchodilator effect and its effect on reducing pulmonary artery pressure, particularly if cor pulmonale develops. It is particularly useful in the management of pulmonary edema. Potential useful therapies in the future may include compounds such as endothelin-1 (ETA) receptor antagonists and inhibitors of fibrosis, such as colchicine.

Prognosis of Interstitial Pneumonia

The prognosis of interstitial pneumonia in horses is uniformly poor to guarded. Affected foals, treated early and aggressively with corticosteroid and antimicrobial therapy, have the best outlook for life. The disease is usually progressive in adults and eventually results in the demise of the horse, although the occasional horse recovers sufficiently to return to previous performance levels. A fair number of adult horses, with continuous intense management, live for a period of time but will be severely compromised, limiting their usefulness.

Exceptions to the poor prognosis may be seen in cases of P. carinii pneumonia in foals if they are treated early and aggressively and in cases of idiopathic interstitial pneumonia in adult horses that are treated early with corticosteroids. A trial of treatment for peracute interstitial disease for 48 hours is warranted and chronic interstitial pneumonia should be treated for a minimum of 2 to 4 weeks before discarding the possibility of recovery.

Categories
Horses

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*
Corticosteroids
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)
Bronchodilators
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)
Cromones
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.