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Respiratory pharmacotherapy in emergency and critical care medicine
Vet Clin Small Anim 32 (2002) 1073–1086
Respiratory pharmacotherapy in emergency and critical care medicine Elizabeth A. Rozanski, DVMa,*, Mark P. Rondeau, DVMb a
Section of Critical Care, Department of Clinical Sciences, Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA b Section of Internal Medicine, Department of Clinical Studies, 3900 Delaney, University of Pennsylvania–Philadelphia, Philadelphia, PA 19104, USA
Diagnosis and management of respiratory conditions in critically ill animals may be challenging. Animals with respiratory impairment may be difficult to evaluate completely because of stress and the potential for subsequent worsening of respiratory distress and hypoxemia. Additionally, because of the significant reserve of the respiratory system, the underlying condition may be quite advanced by the time that respiratory distress becomes apparent. The focus of this article is on pharmacotherapeutics of respiratory diseases affecting critically ill small animal patients. Conditions that often affect the respiratory function of the critically ill dog include upper airway obstruction, trauma, pneumonia, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), pulmonary thromboembolism (PTE), and pulmonary edema (cardiogenic and noncardiogenic). Conditions that frequently affect the cat include asthma/chronic bronchitis, pleural effusion, pulmonary edema, and, rarely, pneumonia. Neoplasia may initially present in both species as respiratory distress, but it is not the focus of this article. Additionally, the interested reader is referred to a multitude of excellent reviews for more information on the management of the patient with chronic pulmonary disease [1–3]. Emergency management of respiratory distress Initial management of the patient with respiratory distress should focus on minimizing patient stress and identifying differentials based on historical * Corresponding author. E-mail address: [email protected] (E.A. Rozanski). 0195-5616/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 1 9 5 - 5 6 1 6 ( 0 2 ) 0 0 0 3 9 - 6
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and brief physical examination findings. Supplemental oxygen may be administered either via a facemask, oxygen cage, or as ‘‘flow-by’’ with oxygen tubing held up close to the mouth and nares. Nasal oxygen may be too stressful to be placed on patient arrival. Rarely, a patient with severe distress requires emergency induction of anesthesia and manual ventilation with an Ambu bag (Harrell Medical, Lake Oswego, OR), anesthesia machine, or mechanical ventilator (Fig. 1). The clinician is urged to remember that in animals with marked distress or respiratory embarrassment, the doses of anesthetic agents required to permit endotracheal intubation are reduced.
Upper airway obstruction Upper airway obstructions can usually be rapidly appreciated as a result of loud and stridorous breathing [4]. The two most common upper airway obstructions identified in a critical care setting are laryngeal paralysis and brachycephalic airway syndrome. Most animals affected with laryngeal paralysis are older large-breed (eg, retrievers and setters) dogs with a more chronic history of loud or harsh breathing and perhaps a change in bark. Dogs are often presented to an emergency facility in moderate to severe respiratory distress with an acute exacerbation. Dogs are often hyperthermic, sometimes in excess of 105°F. Successful pharmacologic management of affected dogs includes supplemental oxygen, sedation, anti-inflammatory agents, intravenous fluids, and, possibly, general anesthesia/tracheostomy (Table 1). The most commonly used drug for sedation is low-dose acepromazine. Typically, many dogs improve if the anxiety associated with upper airway obstruction is relieved. The clinician should recall that laryngeal paralysis is a slowly progressive condition and that a dog may breathe
Fig. 1. A bulldog with a temporary tracheostomy for treatment of severe brachycephalic airway syndrome.
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Table 1 Pharmaceutic agents used in the medical management of upper airway diseasea Pharmaceutic agent
Dose
Route
Comments
Acepromazine
0.01–0.05 mg/kg
IV, IM
Dexamethasone Prednisone Butorphanol
0.01–0.25 mg/kg 0.25–1.00 mg/kg 0.1–0.4 mg/kg
IV SC, PO IV, IM
Sedative, do not exceed 3 mg per dog Anti-inflammatory Anti-inflammatory Analgesic, sedative
Abbreviations: IV, intravenous; IM, intramuscularly; SC, subcutaneously; PO, orally. a Different medications may be combined in an individual patient.
adequately through a small laryngeal aperture. Because of the increased airflow rates across a paralyzed larynx, edema and erythema of the arytenoids are commonly observed. Occasionally, everted laryngeal saccules develop and further occlude the flow of air. Most dogs benefit from some antiinflammatory drugs, such as dexamethasone or prednisone. Long-term therapy may include medical management or surgical palliative procedures. Dogs with laryngeal paralysis are prone to aspiration pneumonia, particularly after surgery because of loss of the ability to guard the airway [5]. Dogs with acute worsening of brachycephalic airway syndrome are typically treated with similar pharmaceutic agents and, eventually, further medical or surgical interventions, such as soft palate resection or even permanent tracheostomy (see Fig. 1). Severe upper airway disease in cats is uncommon but may occur. Nasopharyngeal polyps may result in partial upper airway obstruction, as can laryngeal tumors, laryngospasm, or profound airway swelling. Laryngeal paralysis is rare in the cat but has been reported [6]. Although some cats have a brachycephalic confirmation (eg, Persians), it is uncommon for surgical or medical management to be required. Trauma Dogs frequently experience thoracic trauma. The most common mechanism of injury is being hit by a car, although bite wounds, falls, and kicks also occur. Cats are much less commonly presented with thoracic trauma. Unfortunately, this most likely represents a high immediate death rate in the cat with major thoracic wounds. Thoracic trauma is typically treated with supportive care, including rest, supplemental oxygen, thoracocentesis for pneumothorax, and intravenous fluids as needed to maintain perfusion. A recent retrospective study concluded that antibiotics were unwarranted in isolated canine pulmonary contusions [7]. Some controversy exists regarding fluid therapy in pulmonary contusions [9,34]. Some authors worry that large volumes of crystalloids may leak more easily across a damaged endothelium and magnify extravascular lung water, whereas other investigators believe that extravasation of colloids may be even more detrimental, because
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colloids may persist in the interstitial space for long periods as a result of their greater size. The best current recommendations include maintaining adequate but not excessive intravascular volume and carefully monitoring the animal for progression of respiratory difficulty [7–9]. Diuretics, such as furosemide, should be avoided in an animal with hypovolemia, despite the presence of adventitial lung sounds. The clinician is urged to remember that pulmonary crackles signify fluid rather than being specific for pulmonary edema caused by vascular overload. Pneumonia Pneumonia is both a common presenting complaint and a common development in hospitalized dogs. Pneumonia is quite rare in cats. Most frequently, pneumonia in dogs develops as a result of aspiration, although communityacquired fungal and hematogenous causes are also possible. Clinical findings often include alveolar infiltrates on thoracic radiographs, cough, fever, and lethargy. Some dogs have concurrent megaesophagus, laryngeal paralysis, or a history of extreme weakness or vomiting. Cytologic evaluation of airway secretions, which may be obtained by performing a tracheal wash, can document an inflammatory response. Treatment of pneumonia should include eliminating the underlying cause if possible, using appropriate antibiotics, providing supplemental oxygen as needed, and performing physiotherapy (eg, nebulization with coupage) [10,11]. Antibiotic therapy is ideally chosen based on bacterial culture and sensitivity testing of fluid samples from tracheal wash. Broad-spectrum antibiotics should be initiated as soon as pneumonia is identified and appropriate samples for culture have been obtained while awaiting receipt of culture results (Table 2). For a community-acquired pneumonia thought to be due to Bordetella bronchiseptica, a recent microbiologic survey suggests that most isolates are susceptible to tetracycline, doxycycline, enrofloxacin, and amoxicillin/clavulanic acid [12]. In endemic areas, fungal pneumonias (blastomycosis, histoplasmosis, and coccidiomycosis) may result in moderate to severe pulmonary disease. Table 2 Antibiotics used in treatment of pneumoniaa Antibiotic Ampicillin Cefazolin Gentimicin Enrofloxacin Metronidazole
Dose (mg/kg) 22 every 6 hours 22 every 8 hours 5–6 every 24 hours 2.5–10 every 12–24 hours 10 every 8 hours
Route IV IV IV IM, IV, PO IV
Grampositive
Gramnegative
þþþ þþþ
þ þþ þþþ þþþ
þþþ
Anaerobes þþþ
þþþ
Abbreviations: IV, intravenous; IM, intramuscular; PO, orally; þ, positive. a Many other individual antibiotics and combinations may also be used. Ideal antimicrobial therapy is based on bacterial culture and sensitivity data.
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In critically ill hospitalized dogs, therapy is often begun pending bacterial culture and sensitivity results with intravenous combinations like ampicillin and enrofloxacin or cefazolin, gentamicin, and metronidazole. In hospitalacquired infections expected to be resistant, antibiotic choices may include imipenem, amikacin, or cefoxitin. Nebulization and coupage are often used as adjuvants in therapy of pneumonia, although no controlled trials exist in the veterinary literature reporting their benefit. Cats with suspected pneumonia should also be treated with intravenous antibiotics and supplemental oxygen as required. It is not uncommon for cats that are suspected radiographically of having pneumonia to have congestive heart failure and pulmonary edema.
Acute lung injury and acute respiratory distress syndrome Acute lung injury and acute respiratory distress syndrome are terms that are applied to human beings with respiratory distress. These terms have recently been applied to animals [13,14,33]. These conditions are defined as clinical syndromes of respiratory distress characterized by the presence of an antecedent event (eg, trauma/sepsis), the development of bilateral alveolar infiltrates on thoracic radiographs, decreased pulmonary compliance, and the absence of congestive heart failure (as evidenced by pulmonary capillary wedge pressure of <18 mm Hg) [15]. Differentiation of ALI and ARDS in people is based on the presence of these criteria and assessment of the ratio of PaO2 to the fraction of inspired oxygen (FiO2), with a value of <300 equal to ALI and a value of <200 equal to ARDS. No consensus statement has yet been produced by the American College of Veterinary Emergency and Critical Care to apply to animals, although it seems likely that similar criteria will be proposed in dogs. It is less clear as to whether cats develop ALI or ARDS. Certainly, respiratory distress does develop in the critically ill cat, but it seems that this species is more prone to volume overload/congestive heart failure or the development of pleural effusion rather than to ALI or ARDS. Pharmacologically, no specific therapies have been found to be helpful in the treatment of human beings with ARDS. Altered mechanical ventilatory strategies seem to be beneficial, and many active research programs exist to try to elucidate both the pathogenesis and therapy for ARDS [15]. Current veterinary recommendations include careful monitoring of the patient at risk, limiting peak pressures in ventilated animals, and treating aggressively for the underlying cause (Fig. 2).
Pulmonary thromboembolism PTE is a condition that has been recognized with increasing frequency in critically ill dogs. Cats have been identified with PTE, but it is exceedingly
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Fig. 2. A Labrador Retriever receiving mechanical ventilation for support of acute lung injury after being hit by a car.
rare [16,17]. PTE may be a challenging condition to identify successfully in dogs as well as in people, because the clinical signs may vary from vague to peracute death. In practice, anticipation of the patient at risk for PTE is important. Risk factors that have been documented in dogs with PTE include immune-mediated hemolytic anemia, Cushing’s syndrome, sepsis, and neoplasia [18,19]. Pharmacologic interventions used in the treatment of PTE include anticoagulant therapy and thrombolytic therapies (Table 3). All animals with PTE also benefit from standard hemodynamic and respiratory support. Anticoagulant therapies used in animals include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and warfarin. UFH has been the most widely used anticoagulant in veterinary patients because of its widespread availability and low cost. Both forms of heparin act primarily to limit the eventual conversion of fibrinogen to fibrin by accelerating the action of antithrombin III in inhibiting activated coagulation factors (II, IX, X, XI, and XII). In people, heparin has been associated with the development of heparin-induced thrombocytopenia (HIT). This is an acute onset of marked thrombocytopenia in an individual receiving heparin therapy. Affected patients have a paradoxic tendency for thrombosis instead of hemorrhage. It is thought to be an immune-mediated reaction, with antibodies formed against heparin and complexed with platelet factor 4 [20]. LMWH differs from UFH by being more specific for factor X, having a more predictable anticoagulant effect at a given dosage, and requiring less routine monitoring [21,22]. LMWH also seems less likely to result in the development of HIT. The most often used LMWHs are enoxaparin (Lovenox) and dalteparin (Fragmin) LMWHs are not yet widely used in veterinary medicine because of higher cost and less clinical experience, although a recent
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Table 3 Pharmaceutic agents used in the medical management of pulmonary thromboembolisma Drug
Dose
Mechanism of action
Unfractionated heparin
10–20 IU/kg/h CRI to 300 IU/kg SC every 6 hours
Low-molecular-weight heparin Aspirin Streptokinase
100 IU/kg every 12 hours
Enhance the activity of AT in inhibiting activated clotting factors Same, more predictable efficacy Antiplatelet Thrombolytic
Warfarin
0.5–2.0 mg/kg every 24 hours 25,000 IU for 1 hour, then 10,000 IU/h 0.05–0.2 mg/kg
Anticoagulant, requires careful monitoring
Abbreviations: CRI, continuous rate infusion; AT, antithrombin; SC, subcutaneous. a Pulmonary thromboembolism is a notoriously difficult disease to identify and treat. Dosage are current best recommendations but are not derived from controlled trials.
study reported on the pharmacokinetics of a LMWH in dogs [23]. UFH given as a treatment for PTE should be dosed to result in prolongation of the activated partial thromboplastin time (aPTT) of 1.5 times to twice baseline values. In hypercoagulable animals, this often requires high doses (250–500 IU/kg administered subcutaneously every 6 hours) of UFH. As a result of the properties of the LMWH preparations, prolongations of the aPTT do not occur at therapeutic doses, but patients may be monitored by following clinical signs or by assessing for anti-Xa activity. Warfarin acts to prevent the formation of vitamin K–dependent coagulation factors (II, VII, IX, and X) [24]. Warfarin also inhibits the production of the anticoagulant protein C. The half-life of protein C is shorter than that of the procoagulant factors, so initial overlap with heparin is recommended to prevent a hypercoagulable state. In people, a warfarin-associated skin necrosis has been described, but this has not been documented in animals. Warfarin therapy is challenging in small animals. The prothrombin time (PT) should be followed every 48 hours until stable for several days, then every 3 days for 1 month, and then once a week or every other week. The desired end point is a PT of 1.5 times to twice the baseline value. It is common for the PT to prolong or shorten in dogs without a clear-cut explanation, occasionally severely enough to result in life-threatening hemorrhage. In human medicine, differences in PT reagents are adjusted for via calculation of the international normalized ratio (INR), but this is not frequently performed in animals. It is prudent to use the same machine or laboratory for patient monitoring to try to improve the likelihood of a successful outcome. Thrombolytic agents, such as streptokinase or tissue plasminogen activator (TPA), have been used in people with PTE, but no clinical reports yet exist in dogs. Thrombolytics act to accelerate the fibrinolytic pathways by
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either directly or indirectly activating plasminogen to plasmin. Streptokinase has been most widely evaluated in animals [25–27]. Its action results from binding directly to plasminogen and creating a component that stimulates the conversion of other molecules of plasminogen to plasmin. Streptokinase is not specific for plasminogen bound to fibrin and also acts to deplete fibrinogen and other procoagulant factors; thus, at least theoretically, it may result in an increased hemorrhagic potential. TPA is more specific and has an increased ability to activate the plasminogen that is associated with a thrombus. Indications and guidelines for the use of thrombolytics in dogs with PTE are not yet defined. It seems prudent to consider their use in animals that are hemodynamically unstable from large PTE. At our hospital, the use of streptokinase for large PTE in dogs has not yet been successful; however, this may reflect patient selection and the time frame of intervention rather than failure of the thrombolytic agent. Surgical removal of the clot (thromboembolectomy) has also been recommend in some animals, but, again, clear-cut successful outcomes are rare. Pulmonary edema Pulmonary edema is defined as excessive lung water. Pulmonary edema may develop in dogs as a result of either cardiogenic or noncardiogenic causes. Cardiogenic edema (caused by left-sided congestive heart failure) is more common. Heart failure results in the accumulation of pulmonary edema because of increased hydrostatic pressure when pulmonary venous hypertension develops as a result of increases in left atrial pressure. Left atrial pressure may increase for a variety of reasons, including congenital conditions (eg, patent ductus arteriosus) or acquired conditions (eg, chronic valvular disease or cardiomyopathy). Cardiogenic pulmonary edema is usually recognized radiographically as a heavy interstitial to alveolar pattern, often in association with cardiomegaly and pulmonary venous congestion. Dogs often first develop edema in the perihilar region, and as edema develops, it becomes diffuse. Cats often develop patchy alveolar infiltrates rather than edema in specific locations. Treatment of cardiogenic pulmonary edema includes rest, supplemental oxygen, vasodilators. and diuretic therapy (Table 4). Furosemide is the initial diuretic of choice, although other diuretics often must be added, such as spironolactone or hydrochlorothiazide. In an emergency situation, furosemide is administered either intravenously (preferable) or intramuscularly at 2 to 4 mg/kg. This can be repeated up to once an hour for 4 hours and then decreased to two to four times a day. Excessive use of diuretics may result in marked prerenal azotemia and subsequent anorexia and lethargy. Vasodilators are useful in the treatment of heart failure by reducing both afterload and preload. Commonly used vasodilators in the emergency setting include topical nitroglycerin paste and a continuous rate infusion
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Table 4 Pharmaceutic agents used in the medical management of pulmonary edemaa Drug
Dosage
Route
Mechanism
Furosemide Spironolactone Hydrochlorothiazide Enalapril Nitroprusside Nitroglycerin Hydralazine
1–4 mg/kg 1–2 mg/kg every 12 hours 1–2 mg/kg every 12 hours 0.5 mg/kg every 12–24 hours 0.5–5.0 lg/kg/min 0.125–0.25 in per 10 kg 0.5–1.0 mg/kg every 12 hours
IV, IM, PO PO PO PO IV Topically PO
Diuretic Diuretic Diuretic ACE inhibitor Balanced vasodilator Venodilator Arterial vasodilator
Abbreviations: IM, intramuscularly; IV, intravenously; PO, orally; ACE, angiotensin converting enzyme. a Often, a balanced approach results in the best patient outcome.
of nitroprusside. Nitroprusside is a potent vasodilator, so its use requires an infusion pump and close monitoring. Angiotensin converting enzyme (ACE) inhibitors are also useful for the long-term management of congestive heart failure. Occasionally, intravenous enalaprilat has been used in severe acute cases, but there is little information available in critically ill animals. The ultimate long-term therapy for heart disease depends on the underlying cause but typically include diuretics and vasodilators. Medications to control rate, such as b-blockers, calcium-channel antagonists, or digoxin, are often used as well. Noncardiogenic pulmonary edema may also result in pulmonary infiltrates and respiratory distress. Noncardiogenic pulmonary edema is a high-protein fluid that typically develops after another insult. Common causes of noncardiogenic pulmonary edema include seizures, upper airway obstruction, and electrocution, although a number of diseases have been linked to the formation of noncardiogenic edema [28]. ALI and ARDS are forms of noncardiogenic edema. Thoracic radiographs from affected dogs typically have a dorsal caudal distribution to the pulmonary infiltrates, although in severe cases, the alveolar infiltrates may affect all lung lobes. Therapy of noncardiogenic edema is directed primarily at supportive care and treatment if needed for the underlying disease.
Pleural effusion Pleural effusion may also result in the development of moderate to marked respiratory distress. Affected animals may be presented as an emergency or may be chronically affected. Pleural effusion is a sign rather than a specific diagnosis, so care must be taken to identify fully the underlying cause. Management of the pet with pleural effusion is directed toward removing the effusion and then tailoring treatment to the final diagnosis. Samples of the fluid should be saved for cytologic evaluation and bacterial culture if indicted. Causes of pleural effusion commonly include congestive
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heart failure (particularly in cats), neoplasia, pyothorax, pneumothorax, hemothorax, and chylothorax as well as less common causes, such as lung lobe torsion, pancreatitis, or diaphragmatic hernia. Pharmaceutic agents used in the treatment of pleural effusion include diuretics, antibiotics, chemotherapy, vitamin K/fresh–frozen plasma, rutin, and others.
Allergic airway disease Allergic lower airway disease occurs in cats and, less commonly, in dogs. Mediators of inflammation in people (and likely small animals) include mast cells, eosinophils, and activated T lymphocytes. Clinical signs of cats with lower airway disease include coughing, which may be productive, and respiratory distress. Some cats never develop overt respiratory difficulties beyond coughing, whereas others are presented as emergencies with extreme respiratory distress. Physical examination of cats with severe respiratory distress from lower airway disease frequently documents the presence of pronounced crackles on thoracic auscultation and a normal to elevated rectal temperature. Thoracic radiographs may appear normal, or they may document hyperinflation and a prominent bronchial pattern. Some cats have right middle lung lobe collapse or signs of cor pulmonale. Typically, cats respond rapidly to supportive care and anti-inflammatory therapy. A transoral tracheal wash is commonly performed when the patient is stabilized to evaluate for cytologic abnormalities or signs of infectious or parasitic disease. Bacterial colonization and/or infection may be identified on the basis of a positive airway culture. Antibiotic therapy is warranted in individual cats based on sensitivity data, although it should be remembered that the larger airways in the cats are normally not sterile. Common bacterial species cultured from the airways of apparently healthy cats include Pasteurella spp, Staphylococcus spp, Streptococcus spp, Escherichia coli, and even Pseudomonas spp [29]. Mycoplasma spp have the ability to damage the airway epithelium, so a positive culture for Mycoplasma spp may have more clinical relevance than other isolates and should be treated with appropriate antibiotics. Treatment of the asthmatic cat includes glucocorticoids (prednisone or long-acting reposital preparations) and bronchodilators (Table 5). Cats with documentation or the potential for parasites should also be dewormed. Commonly used bronchodilators include theophylline (sustained release product at night) and b2-agonists like terbutaline or inhaled albuterol. Inhaled b2-agonists may be given via an Aerochamber and associated mask. For most cats, the second smallest size works well. Albuterol (100 lg per puff [200-dose vial]) has immediate effect and typically lasts 4 hours. The usual dose is two puffs twice a day, but it may be given every 30 minutes for up to 4 hours in a crisis. For cats that seem to require daily prednisone, inhaled steroids maybe beneficial. Fluticasone (Flovent, 220 lg per puff) has been used in cats. Theoretically, there is no systemic absorption, so
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Table 5 Pharmaceutic agents used in the medical management of allergic airway diseasea Drug
Dosage
Prednisone
5 mg PO per cat every 12 hours, taper 10–20 mg per cat SC every 2–4 weeks
Methylprednisolone acetate Terbutaline
Theophylline
Zafirlukast (Accolate)
0.625–1.25 mg per cat PO every 8–24 hours 0.01 mg/kg IV or SC every 8 hours 5 mg/kg PO every 8–12 hours
5 mg per cat PO every 12–24 hours
Mechanism of action/ comments Anti-inflammatory, effective, inexpensive Good for the ‘‘hard-to-pill’’ cat, but long-term effects possible b2-agonist
Methylxanthine long-lasting products occasionally available Leukotriene receptor antagonist
Abbreviations: PO, orally; SC, subcutaneously; IV, intravenously. a Also see text for description of aerosol medications.
long-term prednisone side effects are unlikely. Recommended doses include 1 puff per day if asthma is judged to be mild or twice daily in more severe cases. Inhaled steroids seem to take 7 to 10 days to reach efficacy, so a short course of oral prednisone (7–14 days) is required when beginning therapy. Always administer inhaled steroids after bronchodilators so that bronchoconstriction does not interfere with lung distribution of the drug. The procedure for administering inhaled medications includes priming the spacer before first use and after each cleaning by injecting four to five puffs into the chamber. This allows particles to adsorb to the inside of the chamber so that the dose gets to the patient. Wait 15 minutes after priming before using. Apply the required dose into the chamber away from the cat. Apply the mask to the cat’s face gently for 10 breaths or 30 seconds. There is a one-way valve, so the drug only comes out if the cat breathes it. Wait 5 minutes between administering doses. Try to avoid treating the eyes because of the potential for corneal ulceration. The chamber must be cleaned once a week with warm soapy water. Most cats tolerate the face mask well, and it is often easier to use than oral medications. Proposed treatments include leukotriene antagonists (eg, Accolate), cyclosporine A, anti-interleukin 5 antibodies, or cyproheptadine. The prognosis for asthma is usually good, although some cats have recurrent bouts and require frequent medications. Allergic lung disease is less common in dogs than in cats. Pulmonary infiltrates with eosinophilia (PIE), including eosinophilic bronchitis or pneumonitis and eosinophilic pulmonary granulomatosis, have been reported in dogs [30,35]. Clinical signs of affected dogs include cough, respiratory distress,
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and lethargy. Substantial pulmonary infiltrates are usually observed on thoracic radiographs. Differential diagnoses typically include bacterial pneumonia, heartworm, and neoplasia. Affected dogs often have a history of prior antibiotic therapy with little or no improvement. Collection of respiratory samples for cytologic evaluation may be made via a transoral tracheal wash (TTW) or via a transtracheal aspirate (TTA). When a specific cause is identified, eosinophilic pneumonitis has most commonly been associated with occult heartworm infection in dogs. It is proposed that microfilaria become trapped in the pulmonary circulation and then become surrounded by neutrophils and eosinophils. Affected dogs in one report had a 1-week to 6-month history of progressive coughing, dyspnea, and exercise intolerance. All dogs had a peripheral eosinophilia and a preponderance of eosinophils (60%–80%) on TTA cytology [31]. Pulmonary infiltrates consisting of diffuse homogeneous interstitial, peribronchial, and alveolar patterns were detected on thoracic radiography. There was a rapid resolution of clinical (within 24 hours) and radiographic (3–5 days) signs after therapy with prednisone (1–2 mg/kg once a day). Some dogs with developing (early) heartworm infections acquire eosinophilic pneumonitis, and repeat heartworm testing in 3 to 6 months is required to confirm heartworm disease as the cause. Eosinophilic pneumonitis has also been associated with other parasitic infections, such as ascarid migration or lungworm. Eosinophilic pulmonary granulomatosis is the most severe form of pulmonary hypersensitivity. A large study by Calvert et al [32] reported on 11 dogs over an 8-year period. In this report, the dogs ranged in age from 1 to 11 years. Clinical signs included coughing, dyspnea, and lethargy. Seven dogs were identified as having Dirofilaria immitis infections. Radiographic changes included bronchial, interstitial, alveolar, and nodular patterns. Hilar lymphadenopathy was present in some dogs. Dogs were treated with a variety of immunosuppressant agents, including glucocorticoids, azathioprine, and cyclophosphamide. Most dogs initially showed improvement but then usually died or were euthanized within 1 year. Heartworm infection is a clear trigger for allergic lung disease and should be excluded in affected dogs. Most dogs respond to treatment with doses of glucocorticoids that are in an antiinflammatory to immunosuppressive range. Some dogs may require intermittent therapy to remain asymptomatic. Dogs affected with granulomatous changes have a much worse prognosis for long-term survival. Summary Successful pharmacologic management of most respiratory diseases is possible. All moderately to severely affected animals benefit from rest and supplemental oxygen. Careful identification of the underlying cause as well as an understanding of the pathophysiology behind various diseases is essential to successful patient outcome.
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References [1] Ford RB. Chronic lung disease in old dogs and cats. Vet Rec 1990;126:399–402. [2] McKiernan BC. Diagnosis and treatment of canine chronic bronchitis. Twenty years of experience. Vet Clin North Am Small Anim Pract 2000;30:1267–78. [3] Padrid P, Amis TC. Chronic tracheobronchial disease in the dog. Vet Clin North Am Small Anim Pract 1992;22:1203–29. [4] Holt D, Brockman D. Diagnosis and management of laryngeal disease in the dog and cat. Vet Clin North Am Small Anim Pract 1994;24:855–71. [5] MacPhail CM, Monnet E. Outcome of and postoperative complications in dogs undergoing surgical treatment of laryngeal paralysis: 140 cases (1985–1998). JAVMA 2001;218: 1949–56. [6] Schachter S, Norris CR. Laryngeal paralysis in cats: 16 cases (1990–1999). JAVMA 2000;216:1100–3. [7] Powell LL, Rozanski EA, Tidwell AS, Rush JE. A retrospective analysis of pulmonary contusions secondary to motor vehicular accidents in 143 dogs: 1994–1997. J Vet Emerg Crit Care 1999;9:127–36. [8] Cohn SM, Fisher BT, Rosenfield AT, Cross JH. Resuscitation of pulmonary contusion: hypertonic saline is not beneficial. Shock 1997;8:292–9. [9] Richardson JD, Franz JL, Grover FL, Trinkle JK. Pulmonary contusion and hemorrhage– crystalloid versus colloid replacement. J Surg Res 1974;16:330–6. [10] Jameson PH, King LA, Lappin MR, Jones RL. Comparison of clinical signs, diagnostic findings, organisms isolated, and clinical outcome in dogs with bacterial pneumonia: 93 cases (1986–1991). JAVMA 1995;206:206–9. [11] Murphy ST, Ellison GW, McKiernan BC, Mathews KG, Kubilis PS. Pulmonary lobectomy in the management of pneumonia in dogs: 59 cases. (1972–1994). JAVMA 1997;210:235–9. [12] Speakman AJ, Dawson S, Corkill JE, et al. Antibiotic susceptibility of canine Bordetella bronchiseptica isolates. Vet Microbiol 2000;71:193–200. [13] Parent C, King LG, Walker LM, Van Winkle TJ. Clinical and clinicopathologic findings in dogs with acute respiratory distress syndrome: 19 cases (1985–1993). JAVMA 1996; 208:1419–27. [14] Parent C, King LG, Van Winkle TJ, Walker LM. Respiratory function and treatment in dogs with acute respiratory distress syndrome: 19 cases (1985–1993). JAVMA 1996;208:1428–33. [15] The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–8. [16] Sottiaux J, Franck M. Pulmonary embolism and cor pulmonale in a cat. J Small Anim Pract 1999;40:88–91. [17] Whitley NT, Stepien RL. Defaecation syncope and pulmonary thromboembolism in a cat. Aust Vet J 2001;79:403–5. [18] Johnson LR, Lappin MR, Baker DC. Pulmonary thromboembolism in 29 dogs: 1985– 1995. J Vet Intern Med 1999;13:338–45. [19] LaRue MJ, Murtaugh RJ. Pulmonary thromboembolism in dogs: 47 cases (1986–1987). JAVMA 1990;197:1368–72. [20] Deitcher SR, Carman TL. Heparin-induced thrombocytopenia: natural history, diagnosis, and management. Vascular Medicine 2001;2:113–9. [21] Kleinschmidt K, Charles R. Pharmacology of low molecular weight heparins. Emerg Med Clin North Am 2001;19:1025–49. [22] Mammen EF. Low molecular weight heparins and heparin-induced thrombocytopenia. Clinical and Applied Thrombosis and Hemostasis 1999;1(Suppl):S72–5. [23] Mischke R, Grebe S, Jacobs C, et al. Aminolytic heparin activity and values for several hemostatic variables after repeated subcutaneous administration of high doses of a low molecular weight heparin in healthy dogs. Am J Vet Res 2001;62:595–8.
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[24] Monnet E, Morgan MR. Effect of three loading doses of warfarin on the international normalized ration for dogs. Am J Vet Res 2000;61:48–50. [25] Killingsworth CR, Eyster GE, Adams T, Bartlett PC, Bell TG. Streptokinase treatment of cats with experimentally induced aortic thrombosis. Am J Vet Res 1986;47:1351–9. [26] Moore K, Dhupa N, Murtaugh RJ, Rush JE. Retrospective study of streptokinase administration in 46 cats with arterial thromboembolism. J Vet Emerg Crit Care 2000; 10:245–57. [27] Ramsey CC, Burney DP, Macintire DK, Finn-Bodner S. Use of streptokinase in four dogs with thrombosis. JAVMA 1996;209:780–5. [28] Drobatz KJ, Saunders HM, Pugh CR, Hendricks JC. Noncardiogenic pulmonary edema in dogs and cats: 26 cases (1987–1993). JAVMA 1995;206:1732–6. [29] Padrid PA, Feldman BF, Funk K, Samitz EM, Reil D, Cross CE. Cytologic, microbiologic, and biochemical analysis of bronchoalveolar lavage fluid obtained from 24 healthy cats. Am J Vet Res 1991;52:1300–7. [30] Clercx C, Peeters D, Snaps F, Hansen P, McEntee K, Detilleux J, et al. Eosinophilic bronchopneumopathy in dogs. J Vet Intern Med 2000;14:282–91. [31] Corcoran BM, Thoday KL, Henfrey JI, et al. Pulmonary infiltration with eosinophils in 14 dogs. J Small Anim Pract 1991;32:494–502. [32] Calvert CA, Mahaffey MB, Lappin MR, et al. Pulmonary and disseminated eosinophilic granulomatosis in dogs. J Am Anim Hosp Assoc 1987;24:311–20. [33] Frevert CW, Warner AE. Respiratory distress resulting from acute lung injury in the veterinary patient. J Vet Intern Med 1992;6:154–65. [34] Wisner DH, Sturm JA. Controversies in the fluid management of post-traumatic lung disease. Injury 1986;17:295–300. [35] Neer MT, Waldron DR, Miller RI. Eosinophilic pulmonary granulomatosis in two dogs and literature review. J Am Anim Hosp Assoc 1986;22:593–9.
Respiratory pharmacotherapy in emergency and critical care medicine Elizabeth A. Rozanski, DVMa,*, Mark P. Rondeau, DVMb a
Section of Critical Care, Department of Clinical Sciences, Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA b Section of Internal Medicine, Department of Clinical Studies, 3900 Delaney, University of Pennsylvania–Philadelphia, Philadelphia, PA 19104, USA
Diagnosis and management of respiratory conditions in critically ill animals may be challenging. Animals with respiratory impairment may be difficult to evaluate completely because of stress and the potential for subsequent worsening of respiratory distress and hypoxemia. Additionally, because of the significant reserve of the respiratory system, the underlying condition may be quite advanced by the time that respiratory distress becomes apparent. The focus of this article is on pharmacotherapeutics of respiratory diseases affecting critically ill small animal patients. Conditions that often affect the respiratory function of the critically ill dog include upper airway obstruction, trauma, pneumonia, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), pulmonary thromboembolism (PTE), and pulmonary edema (cardiogenic and noncardiogenic). Conditions that frequently affect the cat include asthma/chronic bronchitis, pleural effusion, pulmonary edema, and, rarely, pneumonia. Neoplasia may initially present in both species as respiratory distress, but it is not the focus of this article. Additionally, the interested reader is referred to a multitude of excellent reviews for more information on the management of the patient with chronic pulmonary disease [1–3]. Emergency management of respiratory distress Initial management of the patient with respiratory distress should focus on minimizing patient stress and identifying differentials based on historical * Corresponding author. E-mail address: [email protected] (E.A. Rozanski). 0195-5616/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 1 9 5 - 5 6 1 6 ( 0 2 ) 0 0 0 3 9 - 6
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and brief physical examination findings. Supplemental oxygen may be administered either via a facemask, oxygen cage, or as ‘‘flow-by’’ with oxygen tubing held up close to the mouth and nares. Nasal oxygen may be too stressful to be placed on patient arrival. Rarely, a patient with severe distress requires emergency induction of anesthesia and manual ventilation with an Ambu bag (Harrell Medical, Lake Oswego, OR), anesthesia machine, or mechanical ventilator (Fig. 1). The clinician is urged to remember that in animals with marked distress or respiratory embarrassment, the doses of anesthetic agents required to permit endotracheal intubation are reduced.
Upper airway obstruction Upper airway obstructions can usually be rapidly appreciated as a result of loud and stridorous breathing [4]. The two most common upper airway obstructions identified in a critical care setting are laryngeal paralysis and brachycephalic airway syndrome. Most animals affected with laryngeal paralysis are older large-breed (eg, retrievers and setters) dogs with a more chronic history of loud or harsh breathing and perhaps a change in bark. Dogs are often presented to an emergency facility in moderate to severe respiratory distress with an acute exacerbation. Dogs are often hyperthermic, sometimes in excess of 105°F. Successful pharmacologic management of affected dogs includes supplemental oxygen, sedation, anti-inflammatory agents, intravenous fluids, and, possibly, general anesthesia/tracheostomy (Table 1). The most commonly used drug for sedation is low-dose acepromazine. Typically, many dogs improve if the anxiety associated with upper airway obstruction is relieved. The clinician should recall that laryngeal paralysis is a slowly progressive condition and that a dog may breathe
Fig. 1. A bulldog with a temporary tracheostomy for treatment of severe brachycephalic airway syndrome.
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Table 1 Pharmaceutic agents used in the medical management of upper airway diseasea Pharmaceutic agent
Dose
Route
Comments
Acepromazine
0.01–0.05 mg/kg
IV, IM
Dexamethasone Prednisone Butorphanol
0.01–0.25 mg/kg 0.25–1.00 mg/kg 0.1–0.4 mg/kg
IV SC, PO IV, IM
Sedative, do not exceed 3 mg per dog Anti-inflammatory Anti-inflammatory Analgesic, sedative
Abbreviations: IV, intravenous; IM, intramuscularly; SC, subcutaneously; PO, orally. a Different medications may be combined in an individual patient.
adequately through a small laryngeal aperture. Because of the increased airflow rates across a paralyzed larynx, edema and erythema of the arytenoids are commonly observed. Occasionally, everted laryngeal saccules develop and further occlude the flow of air. Most dogs benefit from some antiinflammatory drugs, such as dexamethasone or prednisone. Long-term therapy may include medical management or surgical palliative procedures. Dogs with laryngeal paralysis are prone to aspiration pneumonia, particularly after surgery because of loss of the ability to guard the airway [5]. Dogs with acute worsening of brachycephalic airway syndrome are typically treated with similar pharmaceutic agents and, eventually, further medical or surgical interventions, such as soft palate resection or even permanent tracheostomy (see Fig. 1). Severe upper airway disease in cats is uncommon but may occur. Nasopharyngeal polyps may result in partial upper airway obstruction, as can laryngeal tumors, laryngospasm, or profound airway swelling. Laryngeal paralysis is rare in the cat but has been reported [6]. Although some cats have a brachycephalic confirmation (eg, Persians), it is uncommon for surgical or medical management to be required. Trauma Dogs frequently experience thoracic trauma. The most common mechanism of injury is being hit by a car, although bite wounds, falls, and kicks also occur. Cats are much less commonly presented with thoracic trauma. Unfortunately, this most likely represents a high immediate death rate in the cat with major thoracic wounds. Thoracic trauma is typically treated with supportive care, including rest, supplemental oxygen, thoracocentesis for pneumothorax, and intravenous fluids as needed to maintain perfusion. A recent retrospective study concluded that antibiotics were unwarranted in isolated canine pulmonary contusions [7]. Some controversy exists regarding fluid therapy in pulmonary contusions [9,34]. Some authors worry that large volumes of crystalloids may leak more easily across a damaged endothelium and magnify extravascular lung water, whereas other investigators believe that extravasation of colloids may be even more detrimental, because
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colloids may persist in the interstitial space for long periods as a result of their greater size. The best current recommendations include maintaining adequate but not excessive intravascular volume and carefully monitoring the animal for progression of respiratory difficulty [7–9]. Diuretics, such as furosemide, should be avoided in an animal with hypovolemia, despite the presence of adventitial lung sounds. The clinician is urged to remember that pulmonary crackles signify fluid rather than being specific for pulmonary edema caused by vascular overload. Pneumonia Pneumonia is both a common presenting complaint and a common development in hospitalized dogs. Pneumonia is quite rare in cats. Most frequently, pneumonia in dogs develops as a result of aspiration, although communityacquired fungal and hematogenous causes are also possible. Clinical findings often include alveolar infiltrates on thoracic radiographs, cough, fever, and lethargy. Some dogs have concurrent megaesophagus, laryngeal paralysis, or a history of extreme weakness or vomiting. Cytologic evaluation of airway secretions, which may be obtained by performing a tracheal wash, can document an inflammatory response. Treatment of pneumonia should include eliminating the underlying cause if possible, using appropriate antibiotics, providing supplemental oxygen as needed, and performing physiotherapy (eg, nebulization with coupage) [10,11]. Antibiotic therapy is ideally chosen based on bacterial culture and sensitivity testing of fluid samples from tracheal wash. Broad-spectrum antibiotics should be initiated as soon as pneumonia is identified and appropriate samples for culture have been obtained while awaiting receipt of culture results (Table 2). For a community-acquired pneumonia thought to be due to Bordetella bronchiseptica, a recent microbiologic survey suggests that most isolates are susceptible to tetracycline, doxycycline, enrofloxacin, and amoxicillin/clavulanic acid [12]. In endemic areas, fungal pneumonias (blastomycosis, histoplasmosis, and coccidiomycosis) may result in moderate to severe pulmonary disease. Table 2 Antibiotics used in treatment of pneumoniaa Antibiotic Ampicillin Cefazolin Gentimicin Enrofloxacin Metronidazole
Dose (mg/kg) 22 every 6 hours 22 every 8 hours 5–6 every 24 hours 2.5–10 every 12–24 hours 10 every 8 hours
Route IV IV IV IM, IV, PO IV
Grampositive
Gramnegative
þþþ þþþ
þ þþ þþþ þþþ
þþþ
Anaerobes þþþ
þþþ
Abbreviations: IV, intravenous; IM, intramuscular; PO, orally; þ, positive. a Many other individual antibiotics and combinations may also be used. Ideal antimicrobial therapy is based on bacterial culture and sensitivity data.
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In critically ill hospitalized dogs, therapy is often begun pending bacterial culture and sensitivity results with intravenous combinations like ampicillin and enrofloxacin or cefazolin, gentamicin, and metronidazole. In hospitalacquired infections expected to be resistant, antibiotic choices may include imipenem, amikacin, or cefoxitin. Nebulization and coupage are often used as adjuvants in therapy of pneumonia, although no controlled trials exist in the veterinary literature reporting their benefit. Cats with suspected pneumonia should also be treated with intravenous antibiotics and supplemental oxygen as required. It is not uncommon for cats that are suspected radiographically of having pneumonia to have congestive heart failure and pulmonary edema.
Acute lung injury and acute respiratory distress syndrome Acute lung injury and acute respiratory distress syndrome are terms that are applied to human beings with respiratory distress. These terms have recently been applied to animals [13,14,33]. These conditions are defined as clinical syndromes of respiratory distress characterized by the presence of an antecedent event (eg, trauma/sepsis), the development of bilateral alveolar infiltrates on thoracic radiographs, decreased pulmonary compliance, and the absence of congestive heart failure (as evidenced by pulmonary capillary wedge pressure of <18 mm Hg) [15]. Differentiation of ALI and ARDS in people is based on the presence of these criteria and assessment of the ratio of PaO2 to the fraction of inspired oxygen (FiO2), with a value of <300 equal to ALI and a value of <200 equal to ARDS. No consensus statement has yet been produced by the American College of Veterinary Emergency and Critical Care to apply to animals, although it seems likely that similar criteria will be proposed in dogs. It is less clear as to whether cats develop ALI or ARDS. Certainly, respiratory distress does develop in the critically ill cat, but it seems that this species is more prone to volume overload/congestive heart failure or the development of pleural effusion rather than to ALI or ARDS. Pharmacologically, no specific therapies have been found to be helpful in the treatment of human beings with ARDS. Altered mechanical ventilatory strategies seem to be beneficial, and many active research programs exist to try to elucidate both the pathogenesis and therapy for ARDS [15]. Current veterinary recommendations include careful monitoring of the patient at risk, limiting peak pressures in ventilated animals, and treating aggressively for the underlying cause (Fig. 2).
Pulmonary thromboembolism PTE is a condition that has been recognized with increasing frequency in critically ill dogs. Cats have been identified with PTE, but it is exceedingly
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Fig. 2. A Labrador Retriever receiving mechanical ventilation for support of acute lung injury after being hit by a car.
rare [16,17]. PTE may be a challenging condition to identify successfully in dogs as well as in people, because the clinical signs may vary from vague to peracute death. In practice, anticipation of the patient at risk for PTE is important. Risk factors that have been documented in dogs with PTE include immune-mediated hemolytic anemia, Cushing’s syndrome, sepsis, and neoplasia [18,19]. Pharmacologic interventions used in the treatment of PTE include anticoagulant therapy and thrombolytic therapies (Table 3). All animals with PTE also benefit from standard hemodynamic and respiratory support. Anticoagulant therapies used in animals include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and warfarin. UFH has been the most widely used anticoagulant in veterinary patients because of its widespread availability and low cost. Both forms of heparin act primarily to limit the eventual conversion of fibrinogen to fibrin by accelerating the action of antithrombin III in inhibiting activated coagulation factors (II, IX, X, XI, and XII). In people, heparin has been associated with the development of heparin-induced thrombocytopenia (HIT). This is an acute onset of marked thrombocytopenia in an individual receiving heparin therapy. Affected patients have a paradoxic tendency for thrombosis instead of hemorrhage. It is thought to be an immune-mediated reaction, with antibodies formed against heparin and complexed with platelet factor 4 [20]. LMWH differs from UFH by being more specific for factor X, having a more predictable anticoagulant effect at a given dosage, and requiring less routine monitoring [21,22]. LMWH also seems less likely to result in the development of HIT. The most often used LMWHs are enoxaparin (Lovenox) and dalteparin (Fragmin) LMWHs are not yet widely used in veterinary medicine because of higher cost and less clinical experience, although a recent
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Table 3 Pharmaceutic agents used in the medical management of pulmonary thromboembolisma Drug
Dose
Mechanism of action
Unfractionated heparin
10–20 IU/kg/h CRI to 300 IU/kg SC every 6 hours
Low-molecular-weight heparin Aspirin Streptokinase
100 IU/kg every 12 hours
Enhance the activity of AT in inhibiting activated clotting factors Same, more predictable efficacy Antiplatelet Thrombolytic
Warfarin
0.5–2.0 mg/kg every 24 hours 25,000 IU for 1 hour, then 10,000 IU/h 0.05–0.2 mg/kg
Anticoagulant, requires careful monitoring
Abbreviations: CRI, continuous rate infusion; AT, antithrombin; SC, subcutaneous. a Pulmonary thromboembolism is a notoriously difficult disease to identify and treat. Dosage are current best recommendations but are not derived from controlled trials.
study reported on the pharmacokinetics of a LMWH in dogs [23]. UFH given as a treatment for PTE should be dosed to result in prolongation of the activated partial thromboplastin time (aPTT) of 1.5 times to twice baseline values. In hypercoagulable animals, this often requires high doses (250–500 IU/kg administered subcutaneously every 6 hours) of UFH. As a result of the properties of the LMWH preparations, prolongations of the aPTT do not occur at therapeutic doses, but patients may be monitored by following clinical signs or by assessing for anti-Xa activity. Warfarin acts to prevent the formation of vitamin K–dependent coagulation factors (II, VII, IX, and X) [24]. Warfarin also inhibits the production of the anticoagulant protein C. The half-life of protein C is shorter than that of the procoagulant factors, so initial overlap with heparin is recommended to prevent a hypercoagulable state. In people, a warfarin-associated skin necrosis has been described, but this has not been documented in animals. Warfarin therapy is challenging in small animals. The prothrombin time (PT) should be followed every 48 hours until stable for several days, then every 3 days for 1 month, and then once a week or every other week. The desired end point is a PT of 1.5 times to twice the baseline value. It is common for the PT to prolong or shorten in dogs without a clear-cut explanation, occasionally severely enough to result in life-threatening hemorrhage. In human medicine, differences in PT reagents are adjusted for via calculation of the international normalized ratio (INR), but this is not frequently performed in animals. It is prudent to use the same machine or laboratory for patient monitoring to try to improve the likelihood of a successful outcome. Thrombolytic agents, such as streptokinase or tissue plasminogen activator (TPA), have been used in people with PTE, but no clinical reports yet exist in dogs. Thrombolytics act to accelerate the fibrinolytic pathways by
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either directly or indirectly activating plasminogen to plasmin. Streptokinase has been most widely evaluated in animals [25–27]. Its action results from binding directly to plasminogen and creating a component that stimulates the conversion of other molecules of plasminogen to plasmin. Streptokinase is not specific for plasminogen bound to fibrin and also acts to deplete fibrinogen and other procoagulant factors; thus, at least theoretically, it may result in an increased hemorrhagic potential. TPA is more specific and has an increased ability to activate the plasminogen that is associated with a thrombus. Indications and guidelines for the use of thrombolytics in dogs with PTE are not yet defined. It seems prudent to consider their use in animals that are hemodynamically unstable from large PTE. At our hospital, the use of streptokinase for large PTE in dogs has not yet been successful; however, this may reflect patient selection and the time frame of intervention rather than failure of the thrombolytic agent. Surgical removal of the clot (thromboembolectomy) has also been recommend in some animals, but, again, clear-cut successful outcomes are rare. Pulmonary edema Pulmonary edema is defined as excessive lung water. Pulmonary edema may develop in dogs as a result of either cardiogenic or noncardiogenic causes. Cardiogenic edema (caused by left-sided congestive heart failure) is more common. Heart failure results in the accumulation of pulmonary edema because of increased hydrostatic pressure when pulmonary venous hypertension develops as a result of increases in left atrial pressure. Left atrial pressure may increase for a variety of reasons, including congenital conditions (eg, patent ductus arteriosus) or acquired conditions (eg, chronic valvular disease or cardiomyopathy). Cardiogenic pulmonary edema is usually recognized radiographically as a heavy interstitial to alveolar pattern, often in association with cardiomegaly and pulmonary venous congestion. Dogs often first develop edema in the perihilar region, and as edema develops, it becomes diffuse. Cats often develop patchy alveolar infiltrates rather than edema in specific locations. Treatment of cardiogenic pulmonary edema includes rest, supplemental oxygen, vasodilators. and diuretic therapy (Table 4). Furosemide is the initial diuretic of choice, although other diuretics often must be added, such as spironolactone or hydrochlorothiazide. In an emergency situation, furosemide is administered either intravenously (preferable) or intramuscularly at 2 to 4 mg/kg. This can be repeated up to once an hour for 4 hours and then decreased to two to four times a day. Excessive use of diuretics may result in marked prerenal azotemia and subsequent anorexia and lethargy. Vasodilators are useful in the treatment of heart failure by reducing both afterload and preload. Commonly used vasodilators in the emergency setting include topical nitroglycerin paste and a continuous rate infusion
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Table 4 Pharmaceutic agents used in the medical management of pulmonary edemaa Drug
Dosage
Route
Mechanism
Furosemide Spironolactone Hydrochlorothiazide Enalapril Nitroprusside Nitroglycerin Hydralazine
1–4 mg/kg 1–2 mg/kg every 12 hours 1–2 mg/kg every 12 hours 0.5 mg/kg every 12–24 hours 0.5–5.0 lg/kg/min 0.125–0.25 in per 10 kg 0.5–1.0 mg/kg every 12 hours
IV, IM, PO PO PO PO IV Topically PO
Diuretic Diuretic Diuretic ACE inhibitor Balanced vasodilator Venodilator Arterial vasodilator
Abbreviations: IM, intramuscularly; IV, intravenously; PO, orally; ACE, angiotensin converting enzyme. a Often, a balanced approach results in the best patient outcome.
of nitroprusside. Nitroprusside is a potent vasodilator, so its use requires an infusion pump and close monitoring. Angiotensin converting enzyme (ACE) inhibitors are also useful for the long-term management of congestive heart failure. Occasionally, intravenous enalaprilat has been used in severe acute cases, but there is little information available in critically ill animals. The ultimate long-term therapy for heart disease depends on the underlying cause but typically include diuretics and vasodilators. Medications to control rate, such as b-blockers, calcium-channel antagonists, or digoxin, are often used as well. Noncardiogenic pulmonary edema may also result in pulmonary infiltrates and respiratory distress. Noncardiogenic pulmonary edema is a high-protein fluid that typically develops after another insult. Common causes of noncardiogenic pulmonary edema include seizures, upper airway obstruction, and electrocution, although a number of diseases have been linked to the formation of noncardiogenic edema [28]. ALI and ARDS are forms of noncardiogenic edema. Thoracic radiographs from affected dogs typically have a dorsal caudal distribution to the pulmonary infiltrates, although in severe cases, the alveolar infiltrates may affect all lung lobes. Therapy of noncardiogenic edema is directed primarily at supportive care and treatment if needed for the underlying disease.
Pleural effusion Pleural effusion may also result in the development of moderate to marked respiratory distress. Affected animals may be presented as an emergency or may be chronically affected. Pleural effusion is a sign rather than a specific diagnosis, so care must be taken to identify fully the underlying cause. Management of the pet with pleural effusion is directed toward removing the effusion and then tailoring treatment to the final diagnosis. Samples of the fluid should be saved for cytologic evaluation and bacterial culture if indicted. Causes of pleural effusion commonly include congestive
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heart failure (particularly in cats), neoplasia, pyothorax, pneumothorax, hemothorax, and chylothorax as well as less common causes, such as lung lobe torsion, pancreatitis, or diaphragmatic hernia. Pharmaceutic agents used in the treatment of pleural effusion include diuretics, antibiotics, chemotherapy, vitamin K/fresh–frozen plasma, rutin, and others.
Allergic airway disease Allergic lower airway disease occurs in cats and, less commonly, in dogs. Mediators of inflammation in people (and likely small animals) include mast cells, eosinophils, and activated T lymphocytes. Clinical signs of cats with lower airway disease include coughing, which may be productive, and respiratory distress. Some cats never develop overt respiratory difficulties beyond coughing, whereas others are presented as emergencies with extreme respiratory distress. Physical examination of cats with severe respiratory distress from lower airway disease frequently documents the presence of pronounced crackles on thoracic auscultation and a normal to elevated rectal temperature. Thoracic radiographs may appear normal, or they may document hyperinflation and a prominent bronchial pattern. Some cats have right middle lung lobe collapse or signs of cor pulmonale. Typically, cats respond rapidly to supportive care and anti-inflammatory therapy. A transoral tracheal wash is commonly performed when the patient is stabilized to evaluate for cytologic abnormalities or signs of infectious or parasitic disease. Bacterial colonization and/or infection may be identified on the basis of a positive airway culture. Antibiotic therapy is warranted in individual cats based on sensitivity data, although it should be remembered that the larger airways in the cats are normally not sterile. Common bacterial species cultured from the airways of apparently healthy cats include Pasteurella spp, Staphylococcus spp, Streptococcus spp, Escherichia coli, and even Pseudomonas spp [29]. Mycoplasma spp have the ability to damage the airway epithelium, so a positive culture for Mycoplasma spp may have more clinical relevance than other isolates and should be treated with appropriate antibiotics. Treatment of the asthmatic cat includes glucocorticoids (prednisone or long-acting reposital preparations) and bronchodilators (Table 5). Cats with documentation or the potential for parasites should also be dewormed. Commonly used bronchodilators include theophylline (sustained release product at night) and b2-agonists like terbutaline or inhaled albuterol. Inhaled b2-agonists may be given via an Aerochamber and associated mask. For most cats, the second smallest size works well. Albuterol (100 lg per puff [200-dose vial]) has immediate effect and typically lasts 4 hours. The usual dose is two puffs twice a day, but it may be given every 30 minutes for up to 4 hours in a crisis. For cats that seem to require daily prednisone, inhaled steroids maybe beneficial. Fluticasone (Flovent, 220 lg per puff) has been used in cats. Theoretically, there is no systemic absorption, so
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Table 5 Pharmaceutic agents used in the medical management of allergic airway diseasea Drug
Dosage
Prednisone
5 mg PO per cat every 12 hours, taper 10–20 mg per cat SC every 2–4 weeks
Methylprednisolone acetate Terbutaline
Theophylline
Zafirlukast (Accolate)
0.625–1.25 mg per cat PO every 8–24 hours 0.01 mg/kg IV or SC every 8 hours 5 mg/kg PO every 8–12 hours
5 mg per cat PO every 12–24 hours
Mechanism of action/ comments Anti-inflammatory, effective, inexpensive Good for the ‘‘hard-to-pill’’ cat, but long-term effects possible b2-agonist
Methylxanthine long-lasting products occasionally available Leukotriene receptor antagonist
Abbreviations: PO, orally; SC, subcutaneously; IV, intravenously. a Also see text for description of aerosol medications.
long-term prednisone side effects are unlikely. Recommended doses include 1 puff per day if asthma is judged to be mild or twice daily in more severe cases. Inhaled steroids seem to take 7 to 10 days to reach efficacy, so a short course of oral prednisone (7–14 days) is required when beginning therapy. Always administer inhaled steroids after bronchodilators so that bronchoconstriction does not interfere with lung distribution of the drug. The procedure for administering inhaled medications includes priming the spacer before first use and after each cleaning by injecting four to five puffs into the chamber. This allows particles to adsorb to the inside of the chamber so that the dose gets to the patient. Wait 15 minutes after priming before using. Apply the required dose into the chamber away from the cat. Apply the mask to the cat’s face gently for 10 breaths or 30 seconds. There is a one-way valve, so the drug only comes out if the cat breathes it. Wait 5 minutes between administering doses. Try to avoid treating the eyes because of the potential for corneal ulceration. The chamber must be cleaned once a week with warm soapy water. Most cats tolerate the face mask well, and it is often easier to use than oral medications. Proposed treatments include leukotriene antagonists (eg, Accolate), cyclosporine A, anti-interleukin 5 antibodies, or cyproheptadine. The prognosis for asthma is usually good, although some cats have recurrent bouts and require frequent medications. Allergic lung disease is less common in dogs than in cats. Pulmonary infiltrates with eosinophilia (PIE), including eosinophilic bronchitis or pneumonitis and eosinophilic pulmonary granulomatosis, have been reported in dogs [30,35]. Clinical signs of affected dogs include cough, respiratory distress,
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and lethargy. Substantial pulmonary infiltrates are usually observed on thoracic radiographs. Differential diagnoses typically include bacterial pneumonia, heartworm, and neoplasia. Affected dogs often have a history of prior antibiotic therapy with little or no improvement. Collection of respiratory samples for cytologic evaluation may be made via a transoral tracheal wash (TTW) or via a transtracheal aspirate (TTA). When a specific cause is identified, eosinophilic pneumonitis has most commonly been associated with occult heartworm infection in dogs. It is proposed that microfilaria become trapped in the pulmonary circulation and then become surrounded by neutrophils and eosinophils. Affected dogs in one report had a 1-week to 6-month history of progressive coughing, dyspnea, and exercise intolerance. All dogs had a peripheral eosinophilia and a preponderance of eosinophils (60%–80%) on TTA cytology [31]. Pulmonary infiltrates consisting of diffuse homogeneous interstitial, peribronchial, and alveolar patterns were detected on thoracic radiography. There was a rapid resolution of clinical (within 24 hours) and radiographic (3–5 days) signs after therapy with prednisone (1–2 mg/kg once a day). Some dogs with developing (early) heartworm infections acquire eosinophilic pneumonitis, and repeat heartworm testing in 3 to 6 months is required to confirm heartworm disease as the cause. Eosinophilic pneumonitis has also been associated with other parasitic infections, such as ascarid migration or lungworm. Eosinophilic pulmonary granulomatosis is the most severe form of pulmonary hypersensitivity. A large study by Calvert et al [32] reported on 11 dogs over an 8-year period. In this report, the dogs ranged in age from 1 to 11 years. Clinical signs included coughing, dyspnea, and lethargy. Seven dogs were identified as having Dirofilaria immitis infections. Radiographic changes included bronchial, interstitial, alveolar, and nodular patterns. Hilar lymphadenopathy was present in some dogs. Dogs were treated with a variety of immunosuppressant agents, including glucocorticoids, azathioprine, and cyclophosphamide. Most dogs initially showed improvement but then usually died or were euthanized within 1 year. Heartworm infection is a clear trigger for allergic lung disease and should be excluded in affected dogs. Most dogs respond to treatment with doses of glucocorticoids that are in an antiinflammatory to immunosuppressive range. Some dogs may require intermittent therapy to remain asymptomatic. Dogs affected with granulomatous changes have a much worse prognosis for long-term survival. Summary Successful pharmacologic management of most respiratory diseases is possible. All moderately to severely affected animals benefit from rest and supplemental oxygen. Careful identification of the underlying cause as well as an understanding of the pathophysiology behind various diseases is essential to successful patient outcome.
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