Inhalant therapy in small animals (Proceedings)

Inhalant delivery of aerosolized medication offers a number of theoretical benefits including an enormous absorptive surface area across a permeable membrane, a low enzyme environment that results in little drug degradation, avoidance of hepatic first-pass metabolism, and reproducible absorption kinetics. When the target of inhaled medications is the respiratory tract itself, additional benefits include the potential for a high drug concentration directly at the site of disease with minimization of systemic toxicity, often at a fraction of the dose required if the same drug was administered through a systemic route.1 Because of these advantages, inhalant delivery of medication has gained widespread use for the treatment of airway diseases in people. There is an enormous body of evidence in the medical literature regarding inhalational drug therapy in people. In veterinary medicine, the literature on inhalant therapy is sparse, and what does exist more often focuses on aerosol drug delivery to horses than to small pet animal species.2 Regardless, aerosol delivery of medication has become popular for the treatment of dogs, and especially cats, with respiratory disease.

Although there are benefits to inhalant drug delivery, there are difficulties in using this route as well. Respiratory defenses are efficient at preventing particulates from reaching the lower airways so it should come as no surprise that only a small proportion of the administered medication reaches the lower airways; a significant amount of drug is lost in the delivery device or deposited in the oropharynx. Another difficulty is that most aerosol drug delivery devices are designed to be used by humans on a voluntary basis and some require purposeful respiration and breath holding. Adaptations of some devices facilitate their use in animals, and modified systems are now marketed for dogs and cats. Drug delivery by the aerosol route depends in part of respiratory depth and rate, tidal volume, and airflow rates, yet all of these may be negatively impacted by respiratory disease. Additionally, not all drugs are suitable for aerosol delivery, and drugs themselves (or preservatives contained in the drug preparation) may cause airway irritation and possible bronchoconstriction potentially worsening respiratory compromise.

Aerosol Delivery Systems

There are two very basic types of aerosol delivery systems in common usage; nebulizers and metered dose inhalers (MDI). The two are quite distinct devices, and have distinct uses. In general, nebulizers deliver much smaller particles allowing deeper respiratory penetration and provide fluid along with drug. MDI devices deliver drug primarily to the larger airways. There are more than 30 drugs available as MDI, including anti-inflammatory drugs and bronchodilators.

Nebulizers utilize compressors to generate relatively high air pressures and flow rates. Generally, there is a source of compressed air or oxygen, a well into which fluid/drug can be placed, and a baffle which when hit by the drug causes the creation of small particles. The basic nebulizer types include jet nebulizers and ultrasonic nebulizers. Modifications exist (eg, spinning disc nebulizers, vibrating mesh nebulizers) to improve delivery or modulate particle size. Nebulizers are available in portable sizes of a modest price, certainly suitable for use in veterinary hospitals and even practical for at-home use by owners. Cost can begin at under $100 for a good nebulizer unit (e.g., Nebulair Veterinary Portable Ultrasonic Nebulizer®, DVM Pharmaceuticals, and many portable products for the human market). Nebulized liquid can be administered to dogs and cats by face mask, by tent, in a closed aquarium type container into which the animal is placed, or into a tracheotomy tube. Any of these should be suitable for airway humidification via saline nebulization. In general, the more removed the particle generator is from the respiratory tract the more drug would be expected to be lost outside of the respiratory tract. For this reason, administration of drugs via nebulization would likely be more effective by mask than when simply administered into a tank containing the pet.

MDI are designed for at-home administration of aerosolized drugs and are the preferred routine route of delivery for glucocorticoid and bronchodilator medications in people with asthma. Particles delivered by MDI are larger than those created by nebulization, and thus do not penetrate as deeply into the respiratory tract. A traditional MDI consists of a mouthpiece and an actuator (holder) into which a canister of medication is inserted. Manually depressing the canister (actuation) results in the release of a single dose of medication (sometimes called a "puff"). People shake the canister, exhale deeply, insert the mouth piece, and simultaneously depress the canister and inhale as deeply as possible. They then hold their breath for as long as possible, exhale, and rinse the mouth and spit to remove the majority of the drug deposited in the oropharynx (only ~10% of each dose reaches the airways). Obviously, dogs and cats can't use a MDI in this way. Spacers devices designed to fit the MDI have allowed their adaptation for use in animals. Several types of spacers are available, from simple tubes inserted between the MDI and the mouth/nose to holding chambers with one-way valves activated by inhalation. Spacers were designed for young children or others with less than ideal coordination so that there is no requirement for simultaneous depression of the canister and inhalation. The spacer also has the advantage of allowing the largest particles to fall out and not enter the patient's mouth. In people, spacers actually improve drug delivery by ~10%, nearly doubling the amount of drug reaching the target site.

Until recently, most MDI used chlorofluorocarbons as propellants. Concerns about the ozone layer have led to new technologies, including alternate propellants and the use of dry powder inhalers (DPI). The DPI devices contain no propellant, but rely on the patient's inhalation through a reservoir containing the dry power dose. The most common types of DPIs are "discus" inhalers and "turbohalers". Because they do not use a spacer device and require a voluntary inhalation of a minimum force to deliver drug these devices may be less useful for small animal patients than MDI attached to spacers. The change to newer formulations of MDI has dramatically increased the cost of some medications formerly available as inexpensive generic prepeartions.

Indications for Nebulization

In small animal medicine, the predominant use of nebulizers has been the treatment of respiratory infection. Nebulizers have long been used to provide airway humidification or to administer antimicrobials directly into the respiratory tract. Mucolytic agents (e.g., N-acetylcysteine) have also been nebulized to treat animals with respiratory infection. Sterile saline nebulization without antimicrobial drugs for 15-30 minutes at a time, administered 3-4 times per day, is safe for the treatment of animals with bronchopneumonia. Although there are no scientific studies to demonstrate utility it is the author's impression that this is a useful therapy.

In people, it is common to include antimicrobials in nebulized solutions to treat severe bacterial pneumonia, particularly in patients with compromised defenses such as in patients with cystic fibrosis.3 There are drugs made especially for delivery by this route which do not contain potentially reactive additives or preservatives (e.g., Tobi®) but these preparations are prohibitively expensive. Veterinarians have used drugs made for parenteral administration in nebulized solutions for the treatment of pneumonia or other respiratory infections, including Bordetella bronchiseptica. Not all liquid antibiotics would be suitable for nebulization. The most frequently used class of antibiotics for nebulization are the aminoglycosides.

There are no well established guidelines for dosing or administration of formulations of drugs not made for aerosol use in veterinary patients. Typically, the dose that would be used systemically of a drug such as gentamicin or amikacin is diluted in saline to be delivered over a single 15-30 minute session with the nebulizer. It should be expected that a percentage of patients, perhaps 5 to 10%, may experience bronchoconstriction in response to such therapies. Pretreatment with bronchodilators may minimize potential reaction to drug carriers and improve drug delivery by the aerosol route. Bronchodilators may be administered by parenteral routes 15 minutes prior to nebulization or via an initial period of nebulization with the bronchodilator added directly to the nebulized fluid before the addition of the antimicrobial drug. Delivery of antimicrobials should not replace systemic antimicrobials in animals with pneumonia. Instead, it should be regarded as a complimentary therapy.

When nebulizers are used in the treatment of pets with contagious respiratory disease, the device itself must be kept meticulously clean to avoid causing iatrogenic respiratory infection. Extreme care should be given to cleaning, and disposable parts of the device should be disposed of when after animals with respiratory infection. Nebulization of a nosocomial Pseudomonas, for instance, could have devastating consequences for an animal with compromised respiratory function.

Indications for MDI

Metered dose inhalers (MDI) are the preferred route of delivery for most asthma medications in people, and they have been advocated for the treatment of feline bronchopulmonary diseases including asthma as well as for the treatment of dogs with chronic bronchitis or related airway disease. The use of inhaled steroids may be particularly helpful in minimizing systemic effects of glucocorticosteroids in asthmatic cats with co-morbid conditions such as diabetes mellitus or congestive heart failure. For any pet, concomitant use of inhaled and systemic steroids may allow minimization of systemic dosages. It is important to note that inhaled steroids take days or weeks to be effective, and thus should not be used for emergent treatment of asthmatic cats. Albuterol delivery by MDI can be useful during exacerbations of asthma, but should not replace parenteral administration of bronchodilators for cats in asthmatic crisis.

A variety of respiratory drugs are available as MDI, including corticosteroids (eg, fluticasone (Flovent)), short acting bronchodilators (eg, albuterol (Ventolin, Proventil)), and non-steroidal anti-inflammaotry drugs such as cromolyn or nedocromil. Some inhaled medications (including most long-acting bronchodilators and combination steroid/bronchodilators) come as DPI instead of MDI and are therefore not as useful in dogs and cats (eg, salmeterol (Serevent); fluticasone and salmeterol combination (Advair); formoterol (Foradil)). Even when the drug is available as a MDI, not all MDI fit the spacers typically used for dogs and cats (eg, triamcinolone acetonide (Azmacort)). It is important that the prescribing veterinarian is certain that the drug prescribed comes in a MDI that will work with the spacer device used by the patient.

There are spacer devices made specifically for veterinary patients (Aerokat®; aerokat.com; Nebulair Feline Mask, Small Animal Aerosol Chamber®, DVM Pharmaceuticals), or devices for people can be adapted for veterinary use. We use the OptiChamber® (Healthscan products, Cedar Grove, NJ; ~$20 not including face mask), but many other types work equally well. The devices for humans can be purchased OTC from any pharmacy. Face masks can be purchased (anesthetic masks ~$40) or fashioned. The MDI fits directly in one end of the spacer. To administer a dose, the animal is turned so that the head faces away and the tail faces into the person delivering the drug. The MDI is shaken, the face mask fitted over the animals face, and the canister depressed (the canister can be depressed immediately before placement of the mask if the noise scares the pet). The animal is then allowed to breathe into the mask for 7 to 10 breaths. In the author's experience, few owners have trouble administering the inhaled medication in this fashion.

Efficacy of Aerosol Drug Delivery in Small Animals

There are very few scientific studies reporting on the safety of efficacy of these aerosol therapies in pet animals. Although there are plentiful descriptions of aerosol therapy in textbooks and at continuing education meetings, and the author is frequently told by other veterinarians about satisfying results using aerosol therapies to treat airway disease, there is nearly nothing available in the way of controlled published studies. Bordetella bronchiseptica is susceptible to aminoglycosides delivered directly onto the respiratory epithelium4, and such administration of aminoglycosides results in little if any systemic drug absorption.5 A published abstract suggests better recovery of dogs with kennel cough treated with nebulized aminoglycosides but this study lacked a control population and there was no confirmation of bacterial infection.6 There is only a single published study demonstrating the ability to deliver particles to the lower airways in conscious, unsedated cats via aerosol, and this study used a nebulizer device designed to create smaller (and therefore more deeply penetrable) particles than would a MDI.7 Inhaled steroids (flunisolide 250 ug BID) reduced eosinophil percentage in cats with experimentally induced asthma but did not effect allergen specific IgE, airway hyperresponsivness, or blood lymphocyte phenotype.8 A recent study by the author found that much lower doses of steroid (44 ug fluticasone BID) was as effective as either 110 or 220 ug of fluticasone BID in reduction of experimentally induced asthma eosinophilic airway inflammation. Other studies demonstrated less endocrine effect with inhaled vs. oral steroids in cats and dogs (respectively) but did not evaluate therapy of any disease state.9,10 Because of the many questions still surrounding efficacy of drug delivery by aerosol, these drugs should generally be used as adjuncts in the treatment of animals with more than mild disease symptoms.

Aerosol Delivery Of Other Therapies

Other uses for inhalation therapy include treatment of lung cancer and systemic disease. Several reports describe the use of aerosolized drug delivery with chemotherapeutic or immunomoduling drugs in the treatment of spontaneous primary and metastatic cancers in dogs.11-13 Dogs have also been used as a model in the development of insulins to be delivered via a needle-free aerosol.14 Such insulin products should soon gain FDA approval for use in people (Exubera®, Pfizer, Nektar). Small animals have been used as models for other aerosol therapies, including treatment aimed at cardiovascular and hemodynamic perturbations (eg, inhaled nitric oxide for pulmonary hypertension), vaccination, or even gene therapy.15 As delivery systems are developed specifically for animal patients, and as our knowledge of the efficacy of this system of drug delivery grows, we are likely to use more and more inhalational therapy in small animal patients.

References

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2. Duvivier, DH, et al. Vet J, 1997;154:189.

3. Conway SP. Chronic Resp Dis 2005;2:35.

4. Bemis DA, et al. JAVMA 1977;170:1082.

5. Riviere JE, et al. JAVMA 1981;179:166.

6. Miller CJM et al, J Vet Intern Med 2003;17:386 (abstract).

7. Schulman RL, et al. AJVR 2004;65:809.

8. Reinero CR, et al. AJVR 2005;66:1121.

9. Cohn et al, JVIM 2008.

10. Reinero CR, et al JVIM

11. Hershey AE, et al. Clin Cancer Res 1999;5:2653-2659.

12. Khanna C, et al. Curr Cancer Drug Targets 2003;3:265.

13. Khanna C, et al.. Cancer 1997;79:1409.

14. Cherrington AD, et al. Diabetes 2004;53:877.

15. Laube BL. Resp Care 2005;50:1161.