Lower Airway Disease in Cats
Chronic bronchial disease in cats occurs most commonly in two forms: chronic bronchitis and asthma. Chronic bronchitis is defined as an inflammatory disorder of the lower airways that causes a daily cough, for which other causes of cough (including heartworm disease, pneumonia, lungworms, and neoplasia) have been excluded. Asthma is more loosely defined as a disorder of the lower airways that causes airflow limitation, that may resolve spontaneously or in response to medical treatment. "Airflow limitation" is generally the result of some combination of airway inflammation, accumulated airway mucus, and airway smooth muscle contraction. The symptoms of asthma can be dramatic, including acute wheeze and respiratory distress. Sometimes however, the only symptom of asthma-induced airflow limitation is a daily cough, and in human patients, this is referred to as "cough-variant" asthma.
Definitive diagnosis of asthma is usually based on specific pulmonary function studies that require patient cooperation. Because both disorders, bronchitis and asthma, can cause a daily cough as the only clinical sign, there are many times when it is not possible to distinguish bronchitis from asthma in the feline patient. Nevertheless, the diagnosis, prognosis and treatment options for both diseases overlap with great frequency. The purpose of this article is to review the use of inhaled medications to treat chronic bronchial disease in the feline species.
Inhaled corticosteroids and bronchodilators have been formally recommended to treat cats with bronchial asthma since at least 1993. Since then, a number of manuscripts have demonstrated the clinical effectiveness of fluticasone (Flovent) for treatment of cats with allergic rhinitis, bronchitis and asthma (both naturally occurring and experimentally induced). There have been no controlled published studies to determine the optimal dose or interval for use of Flovent® in cats. Thus, anecdotal experience by the author in reference to more than 300 small animal patients treated with fluticasone and albuterol over a period covering 1995-2006 will serve as the basis for this lecture. Dosage recommendations are based on these observations and recently published studies.
Aerosol administration of the medications to small animals relies on delivery of drug to the distal airways, which in turn depends on the size of the aerosol particles and various respiratory parameters such as tidal volume and inspiratory flow rate. Even in co-operative human patients, only approximately 10-30% of the inhaled dose enters the lungs. Recent published studies in cats have demonstrated that passive inhalation thru a mask and spacer combination (aerokat) is an effective method of delivering sufficient medication to be clinically effective.
Drugs for inhalation typically come in a rectangular metered dose inhaler (MDI) or a round "diskus" form. At the present time, only the MDI form is practical for use in animals. Recently, the propellants used for these medications have changed. The efficacy of the medication delivered by the newer propellant has not been affected by this change.
The most effective means of using an MDI involves coordination between inhalation and actuation of the device, something that is not reliable in most infants, small children, or animals. For this reason, an alternative involves the use of a spacer device and a mask specifically designed for cats. A small, aerosol-holding chamber is attached to an MDI on one end and a face mask on the other. The spacer is approximately the size of the inner cardboard roll used with toilet paper. The MDI supplies precise doses of the aerosol drug, and the holding chamber contains the aerosol so it can be inhaled when the patients inspires. The mask is designed to cover the nose of the cat.
The designers of the aerokat® spacer have shown that a holding chamber with a length of 11 cm and a diameter of >3.5 cm delivered almost all of a therapeutically "ideal" aerosol (i.e., aerosol of equivalent aerodynamic diameter <2.8 μm) produced by an MDI, and in some cases delivery was enhanced because of evaporation of large, suspended particles. The choice of spacer is relevant as cats have a tidal volume of between 5-10 cc inspired air per pound of body weight. Currently, only the aerokat® brand spacers (Trudell Medical Inc., Ontario CA) have been designed specifically based on the tidal volume characteristics and inspiratory inhalation pressures of the cat. Using these spacer devices, cats will inhale the majority of drug propelled into the spacer by breathing 7-10 times through the spacer- mask combination after actuation of the MDI. It is important to teach the owner to observe the pet actually breathing, because cats may initially hold their breaths when introduced to this form of treatment.
The procedure is not time consuming, but it can be helpful to acclimate the cat to the mask. When administering inhalation therapy, the MDI is first shaken to open an internal valve within the canister, and then it is attached to the spacer. The mask attached to the other end of the spacer is placed snuggly on the animal's nose or muzzle, and the MDI is pressed to release the medication into the spacer.
Fluticasone Propionate (Flovent)
The primary signs of chronic bronchial disease include cough and wheeze, and these signs are frequently the result of some degree of airway smooth muscle contraction. In clinical practice, it is usually difficult to distinguish between chronic bronchitis and asthma in coughing feline patients. It is tempting to treat coughing cats with suspected bronchial disease by using only bronchodilators to relax the airway smooth muscle contraction. Although this is a central method of treatment when acute signs develop, it is critically important to understand that human (and perhaps feline) asthmatic and bronchitic airways show evidence of chronic ongoing inflammation whether the patient is symptomatic or not. Therefore, treatment strategies are most successful if they are directed toward decreasing the underlying inflammatory component of the disease in addition to addressing the acute clinical signs of cough, wheeze, and increased respiratory effort.
The most effective long-term treatment of chronic non-infectious bronchial disease is systemically administered corticosteroids. This class of drugs is most likely to suppress airway inflammation, a process orchestrated by a network of proteins (cytokines) that act on circulating and structural airway cells. An important effect of steroids is to inhibit the synthesis of genes for cytokines that are important in generating airway inflammation.
The side effects of systemic steroid medications given for long periods are undesirable. Fortunately, inhaled steroids have become available that do not cause systemic side effects, and this therapeutic approach has greatly enhanced our ability to treat patients with bronchial disease (see below). The author begins treatment of bronchitic or asthmatic cats with signs that occur more than once weekly (without medication) with prednisolone, 1 to 2 mg/kg PO every 12 hours for 5-7 days. At this point, the majority of newly diagnosed cats have greatly diminished signs. The dose of steroids is then tapered slowly, over at least 2 to 3 months. This approach is much more effective than giving low doses of prednisone given for short periods and in response to acute flare-ups.
Patients with symptoms that occur less than once weekly (without medication) are generally not considered to have chronic active inflammatory airways. These patients may be safely treated with bronchodilators when needed.
Some cats are effectively and safely managed by administration of low dose, alternative day corticosteroids. However, most cats with chronic bronchial disease continue to wheeze/cough when treated in this conservative manner. For patients with a good response to higher doses of consistently administered systemic corticosteroids, inhaled corticosteroid therapy should be encouraged as an alternative to reduce adverse effects (see below).
The most commonly used inhaled corticosteroid is fluticasone propionate, a synthetic corticosteroid with an 18-fold higher affinity for the corticosteroid receptor when compared to dexamethasone. Binding of the steroid to this receptor results in a new molecular complex that leads to up or down regulation of the gene and its products. Fluticasone, like other corticosteroids, acts to inhibit mast cells, eosinophils, lymphocytes, neutrophils and macrophages involved in the generation and exacerbation of allergic airway inflammation by transcriptional regulation of these target genes. Preformed and newly secreted mediators including histamine, eicosanoids, leukotrienes and multiple cytokines are inhibited as well.
Fluticasone is a large molecule and acts topically within the airway mucosa. Because there is poor absorption across gut epithelium there is minimal oral systemic bioavailability. Plasma levels do not predict therapeutic effects. This explains the lack of systemic side effects, however it also suggests that clinically effective absorption into the airway mucosa is also delayed. Optimal clinical effects therefore may not occur for 1-2 weeks.
Flovent comes in three strengths; 44 µg, 110 µg and 220 µg per actuation. The author has found that 44 µg dosing twice daily does not consistently result in acceptable clinical responses. For cats with mild/moderate disease, 110 µg given twice daily frequently results in clinical responses equivalent to that achieved by administration of 5 mg oral doses of prednisone given BID. Cats with more serious disease may require 220 µg inhaled BID. Administration of fluticasone more than twice daily has not resulted in clinical benefit in the author's experience.
The use of bronchodilators including albuterol is based on the assumption that clinically significant bronchoconstriction is evident. Cats develop naturally occurring and clinically significant bronchoconstriction that in severe cases can be life-threatening Bronchodilator drugs can be beneficial to these patients. These drugs are classified generally as beta-receptor agonists, methylxanthine derivatives, or anti-cholinergics.
Albuterol is a selective beta2-receptor agonist that produces relaxation of the smooth muscle found principally in bronchial, vascular and uterine tissues. The exact mechanism by which activation of beta2 receptors results in smooth muscle relaxation is not totally understood, but it likely involves intracellular cAMP induced suppression of the kinase controlling myosin and actin interaction.
At usual doses, albuterol has little effect on beta1 receptors; hence, direct cardiostimulatory effects are minimal. However, albuterol should always be used with care in patients who may have increased sensitivity to adrenergic agents--in particular, cats with pre-existing cardiac disease, diabetes mellitus, hyperthyroidism, hypertension, or seizure disorders. All beta2-agonists may lower plasma potassium; hence, in at-risk patients receiving long-term albuterol therapy, it may be prudent to monitor serum potassium levels. In clinical practice and experimentally it is rare to find beta-2 agonist associated hypokalemia in cats.
When albuterol is used with other sympathomimetics, the risk of adverse cardiovascular effects increases, as does its concurrent use with digoxin, tricyclic antidepressants and monoamine oxidase inhibitors. These potential effects are more likely in patients with pre-existing cardiac disease, especially hypertrophic cardiomyopathy. Use with various inhalation anesthetics may predispose the patients to ventricular arrhythmias.
Albuterol is available as a tablet, syrup, and contained in various inhalants. The author has only used the inhaled form of albuterol in feline patients. The inhaled form of albuterol comes as a single strength 17g metered dose inhaler, and delivers 90 mcg per actuation of the device.
The pharmacokinetic profile of albuterol in cats has not been reported. When administered by inhalation to humans, albuterol produces significant bronchodilation within 15 min that lasts for 3-4 h. It is also well absorbed orally and may have bronchodilatory effects for up to 8 h. Anecdotal experience with this drug in clinical practice suggests a similar pharmacokinetic profile in cats. Albuterol can be used once daily prior to administering fluticasone or as needed for acute coughing and wheezing. In emergency cases, albuterol can be used q 30 minutes for up to 4 to 6 hours without serious side effects.
Albuterol undergoes extensive hepatic metabolism. After oral administration approximately 58-78% of the dose is excreted in the urine over 24 h, with 60% of the drug in an inactive form.
Rarely, adverse effects include mild skeletal muscle tremors and restlessness, which generally subside after 2-3 days.
The use of inhaled medications to treat asthma and bronchitis is considered the standard of care in humans and is now widely recommended for cats with chronic bronchial disease. This approach avoids many of the side effects previously seen in patients treated with systemic medications.