Equine Respiratory Pharmacology

CLINICAL PHARMACOLOGY AND THERAPEUTICS

0749-0739/99 $8.00 + .00

EQUINE RESPIRATORY PHARMACOLOGY Jonathan H. Foreman, DVM, MS

Diseases of the equine respiratory tract are frequently divided into upper and lower tract conditions. Differentiation is based on history, clinical signs, endoscopy (primarily of the upper tract), and lower tract assessments, including auscultation, imaging (radiography, ultrasonography, scintigraphy), and airway sampling (transtracheal wash, bronchoalveolar lavage).5 Treatment of the various conditions of the respiratory tract is necessarily governed by the specific diagnosis. UPPER RESPIRATORY TRACT

Significant viral upper respiratory tract (URT) infectious diseases include equine influenza, rhinopneumonitis, and viral arteritis. Coughing, nasal discharge, or fever can be a significant component in any of these diseases, but their clinical course is usually self-limiting without adjunctive therapy. Other URT conditions in horses include pharyngitis, laryngitis, tracheitis, sinusitis, dorsal displacement of the soft palate, aryepiglottic entrapment, arytenoid chondritis or chondroma, guttural pouch empyema or mycosis, and submandibular and retropharyngeal lymphadenopathies caused by strangles. These conditions can be properly diagnosed by history, physical examination, endoscopy, imaging (radiography, ultrasonography), and culture and sensitivity testing if exudate can be sampled. Therapy is specific to the condition and entails correction of the upper airway obstruction through surgery; enforced rest; flushing of localized abscesses, guttural pouch disease, or sinusitis; and possibility oral or parenteral antibiotic and anti-inflammatory therapy. Strangles

Strangles is a condition unique to equids. Streptococcus equi subspecies equi (previously called simply Streptococcus equi) causes focal lymphadenopathy and From the Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois

VETERINARY CLINICS OF NORTH AMERICA: EQUINE PRACTICE VOLUME 15 • NUMBER 3 • DECEMBER 1999

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abscessation in the submandibular and retropharyngeal lymph nodes. Rarely, there is a metastasis of infection to other body systems, resulting in guttural pouch empyema, deep internal abscesses, purpura hemorrhagica, or glomerulonephritis. The type of treatment is usually linked to the stage and severity of the disease. Early in an infection when only fever and depression are present in the face of a history of s. equi exposure, immediate antibiotic therapy may be curative and may prevent focal abscessation (stage 1). Penicillin (either procaine penicillin G [22,000 IU / kg administered intramuscularly (1M) or subcutaneously (SC) every 12 hours], aqueous penicillin salts [sodium or potassium penicillin, 22,000 IV / kg intravenously (IV), 1M, or SC every 6 hours]) or ceftiofur sodium (2.2 mg / kg 1M every 12-24 hours) may be given to prevent strangles abscesses in acutely febrile horses in barns undergoing an outbreak. Once an external lymphadenopathy is detected in an otherwise alert and healthy horse, antibiotic therapy is probably contraindicated in that it only prolongs the inevitable enlargement and eventual rupture of the lymph node abscess (stage 2). Even in the face of detectable lymphadenopathy, if the horse is febrile, depressed, anorexic, and especially manifesting dyspnea as a result of partial upper airway obstruction, antibiotic therapy (same drugs and doses as above) is indicated to decrease abscess size and prevent complete airway obstruction (stage 4). Tracheostomy may also be indicated in the face of audible dyspnea. Some clinicians believe strongly that antibiotic therapy after abscesses have ruptured may hasten recovery and cause the horse to eat better and therefore lose less body condition while recovering from strangles (stage 3). Surgical rupture of lymphadenopathies is sometimes indicated should they not rupture spontaneously; however, it is critical to intervene surgically only once the abscess has matured and thinned out ventrally. Earlier surgical intervention may only result in minimal exudate drainage and continued lymph node swelling, because the abscess still has enough internal structure (honeycombed loculations) to prohibit complete drainage through a single surgical incision. Topical treatments such as icthamol or a hot pack may be applied to encourage the abscess "to come to a head" faster, although objective controlled data supporting the use of these techniques are lacking. Guttural Pouch Empyema

Guttural pouch empyema is seen occasionally following upper airway infections. Organisms commonly cultured are not difficult to kill with antibiotics (Table 1), but local flushing may be required to completely quell the infection as it is within a closed compartment not unlike a localized abscess. Chronic infection may result in or be the result of the presence of chondroids or coalesced concretions of exudate with a rubbery consistency. When presented with chondroids, surgical drainage of the guttural pouch may be necessary either through the classic Viborg's triangle approach or through the more recent ventral Whitehouse approach. Solutions of acetylcysteine (20°fc,) have been used for instillation into the guttural pouch to aid in breaking up chondroids chemically and to avoid the need for surgical removal. 7 Guttural Pouch Mycosis

Guttural pouch mycosis usually presents with unilateral epistaxis in a sometimes dramatic fashion. Once hemorrhage subsides either spontaneously or

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Table 1. EQUINE RESPIRATORY BACTERIAL PATHOGENS AND COMMONLY USED ANTIBIOTICS FOR EACH PATHOGEN Pathogen

Gram-positive aerobes Streptococcus equi subsp. 200epidemiclls

Streptococcus equi subsp. equi

Rhodococcus equi Gram-negative aerobes Pasteurella spp.

Actinobacillus equuli

Escherichia coli

Bordetella bronchiseptica Salmonella spp.

Klebsiella pneumoniae Pseudomonas aeruginosa Anaerobes Bacteroides fragilis Other anaerobes

Antibiotics

Penicillin Ampicillin Ceftiofur Trimethoprim-sulfonamide Penicillin Ampicillin Ceftiofur Trimethoprim-sulfonamide Erythromycin Erythromycin plus rifampicin Gentamicin Ceftiofur Trimethoprim-sulfonamide Tetracycline Gentamicin Ceftiofur Trimethoprim-sulfonamide Tetracycline Gentamicin Amikacin (neonates) Ceftiofur (sometimes effective) Gentamicin Amikacin (neonates) Tetracycline Gentamicin Trimethoprim-sulfonamide Chloramphenicol Gentamicin Amikacin (neonates) Trimethoprim-sulfonamide Chloramphenicol Gentamicin Amikacin (neonates) Gentamicin Amikacin (neonates) Chloramphenicol Metronidazole Penicillin Ceftiofur Chloramphenicol Metronidazole

Original data and data from Baggot JD, Prescott JF: Antimicrobial selection and dosage in the treatment of equine bacterial infections. Equine Vet J 19:92-96, 1987; Beech J, Sweeney CR: Infections caused by bacteria, mycoplasmas, parasites, and fungi. In Equine Respiratory Disorders. Philadelphia, Lea & Febiger, 1991, pp 181-207; and Brumbaugh GW: Rational selection of antimicrobial drugs for treatment of infections in horses. Vet Clin North Am Equine Pract 3:191-220, 1987.

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via surgical intervention, endoscopy reveals the presence of one or more fungal plaques in the dorsomedial region of the ipsilateral guttural pouch. The hemorrhage originates from fungal erosion into the internal carotid artery in the wall of the guttural pouch. Correction should be surgical via either placement of a balloon catheter or ligation of the ipsilateral internal carotid artery midcervically.40, 42, 43 Interestingly, removing the blood supply to the region by carotid ligation is usually curative of the fungal lesion, which slowly recedes. 40, 102 Local lavage has been performed with miconazole (10 mg/kg daily in 250 mL of normal saline,21 thiabendazole (20 mg/kg daily)14, 21 mixed with dimethyl sulfate (50 mg/kg) in 225 mL of saline,21 enilconazole (60 mL of a 33.3-mg/mL solution sprayed onto the lesion via endoscopic guidance),21 nystatin,14 and natamycin. 49 Systemic therapy has also been used with itraconazole (5 mg / kg orally [PO] every 24 hours for 2 weeks),21 thiabendazole,14 and iodides. 71 Sinusitis

Most sinusitis problems in older horses are attributable to tooth root abscesses. 41 Repulsion of the offending tooth out of the sinus is curative of the sinusitis. Primary sinusitis does occur in younger horses subsequent to upper airway infections. Diagnosis is by documentation of a unilateral nasal discharge (history, physical examination), auscultation, percussion, endoscopy, and trephination using a Steinmann pin through a local block. Samples for culture and sensitivity may be obtained via this focal sinusotomy. Local flushing and antibiotic instillation may also be performed through the sinus trephination hole. Most of these infections are simple Streptococcus spp. infections sensitive to parenteral penicillin or ceftiofur therapy. LOWER RESPIRATORY TRACT Pneumonia and Pleuropneumonia

Although the equine respiratory viruses (equine influenza, rhinopneumonitis, and viral arteritis) result in primarily URT signs, it must be emphasized that they also infect the lower respiratory tract (LRT) epithelium, resulting in paralysis and sloughing of ciliated epithelium, decreased mucociliary clearance, and compromised LRT defense mechanisms. Pneumonia and pleuropneumonia often follow, particularly in the face of additional stressors such as transport and exercise. 2 The hallmarks of treating equine pneumonia are antimicrobials, antiinflammatories, and rest. Pleural drainage is the fourth major therapeutic measure combined with the others for the treatment of pleuropneumonia. Both pneumonia and pleuropneumonia are also often treated with bronchodilators (see section on chronic obstructive pulmonary disease [COPD] and inflammatory airway disease [lAD]). Antibiotics

The most common bacterial pathogen cultured from the equine LRT is S.

equi subspecies zooepidemicus (previously called simply Streptococcus zooepidemiCUs).6, 35, 37, 38, 64, 107 Fortunately, S. zooepidemicus is rarely difficult to kill and is usually sensitive to penicillins and cephalosporins. Penicillin is administered to horses as either procaine penicillin G (22,000 IU / kg 1M or SC every 12 hours)

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or aqueous penicillin salts (sodium or potassium penicillin, 22,000 IU / kg 1\1, 1M, or SC every 6 hours).33, 104 The procaine salt causes a positive drug test in race horses or show horses if administered too close to a competition. Potassium salts should be used intravenously with caution because they may have cardiodepressant effects. Ampicillin sodium has also been used with good efficacy against S. 200epidemicus at 6.6 mg / kg intramuscularly every 12 hours, but higher doses (11 mg/kg every 8 hours) may be needed for other common respiratory pathogens (see Table 1).11,35 One third-generation cephalosporin, ceftiofur sodium, was recently approved by the US Food and Drug Administration (FDA) for use in treating respiratory S. 200epidemicus in horses (New Animal Drug Application [NADAl 140-338; The Upjohn Company, Kalamazoo, MI).35-37, 39, 55 In separate studies against both negative (saline) (NADA 140-338) and positive (ampicillin) (NADA 140-338)35-37 controls, ceftiofur (2.2 mg/kg 1M every 24 hours) showed excellent efficacy in treating spontaneous clinical and posttransport pneumonia associated with S. 200epidemicus and other common respiratory pathogens such as other streptococci, Actinobacillus equuli, and Pasteurella spp. One advantage of ceftiofur is that it can be given once daily intramuscularly and is still efficacious against the most common respiratory pathogens at trough concentrations 24 hours later (NADA 140_338).15,35-37,39 Use of higher dosages than those recommended on the label (2.2-4.4 mg / kg 1M every 24 hours) should be discouraged, as they are cost-prohibitive and have been rarely but occasionally associated with diarrhea. 36 The only reason to use higher doses is to treat more difficult-to-kill organisms such as Pseudomonas spp., Proteus spp., and Klebsiella spp., but successful treatment of these pathogens can be achieved with aminoglycosides with less cost, better efficacy, and minimal gastrointestinal upset. 36 Another disadvantage of ceftiofur is that once it is reconstituted, it is stable for only 12 hours at room temperature; however, it can be refrigerated for up to 7 days without losing potency.37 Unused reconstituted drug can be frozen and stored for up to 8 weeks without sacrificing potency on thawing once but not twice. Ceftiofur hydrochloride has been marketed for use intramuscularly in swine but is too irritating for use in horses. Trimethoprim-sulfonamide (TMS) combinations (15-30 mg/kg PO every 12 hours) are commonly used in the treatment of equine respiratory tract infections,119 particularly because they can easily be given orally by clients. They are more readily absorbed from a fairly empty upper gastrointestinal tract; thus, it is best to administer drug approximately 30 minutes prior to feeding hay (although grain appears to have minimal effect). The synergistic combination of both a sulfonamide (inhibiting dihydropteroate's conversion of para-aminobenzoic acid to dihydrofolate) and trimethoprim (inhibiting dihydrofolate reductase's conversion of dihydrofolate to tetrahydrofolate) renders the combination bactericidal, whereas either drug alone is considered to be bacteriostatic. 119 This combination has been associated with mild diarrhea, which is usually responsive simply to discontinuation of the drug. 114 Recently, however, prior administration of potentiated sulfonamides was implicated as a significant risk factor for increased mortality (4.5 times higher) in equine diarrhea. 16 Another disadvantage is that approximately 300/0 of S. 200epidemicus cultured from horses are resistant to this combination; thus, any horse initially treated for pneumonia and unresponsive to this combination should be considered as possibly TMS resistant, and antibiotic therapy should be altered accordingly. Rhodococcus equi causes severe abscessing pneumonia in suckling and wean·· ling foals. The organism is airborne and thus is worse in environments with dry climates (e.g., California, Texas) and higher horse densities (overcrowded farms).

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The intracellular organism is sensitive to many antibiotics in vitro but often is not killed in vivo by those same drugs (e.g., gentamicin), presumably because of the tough thickened capsule preventing movement into the abscess of most molecules with any polarity (gentamicin, penicillin). The macrolide antibiotic erythromycin (25 mg/kg PO every 12 hours) is normally not used routinely in horses because of its tendency to cause diarrhea via its prokinetic mechanisms, but its use has become widespread in recent years in foals with R. equi pneumonia.82, 109 Erythromycin penetrates well intracellularly and demonstrates good in vitro and in vivo efficacy against the organism. It is often used in combination with the antileprosy drug rifampin (3-5 mg/kg PO every 12 hours)/52 but in this author's experience, erythromycin alone is still quite effective in situations where the addition of rifampin becomes cost-prohibitive for the client. Rifampin should never be used alone, as microbial resistance to it can develop rapidly and with no apparent warning. Treatment with erythromycin should be continued for 4 to 6 weeks or until it is seen radiographically that the patient's lungs are clear of abscesses and the clinical appearance is of a relatively normal foal. The administration of plasma with anti-Rhodococcus spp. antibodies has been advocated both as a preventative measure and a therapy even in the face of clinical disease. 66,68 Most gram-negative aerobes in horses are sensitive in vitro and in vivo to one or more of the aminoglycosides. Gentamicin (6.6 mg/kg IV or 1M every 24 hours) is the most commonly used of these drugs, at least in adult horses. Kanamycin (7.5 mg/kg IV or 1M every 8 hours) was used frequently in horses approximately 10 to 15 years ago, but its use in the treatment of respiratory infections has been minimized recently by lower prices for gentamicin. Recent work has shown that the killing power of gentamicin remains the same (possibly a result in part of a postantibiotic effect) and that its toxicity is minimized (as a result of minimizing chronic but detectable toxic plasma concentrations) by oncedaily use rather than the more conventional thrice-daily dosage. 67 Obviously, the once-daily dosage is also more convenient for the practitioner. Amikacin (21 mg / kg IV or 1M every 24 hours) is synthesized from kanamycin and is often used for gram-negative respiratory infections in foals as it is more nephrosparing than gentamicin, and, luckily, it is also much more affordable in the smaller horse.20, 79 As a result of anecdotal reports of a possible association with antibioticinduced diarrhea,17 tetracycline use in horses has diminished over the last 25 to 30 years. With the demonstrated efficacy of oxytetracline (6.6 mg / kg IV every 12-24 hours) in the treatment of Potomac Horse Fever, its use has resurged but with no significant additional reports of increased diarrhea associated with its administration. To avoid the lingering soreness associated with the intramuscular administration of procaine penicillin G (as well as to avoid a procainepositive drug test), many racetrack practitioners still use oxytetracycline intravenously/ reportedly with little or no diarrheagenic effect. Doxycycline has also been used successfully when given orally in horses at a dose of 10 mg / kg every 12 hours, but intravenous use has been associated with fatal diarrhea. 85 Because anaerobes are cultured more frequently from the respiratory tract than from other sources in horses, therapy must sometimes be aimed toward elimination of an anaerobe as well as aerobic bacteria. Most respiratory anaerobes are susceptible to standard antiaerobe doses of the penicillins, cephalosporins, and chioramphenicol. 106 One of the most common anaerobes cultured from the respiratory tract, Bacteroides fragilis, is routinely resistant to both penicillins and cephalosporins, however. 106 For this reason, many clinicians now routinely include metronidazole (15 mg / kg PO every 6-8 hours) as part of the initial

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antimicrobial regimen for treating any moderately to severely affected horse with pneumonia or pleuropneumonia. 108 Once anaerobic respiratory tract cultures have yielded no anaerobic growth (or no growth specifically of B. fragilis), metronidazole can often be discontinued. Side effects of metronidazole include central nervous system signs such as acute onset depression, head tilt, or circling; in that event, treatment should be discontinued or the dosage should be decreased (or one daily dose should be dropped) to decrease plasma concentrations below toxic levels. Metronidazole cannot be used in food animals. Chloramphenicol (55 mg/kg PO every 6 hours) is frequently used for mixed or resistant infections in horses because it is effective against gram-positive and gram-negative aerobes as well as anaerobes, including penicillin-resistant B. fragilis. 3, 12 Intravenous chloramphenicol is not used in horses because of its short half-life, which precludes achievement of effective plasma concentrations. 22, 99 Human exposure must be minimized (by the use of gloves and masks to prevent cutaneous and aerosol exposure, respectively) as it has been associated rarely with two different types of aplastic anemia resulting in death. Ideally, mixing of oral chloramphenicol should be performed under a vacuum hood, but this technique is rarely practical in a clinical setting. Fortunately, chloramphenicol tablets dissolve readily in water without resorting to grinding them into a powder; thus, greater safety can be achieved by adding water to each dose of tablets in individual disposable cups and then simply allowing the tablets to dissolve to form a chloramphenicol solution or paste with minimal aerosolization from grinding. Chloramphenicol injections given intramuscularly are associated with moderate to severe pain and are rarely used in horses. Chloramphenicol cannot be used in food animals. The use of fluoroquinolones in horses has not been approved. Reports on the pharmacokinetics of enrofloxacin (2.5-5 mg/kg PO or IV every 12 hours) have shown drug concentrations higher than serum in synovial fluid, urine, and endometrium and lower in peritoneal and cerebrospinal fluids. 44, 45, 61 Anecdotal reports on the use of enrofloxacin have cited good efficacy, but there are concerns over possible arthropathies associated with cartilage damage and synovitis. A recent preliminary report on the chronic use of injectable enrofloxacin in normal adult horses included infrequent and transient but still detectable joint effects. 8 Nonetheless, the use of fluoroquinolones in young growing horses «4 years old) should be discouraged because of possible cartilage damage. Anthelmenthics

The equine lungworm Dictyocaulus arnfieldi is carried asymptomatically by donkeys and mules. Preliminary diagnosis is based on history, presence of a chronic nonproductive cough, and finding increased eosinophils in peripheral blood smears and tracheal or bronchial aspirates. Definitive diagnosis is by identification of the larvae in tracheal aspirate or bronchoalveolar fluid, or by Baerman examination of feces. Ivermectin (200 f-1g/kg PO) is curative and preventative. 65 Prevention is further achieved by not pasturing donkeys and mules with horses. Pascaris equorum lung infections should be suspected in unthrifty foals with nonproductive chronic coughs that are unresponsive to antibiotics. Definitive diagnosis is by demonstration of ascarid ova in the patient's feces. Therapy with ivermectin (200 f-1g / kg PO once) or benzimidazoles (thiabendazole, 88 mg / kg PO; fenbendazole, 10 mg/kg PO) is curative, although the cough may persist for some time while the inflammatory changes recede. Prevention is by anthelminthic administration to all other horses to whose feces foals may be exposed,

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pasture management, and deworming of mares in the last month before they foal. Antifungals

Primary fungal pneumonia is rare in horses and is associated with high fatality in spite of therapy. In addition to respiratory signs, horses often have chronic weight loss, septicemia, enterocolitis, and peritonitis. 51 , 59, 81, 90, 100, 105, 120 Secondary Aspergillus spp. infections occur rarely during and after chronic antibiotic administration to treat a primary underlying bacterial pneumonia. Even secondary Aspergillus spp. pneumonia is overdiagnosed when clinicians observe Aspergillus spp. hyphae in tracheal aspirate fluid, an interesting but otherwise unimportant finding,S, 105, 107 because Aspergillus spp. frequently can be found in hay and bedding. 117 A definitive diagnosis is made by characteristic starburst or miliary radiographic patterns in lung radiographs; high plasma titers to rare organisms such as Coccidioides immitis, Cryptococcus neoformans, or Histoplasma capsulatum; and a positive culture from lung biopsy, blood, or other tissue or exudate. Increased plasma titers to Aspergillus spp. are common and do not indicate active fungal disease. 6, 105 Treatment of fungal pneumonia involves the use of systemic antifungals that are typically quite toxic. 90 Aspergillus spp. pneumonia has been treated successfully in horses using a graduated dosage regimen of intravenous amphotericin B as follows: day I, 0.3 mg/kg; day 2, 0.4 mg/kg; day 3, 0.5 mg/kg; day 4, no treatment; and day 5 and continued every other day for 1 month total, 0.5 mg/kg. 90 Renal function frequently is compromised, and renal disease may require that treatment be discontinued for periods of up to 5 consecutive days. Pneumonia associated with histoplasmosis has been treated successfully in one horse using a reported graduated dosage regimen of intravenous amphotericin B as follows: day I, 0.3 mg/kg; day 2, 0.45 mg/kg; day 3, 0.6 mg/kg; days 4 through 7, no treatment; and then continued every other day until a total cumulative dose of 6.75 mg/kg has been administered. 19 Administration of amphotericin B via a catheter in a dilute form (in 1 L of isotonic dextrose) is thought to minimize potential renal effects. A recent anecdotal report on the use of itraconazole (3 mg / kg PO every 24 hours) cited promising results in a miniature horse, although the drug remains prohibitively expensive for most full-sized adult equine patients (]. Cannon, DVM, personal communication, 1999). Some of the systemic fungal pneumonias in horses (e.g., histoplasmosis) are zoonotic and therefore must be considered to be communicable to the attending veterinarian, staff, and client; this reason alone may be sufficient ethical justification to refuse to treat primary fungal pneumonia in horses. Antiprotozoals

Pneumocystis carinii is cultured sometimes from immunocompromised patients such as those Arabian foals suffering from severe combined immunodeficiency. It has also been cultured in association with either R. equi or Bordetella bronchiseptica. 98 TMS at standard dosages (15-30 mg/kg PO every 12 hours) is effective against P. carinii, but one must remember to treat for the bacteria cultured from the same pulmonary sample. Anti-Inflammatories

Inflammation constitutes a significant portion of the disease process in both infectious and allergic respiratory conditions in horses. Toxins released from pulmonary and pleural infections, particularly those involving gram-negative

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bacteria (releasing endotoxins), may result in laminitis. Relieving fever and pain encourages a better appetite and allows increased productive coughing in the face of painful pleural conditions. Better dietary intake minimizes colic, antibiotic-induced diarrhea, and weight loss during infectious respiratory conditions. Pleural pain relief allows greater thoracic expansion, resulting in greater tidal volume, decreased atelectasis, and increased movement of air through the lungs. Nonsteroidal Anti-Inflammatory Drugs. Standard dosages of nonsteroidal anti-inflammatory drugs (NSAIDs) may be given to decrease fever and relieve pain (e.g., pleurodynia, dysphagia from strangles, laminitis). The most commonly used NSAIDs in respiratory conditions are flunixin meglumine (1.1 mg/ kg IV or PO every 12 hours), phenylbutazone (4.4 mg/kg IV or PO every 12 hours), and ketoprofen (2.2 mg/kg IV or 1M every 12 hours). Glucocorticosteroids. Corticosteroids are usually contraindicated in the face of LRT infections, as their immunosuppressive effects eventually result in exacerbation of the infection. A steroid-responsive syndrome of bronchointerstitial pneumonia and respiratory distress recently has been described in foals under 7 months of age, however. 6o These foals presented with apparently severe bronchopneumonia and respiratory distress based on history, clinical signs, and airway exudate sampling. Treatment with antibiotics, intranasal oxygen, and bronchodilators sometimes made the foals somewhat better, but they did not recover fully and often worsened in the face of this typical antipneumonia regimen. Radiographs demonstrated more of an interstitial pattern than a classic bronchial pattern. It was not until corticosteroids (dexamethasone or prednisolone sodium succinate) were added to the antibiotic therapy that these foals made considerable positive progress: of the 13 foals presented alive (of 23 total in the report), 10 were treated with corticosteroids, and 9 of these 10 survived. 60 There was also a clear association with increased environmental heat exacerbating these cases. Immunostimulants

The use of mycobacterial cell wall to stimulate immunologic reactions has long been known. A commercially available preparation of mycobacterial cell wall extract is licensed for intravenous treatment of acute LRT disease in horses (Equimune IV; Vetrepharm, London, Ontario, Canada).18 Another similar commercial product is derived from Propionibacterium acnes (previously Corynebacterium parvum) and is licensed for intramuscular treatment of viral respiratory disease in horses (EqStim; Immunovet, Tampa, FL).32,113 Both compounds are believed to be ingested by alveolar macrophages, which are then stimulated to increase cytokine production (tumor necrosis factor-a, interleukin [IL]-I, IL-6), resulting in T-cell activation and differentiation, lymphokine release, increased maturation of B- and T-cell precursors, and interferon (IFN) production and release. Both products are thought to assist the immune system in shedding viral infections and allowing horses to return to normal athletic function more quickly. In vitro and in vivo data support the efficacy of each product, but wellcontrolled double-blind clinical trials with large numbers of horses need to be performed to better document clinical efficacy. One recent report documented significant changes in normal weanlings after administration of P. acnes stimulant (EqStim IV) three times every other day.34 Significant peripheral blood changes included increased peripheral white blood cell count, increased total and relative CD4 + T-Iymphocyte counts, increased nonopsonized phagocytic activity, and enhanced lymphokine-activated killing cell activity. Significant changes in bronchoalveolar lavage fluid included decreased total cell, lymphocyte, and macrophage counts; decreased lymphocyte and increased macrophage

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proportions (relative counts); increased proportions of C04 +, COS +, and major histocompatibility complex II lymphocytes; and enhanced lymphokine-activated killing cell activity. There were no significant changes in peripheral blood IgG and IgM concentrations. Many equine practitioners administer these products as preventative measures before horses are transported long distances, because transport is so clearly a significant risk factor in the development of pleuropneumonia. 2 The development of fever is expected after each product is administered, because IL-1 is the primary endogenous pyrogen. This fever is cited by the manufacturers as evidence that an immune response has been stimulated, but this response clearly may mask the clinician's detection of fever associated with respiratory infection as well. In the same recent study on the efficacy of one of these products (EqStim), fever was observed 24 hours after the first two of the three administrations. 34 One report cited the rare development of granulomatous pulmonary histologic changes in five horses that previously received the intravenous product. 116 The proposed pathophysiology was that the intravenous route allowed the product to circulate directly to the pulmonary parenchyma and initiated a significant localized cell-mediated response, resulting in chronic multifocal pulmonary granulomas, bronchiolitis, and fibrosis detectable on percutaneous lung biopsy. Drainage

Proper surgical drainage of closed-compartment infections is indicated to rid the body of infectious exudate and to promote maximal lung expansion (in the case of pleural infections). Pleural effusions are usually drained using largebore (28-36 French) catheters placed temporarily or secured as indwelling drains. Standing thoracotomy is used rarely as a salvage procedure to promote chronic pleural drainage in horses with a unilateral pleural infection. Chronic Obstructive Pulmonary Disease and Inflammatory Airway Disease

Adverse pulmonary reactions to environmental stimuli include capo and IAO.63, 73 The most commonly employed therapies for early inflammatory and chronic allergic obstructive conditions include bronchodilators and anti-inflammatories.63, 73 Bronchodilators

Any LRT disease in which bronchoconstriction plays a significant role may respond favorably to bronchodilators. Such conditions include bronchopneumonia, pleuropneumonia, capo, lAD, and pulmonary edema. Families of bronchodilators used commonly in horses act either as parasympatholytics (anticholinergics), phosphodiesterase inhibitors (methylxanthines), or sympathomimetics ((32 agonists). Routes of administration have traditionally been oral; however, inhaled bronchodilator therapy has recently revolutionized the use of bronchodilators in horses. Anticholinergics. The anticholinergic agent atropine competitively inhibits acetylcholine at the motor end plate, resulting in blockade of muscarinic receptors (Fig. 1).86,87 It is not used commonly as a daily bronchodilator in horses but

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Methylxanthines Adenosine

+

Anticholinergics Acetylcholine

Antihistamines

+

Ca++-+"-----.. ~ ..-

~2

V

+

5;cAMP .~----------

1

®

Methylxanthines

~ Phosphodiesterase icAMP

agonists

1(

~

Adenyl cyclase

ATP

Figure 1. Mechanisms of bronchoconstriction (Le., bronchial smooth muscle contraction) and bronchodilation (Le., bronchial smooth muscle relaxation). H1 and M3 are histaminic and muscarinic receptors, respectively, in bronchial smooth muscle. Antihistamines and anticholinergics (e.g., atropine) competitively inhibit the H1 and M3 receptors, respectively, leading to bronchodilation. (32 agonists (e.g., clenbuterol and albuterol) stimulate (32 receptors, and methylxanthines (e.g., aminophylline) inhibit phosphodiesterase. Both result in increased intracellular cAMP and bronchodilation. Methylxanthines also affect intracellular Ca + + flux and competitively inhibit the interaction of adenosine with its smooth muscle receptor, resulting in smooth muscle relaxation and bronchodilation. Receptors (ovals).

has been used as a screening test to determine the potential efficacy of bronchodilator therapy in horses suffering from COPD. Administration of 5 mg of atropine intravenously to a typical 450-kg horse should result in significant improvement in respiratory function if reversible bronchoconstriction comprises an important component of the individual's disease process. Improvement is manifested by decreased tachypnea and dyspnea and by improved oxygenation of arterial blood gas samples when compared with pre-atropine arterial samples. Routine use of atropine as a therapeutic bronchodilator is prohibited by its other anticholinergic effects, especially ileus; colic is probably the most common side effect of atropine administration for assessing potential response to bronchodilator therapy. The anticholinergic glycopyrrolate (0.011 mg/kg 1M, IV or SC every 8 hours) has been used with some clinical success as a bronchodilator agent in a horse with COPD.46 More recently, the use of inhaled powdered ipratropium bromide has been described in horses. 27- 29,88 Although ipratropium functions as a bronchodilator in the same manner as do atropine and glycopyrrolate, administration via an inhaler minimizes the dose required for bronchodilation and thus minimizes the prohibitive gastrointestinal side effects often ascribed to intravenous atropine. Its quartenary structure minimizes absorption from the airway epithelium after

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inhalation therapy.23 Unlike other anticholinergics, ipratropium does not inhibit mucociliary clearance. 23 Administration via ultrasonic nebulizer (2-3 f-lg/kg) results in significant bronchodilation for 4 to 6 hours. 88 In a recent study, inhaled ipratropium effected significant bronchodilation in horses pre-exercise but did not cause more bronchodilation than did exercise itself, which also dilates previously constricted airways.28 Methylxanthines. In the normal animal, increased bronchodilation results from bronchial and bronchiolar smooth muscle relaxation mediated by increased intracellular cyclic adenosine monophosphate (cAMP) concentrations (see Fig. 1).87 Phosphodiesterase is the intracellular enzyme responsible for conversion of cAMP (bronchodilation) to 5-adenosine monophosphate (bronchoconstriction).87 The methylxanthines (caffeine, theophylline, theobromine, and aminophylline) inhibit phosphodiestrase, thus inhibiting intracellular destruction of cAMP. This increased cAMP results in bronchodilation,86, 87 although the efficacy of this mechanism at therapeutic doses in vivo has been questioned. 53 Methylxanthines are thought to affect intracellular calcium flux, resulting in smooth muscle relaxation and bronchodilation. 86,87 They also are believed to prevent bronchoconstriction by competitively inhibiting adenosine's interaction with its smooth muscle receptor. 53 Aminophylline (11 mg / kg PO or IV every 8-12 hours )48 and its active metabolite theophylline are commonly used in horses, but their administration can be associated with side effects such as agitation and tachycardia. These drugs are highly protein bound; thus, a loading dose (double the normal dose) may be necessary initially to achieve therapeutic plasma concentrations more quickly in the patient in need of acute bronchodilation. Another option for loading is to administer both an oral and intravenous dose simultaneously to achieve higher concentrations faster. Intravenous administration should be as an approximate 1-L infusion over 20 to 60 minutes to minimize side effects. Oral absorption may be variable in horses; thus, monitoring of plasma concentrations is ideal but rarely practical. P2-Adrenergic Agonists. Sympathomimetic bronchodilators that bind to rJ2 adrenoreceptors in airway smooth muscle induce increased intracellular concentrations of cAMr, resulting in smooth muscle relaxation and bronchodilation (see Fig. 1).87 Some sympathomimetics (e.g., isoproterenol, ephedrine) act as bronchodilators but are not desirable for daily use because of their simultaneous stimulation of cardiac and peripheral rJl receptors, resulting in tachycardia, agitation, sweating, and muscle tremors. Purer rJ2 agonists are more desirable for bronchodilation and include clenbuterol, albuterol, pirbuterol, and terbutaline. Chronic daily use of rJ2 adrenergics (>30 days) may be associated with downregulation of rJ2 receptors and decreased efficacy. Clenbuterol was licensed throughout the United States for use as a bronchodilator as of May II, 1998. Flexible label dosing by the FDA allows its use at various doses, starting at 0.8 f-lg / kg PO every 12 hours for 3 days and increasing by 0.8 f-Lg / kg every 3 days to a maximum of 3.2 f-lg / kg PO every 12 hours, at which point its use should be terminated if there is no appreciable positive response. 30,112 Possible side effects include abortion in pregnant animals. The original release of clenbuterol was delayed in the United States at least in part because of concerns over the possible anabolic effects of the drug; thus, its dispensation, storage, and use should be controlled carefully. In the early 1990s, clenbuterol was the anabolic drug of choice after testerosterone and its related

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anabolic hormones for human weight lifters and weight throwers (discus, shot put). Clenbuterol has been associated with human illnesses after ingestion of meat from animals to which it had been administered, however; thus, its use in food animals is prohibited. 9, 10,83,95,103 One concern with oral J32-adrenergic agents is that much of the dose can be removed from circulation on the first pass through the liver after gastrointestinal absorption. This massive loss may result in variable clinical responses, but it may be avoided using other J32 agonists administered by inhalant therapy.23-26, 53, 54, 94, 96, 110 As central airways become bronchodilated after initial therapy, doses of inhaled J32 adrenergics can be decreased, because the initial bronchodilation allows deeper penetration of inhaled drug into smaller airways.23,110 Aerosols with a mass median diameter of less than 5 Jl, are believed to reach the lower airways most effectively with inhalation therapy.23, 115 Albuterol (2-3 Jl,g / kg) has been administered to horses via inhalation23, 53 using a specially designed face mask and spacer (Aeromask and AeroVet Accessories; Trudell Medical International, London, Ontario, Canada) that allow more complete inhalation, despite the lack of a maximal voluntary inspiratory effort as is prescribed for the use of inhalers in human patients. 11o Recent dose-titration data have shown that either 360 or 720 Jl,g of albuterol administered via aerosol effected significant bronchodilation in horses with COPD.25 Furthermore, 360 Jl,g of aerosolized albuterol has recently been shown to improve pulmonary distribution of aerosolized technetium pentetate in horses with COPD but did not affect pulmonary distribution in normal horses. 94 Pirbuterol (1-2 Jl,g / kg) may be more effective as an inhaled bronchodilator than albuterol (at a similar dose of 1-2 Jl,g/kg) when administered to horses using a special handheld metered dose inhaler that is currently undergoing an FDA approval process. 24,26 Both albuterol and pirbuterol have no side effects at 1 to 2 Jl,g/kg but manifest typical adrenergic overdose signs (agitation, tremors, tachycardia, sweating) when inhalation doses exceed 6 Jl,g/kg. 24 Successful inhalant bronchodilation in horses has also been described with fenoterol (2-3 Jl,g / kg) via a face mask 110 and terbutaline (20 Jl,g / kg) via an ultrasonic nebulizer,76 although the published higher dose for terbutaline is thought to be a result of the route used for powdered terbutaline rather than the drug itself. Even with inhalation, some plasma concentration of drug may be detectable immediately after administration; thus, inhalation therapy should not be considered a safe method of subverting regulations prohibiting the use of J32 adrenergics during racing or showing. These regulations were enacted because it was suspected that the J32 adrenergics may enhance performance in horses. 89 First, if they successfully promote bronchodilation, they would be giving one horse a significant advantage over the others performing without benefit of J32 adrenergics. Second, some drugs (e.g., clenbuterol) appear to have significant anabolic effects; thus, their use leading up to a race or show might allow more muscling and greater strength and easier recovery from exercise. One recent study has shown that inhaled albuterol allowed significantly longer exercise to fatigue than did placebo when administered before exercise. 4 Recent positive drug tests for clenbuterol in nanogram per milliliter concentrations in postrace plasma in US racehorses demonstrate the sophistication of current testing methodologies. Clenbuterol may be detectable in plasma for as many as 14 days after administration in some horses; thus, it should be discontinued at least 2 weeks before competitions at which drug testing can be expected.

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Anti-Inflammatories

Glucocorticosteroids. Corticosteroids are indicated as anti-inflammatories when there is no infectious process or when the infectious process has previously been treated with antibiotics to minimize its chances of exacerbation with immunosuppression from corticosteroid therapy. Most commonly, corticosteroids are used in allergic lung disease or capo. Parenteral dexamethasone (up to 0.1 mg/kg every 24 hours or split every 12 hours IV or 1M) may be used in the acute case. Eventually, the horse can be switched for longer term therapy to oral prednisolone (up to 2.2 mg/kg every 12 hours) or prednisone (methylated in the liver to prednisolone). One dose (0.09 mg / kg 1M) of triamcinolone acetonide improves respiratory function for up to 3 weeks when administered to horses suffering from COPD,62 but this injectable corticosteroid has long been associated with the precipitation of laminitis. Chronic oral prednisolone therapy may be associated with some degree of adrenal suppression; thus, withdrawal may need to be gradual if treatment has been over 1 week in duration. Higher doses of systemic corticosteroids may result in laminitis. The use of inhaled corticosteroids has altered dramatically the treatment of asthma in humans,?7, 80, 84 Because extremely low doses can be delivered directly to the tissue of concern (airway receptors) without passage through the gastrointestinal tract, liver, and bloodstream, inhaled corticosteroids provide anti-inflammatory relief with minimal systemic side effects. Surprisingly, inhaled corticosteroids take longer to have an effect when initially administered (perhaps as long as 3-4 days )63; thus, they seem to be more valuable in preventing rather than treating acute exacerbations of capo, particularly in horses with a previously documented seasonality to their chronic condition. 53 Higher lipophilicity results in prolonged direct airway receptor contact and thus a longer duration of action. 53,56 Lipophilicity and receptor affinity are ranked as follows in declining order: fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, and then flunisilide, with fluticasone being at least 300 times more lipophilic than the others. The use of inhaled beclomethasone in horses has shown some benefit at dosages of 1.32 mg/ d/1-93 3.75 mg/ d,1 or 5 mg/ d. 53 Mast Cell Stabilizers. Allergen contact with airway mast cells causes degranulation and release of inflammatory mediators (cytokines, leukotrienes, histamine).53 These mediators then result in increased airway inflammation, including edema and bronchoconstriction. The use of sodium cromoglycate in horses is believed to prevent this mast cell degranulation, resulting in prevention of COPD clinical signs. A dose-dependent relationship between preventative cromolyn administration and the development of equine capo signs has been demonstrated. III Other reported benefits include improvements in pulmonary mechanics in capo (520 mg)101 and in clinical appearance in IAD53 as well as decreases in bronchoalveolar lavage-derived mast cell histamine content (200 mg every 12 hours).50 It must be emphasized, however, that cromolyn efficacy in equine airway disease has only been demonstrated prophylactically and not therapeutically. Antihistamines. There is no verifiable evidence of the significance of histamine as a mediator of airway inflammation in horses. Antihistamines are often prescribed for capo but have minimal clinical success, probably because there are numerous other more significant factors than mast cell degranulation accounting for bronchospasm in equine airway disease. 87

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Desensitization

As is the case with many allergic conditions in other species, equine respiratory allergies have been treated with desensitization therapy, but success is limited by improper identification of local allergens responsible for the disease, insufficient dosage or availability of indicated allergens, poor client compliance, insufficient limitation of environmental allergens causing continued exposure of the patient's respiratory tract, and disease processes (i.e., COPD) severe and chronic enough to prohibit complete reversal of pathologic airway changes. Immunomodulators: Interferon

IFN has been used recently as a means to stimulate resistance to viral infection and lAD in horses. 72, 74, 75 IFN molecules are thought to be speciesspecific, although some cross-reactions have been described.7° IFN-)' is produced primarily by lymphocytes and differs significantly in structure from IFN-a (from leukocytes) and IFN-fj (from fibroblasts). Overall, IFNs are considered to be immunosuppressive; for instance, they have the ability to decrease viral replication. Because IFN is produced naturally in response to viral replication, administration of additional exogenous IFN may not be as efficacious as would initially appear. Human IFN-a has been touted for use in preventing or treating viral respiratory disease in horses, but some investigators consider the reported doses to be inadequate for proper therapy.7° Furthermore, because these proteins should be digested by normal gastric peptidases, efficacious oral administration is not thought by some to be possible.7° Others argue that oral administration results in systemic effects by stimulating oropharyngeal lymphoid tissue. 72 Two recent reports on the use of low oral doses of human IFN-a (50 IV total, or 0.1 IV / kg) in the treatment of lAD in Standardbred racehorses demonstrated reduced tracheal and pharyngeal exudate. 74,75 Bronchoalveolar lavage fluid from treated horses also had decreased total cell counts 74; altered cell differentials 74; decreased total protein, albumin, IgG, and IgA concentrations 75; and decreased procoagulant activity.75 Another earlier report on the use of human IFNa-2a (0.22-2.2 IV / kg) showed no effect on severity of clinical disease or duration of viral shedding in horses with experimentally induced equine herpesvirus-1 infections. 97 Failure of IFNa-2a efficacy in this latter study has been attributed to preexisting herpesvirus antibody, overwhelming viral dose, or an insufficient dose of a single subtype of recombinant human IFN-a, because single subtypes like IFNa-2a are thought to be less efficacious than mixed IFN-a. 72 Expectorants

Perhaps the best expectorant for horses is proper hydration or even slight overhydration. Tenacious airway mucus and mucous plugging of the LRT may be alleviated simply by administration of intravenous crystalloid fluids. By moistening and softening the LRT airway exudate, it becomes easier for the horse to expel it via normal coughing and mucociliary clearance. Horses suffering from COPD may benefit the most from this type of therapy, particularly on initial diagnosis or during an acute exacerbation of a previously diagnosed chronic problem. A common initial treatment for COPD in Germany is to administer as much as 40 L of intravenous fluids to moisten and lubricate airway exudate, making movement via normal mucociliary clearance easier. If airway exudate continues to be difficult for the equine patient to clear or if insufficient coughing is present to clear the LRT, sodium or potassium iodide

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(20-40 mg / kg PO every 24 hours) or guaifenesin may be prescribed to assist as an expectorant. As an innocuous method of trying to maximize airway diameter by helping to mobilize airway secretions, iodides have been used for years as part of an intravenous fluid concoction administered pre-race in North America (a so-called "jug"). Mucolytics and Mucokinetics

When exudate is particularly tenacious, mucolytics (acetylcysteine, dembrexine) and mucokinetics (iodides, bromohexine) may be helpfu1. 69 Acetylcysteine has been used as part of a nebulizing regimen to help mobilize airway secretions in the treatment of acute obstructive pulmonary disease after severe smoke inhalation.57 Antitussives

Medication to prevent excessive coughing is used rarely in horses, simply because coughing is usually productive, particularly with proper hydration. If coughing becomes excessive, therapy with standard doses of narcotics (morphine, meperidine, codeine) or narcotic-like synthetics (butorphanol, 0.02 mg/ kg 1M) may be palliative/8 but treatment of the underlying cause of the cough is mandatory to prevent recurrence. Acute Respiratory Distress

Acute respiratory distress, particularly acute pulmonary edema, should be treated with intravenous diuretics, usually furosemide (1 mg/kg IV).58 Diuresis promotes fluid movement from the lung and pleural space and decreases further fluid movement into those compartments by converting intravascular fluid (plasma) into urine and decreasing the plasma volume available for movement into pulmonary or pleural spaces. Furosemide works as a loop diuretic and causes kaliuresis, thus decreasing whole-body potassium stores with chronic use. Oral potassium supplementation (30-60 g PO every 6-24 hours) may be necessary to offset urinary potassium losses once the acute crisis is over. Intranasal oxygen, bronchodilators, and corticosteroids and alleviation of the underlying cause (overhydration, heart failure, liver disease, pneumonia, smoke inhalation) are also necessary for full recovery. Exercise-Induced Pulmonary Hemorrhage

Furosemide has also been used in North America as a race-day preventative for exercise-induced pulmonary hemorrhage. Although the mechanism of its action in preventing or decreasing exercise-induced pulmonary hemorrhage is unproven, most investigators agree that it causes a dose-dependent decrease in cardiac preload sufficient to result in decreases in pulmonary artery pressure and right atrial pressure,31 thus making pulmonary capillary stress failure 118 less likely or less severe. Furosemide is usually dosed at 250 mg given intravenously 4 hours prior to racing. Recent studies have shown no additional benefit from repeating the dose a second time before racing. 47 Furosemide is prohibited under Federation Equestrienne Internationale, American Horse Shows Association, and non-North American racing rules, because its diuresis is suspected to mask

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valid detection of other potential performance-enhancing agents. Some recent data have shown that furosemide is probably a performance-enhancing agent itself (K. Hinchcliff, BVSc, PhD, personal communication, 1998), lending further credence to the arguments that its race-day use should be prohibited.

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21. Davis EW, Legendre AM: Successful treatment of guttural pouch mycosis with itraconazole and topical enilconazole in a horse. J Vet Intern Med 8:304-305, 1994 22. Davis LE, Neff CA, Baggot JD, et al: Pharmacokinetics of chloramphenicol in domesticated animals. Am J Vet Res 33:2259-2266, 1972 23. Derksen F: Inhalation therapy for the treatment of lower respiratory tract disease. In Robinson NE (ed): Current Therapy in Equine Medicine 4. Philadelphia, WB Saunders, 1997, pp 429-431 24. Derksen FJ, Robinson NE, Berney CE: Aerosol pirbuterol: Bronchodilator activity and side effects in ponies with recurrent airway obstruction (heaves). Equine Vet J 24:107-112, 1992 25. Derksen FJ, Olszewski MA, Robinson NE, et al: Aerosolized albuterol sulfate used as a bronchodilator in horses with recurrent airway obstruction. Am J Vet Res 60:689-693, 1999 26. Derksen FJ, Olszewski M, Robinson NE, et al: Use of a hand-held, metered-dose aerosol delivery device to administer pirbuterol acetate to horses with "heaves." Equine Vet J 28:306-310, 1996 27. Duvivier DH, Votion D, Vandenput S, et al: Airway response of horses with COPD to dry powder inhalation of ipratropium bromide. Vet J 154:149-153, 1997 28. Duvivier DH, Bayly WM, Votion D, et al: Effects of dry powder ipratropium bromide on recovery from exercise of horses with COPD. Equine Vet J 31:20-24, 1999 29. Duvivier DH, Votion D, Vandenput S, et al: Technical validation of a face mask adapted for dry powder inhalation in the equine species. Equine Vet J 29:471-476, 1997 30. Erichson DF, Aviad AD, Schultz RH, et al: Clinical efficacy and safety of clenbuterol HCI when administered to effect in horses with chronic obstructive pulmonary disease (COPD). Equine Vet J 26:331-336, 1994 31. Erickson HH, Hopper MK, Olsen SC, et al: Cardiopulmonary mechanisms of exerciseinduced pulmonary hemorrhage and action of furosemide. In Proceedings of 37th Annual Convention of American Association of Equine Practitioners, San Francisco, 1991, pp 651-661 32. Evans DR, Rollins JB, Huff GK, et al: Inactivated P. acnes as adjunct to conventional therapy in the treatment of equine respiratory disease. Equine Pract 10:17-21, 1988 33. Firth EC, Nouws JFM, Driessens F, et al: Effect of injection site on the pharmacokinetics of procaine penicillin G in horses. Am J Vet Res 47:2380-2384, 1986 34. Flaminio MJBF, Rush BR, Shuman W: Immunologic function in weanling foals after administration of a nonspecific immunostimulant. Vet Immunol Immunopathol 63:303-315, 1998 35. Folz SD, Hanson BJ, Griffin AK, et al: Clinical use of ceftiofur sodium as a treatment for naturally acquired respiratory infections in horses. Equine Vet J 24:300-304, 1992 36. Foreman JH: Does ceftiofur cause diarrhea? In Proceedings of 44th American Association of Equine Practitioners Convention. Baltimore, 1998, pp 146-147 37. Foreman JH: Practical considerations in the use of ceftiofur sodium in the treatment of equine respiratory tract infections. In Proceedings of 38th American Association of Equine Practitioners Convention, Orlando, 1992, pp 307-310 38. Foreman JH, Hungerford LL, Folz SD: Transport stress-induced pneumonia: A model in young horses. In Plowright W, Rossdale PD, Wade JF (eds): Equine Infectious Diseases VI, Proceedings of the Sixth International Conference. Newmarket, R&W Publications, 1992, p 313 39. Foreman JH, Hungerford LL, Folz SD, et al: Ceftiofur sodium for the treatment of naturally acquired respiratory tract infections in horses [abstract]. J Vet Intern Med 5:115, 1991 40. Freeman DE: Guttural pouches. In Beech J (ed): Equine Respiratory Disorders. Philadelphia, Lea & Febiger, 1991, pp 305-330 41. Freeman DE: Paranasal sinuses. In Beech J (ed): Equine Respiratory Disorders. Philadelphia, Lea & Febiger, 1991, pp 275-303 42. Freeman DE, Donawick WJ: Occlusion of the internal carotid artery in the horse by means of a balloon-tipped catheter: Evaluation of a method to prevent epistaxis caused by guttural pouch mycosis. J Am Vet Med Assoc 176:232-235, 1980 43. Freeman DE, Donawick WJ: Occlusion of the internal carotid artery in the horse by

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