Inhalant therapy: Finding its place in small-animal practice

The use of inhaled respiratory medications in dogs and cats is becoming more common. 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 attaining a high drug concentration directly at the disease site with minimal systemic absorption and toxicity. Often, therapeutic effect can be achieved with only a fraction of the dose required for systemic delivery of the same drug.1

Because of these advantages, inhalant delivery of medication has gained widespread use for treating airway diseases in people. More than 30 drugs licensed for people are available for inhalation, including anti-inflammatory drugs and bronchodilators. An enormous body of evidence in the medical literature exists regarding the efficacy and toxicity of inhalational drug therapy in people. In veterinary medicine, the literature on inhalant therapy to treat naturally occurring disease is sparse. Regardless, aerosol delivery of medication has become popular for treating dogs and, especially, cats with respiratory disease.

CAUTIONS

Although inhalant drug delivery has many benefits, difficulties in using this route exist 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 marked amount of drug is lost in the delivery device or deposited in the oropharynx.1 In animals, another portion will be deposited on the fur, especially if an animal is placed in a tent or tank, and can be ingested through grooming.

Another difficulty is that most aerosol drug delivery devices are designed to be used by people 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 (e.g. Aerokat—Trudell Medical International; NebulAir Small Animal Chamber—DVM Pharmaceuticals; Breathe Easy—Jorgensen Laboratories).

Drug delivery by the aerosol route depends in part on respiratory depth and rate, tidal volume, and airflow rate, yet all of these may be negatively affected by respiratory disease. Additionally, not all drugs are suitable for aerosol delivery, and the drugs themselves (or preservatives contained in the drug preparation) may cause airway irritation and possible bronchoconstriction that could worsen respiratory function.

AEROSOL DELIVERY SYSTEMS

Two basic types of aerosol delivery systems are used in veterinary practice: nebulizers and pressurized metered dose inhalers (MDIs). The two are distinct devices with different uses. In general, nebulizers deliver much smaller particles, allowing deeper respiratory penetration, and provide fluid along with the drug.1 MDI devices deliver drugs primarily to the larger airways.

Nebulizers

Basic nebulizer types include jet nebulizers and electronic nebulizers. Modifications exist (e.g. spinning disk nebulizers, vibrating mesh nebulizers) to improve delivery or modulate particle size.

How they work. Jet nebulizers have a compressed air or oxygen source, a well into which fluid or a drug can be placed, and a baffle that when hit by the drug creates small particles. Jet nebulizers tend to be larger and sturdier than electronic nebulizers. Electronic nebulizers use membrane vibration to produce an aerosol and are much smaller since no air compressor is required. However, in my and other clinicians' experience, electronic nebulizers tend to malfunction more easily than jet nebulizers do.

Equipment needed. Both types of nebulizers are available in portable sizes at a modest price, suitable for use in veterinary hospitals and at home (e.g. Nebulizer compressor—Jorgensen Laboratories; NebulAir Veterinary Portable Ultrasonic Nebulizer or Vet Neb Express Nebulizer—various veterinary suppliers; nebulizers from human medical supply companies). The cost starts at less than $100 for a good nebulizer unit, and small ultrasonic or used jet nebulizers can be purchased for under $50. Alternatively, with a prescription, many respiratory supply pharmacies will rent nebulizers directly to clients and provide instructions for use.

1. Portable electronic nebulizers can be adapted for use in pets by attaching a face mask.

Nebulized liquid can be administered to dogs and cats by face mask (Figure 1), by tent (Figure 2), in a closed aquarium-type container into which the animal is placed, or through an endotracheal or tracheotomy tube. Any of these routes are suitable for airway humidification by saline nebulization. In general, the more removed the particle generator is from the respiratory tract, the more the drug will be lost outside of the respiratory tract. For this reason, drug administration by nebulization is more effective by mask than by simply administering the drug into a tank containing the pet. Tank or tent drug delivery also results in marked drug wasting, and drug deposition on the fur allows oral ingestion after grooming.

2. Sturdy jet nebulizers are better-suited to use with tanks or tents (as seen here) than electronic nebulizers are. These systems work well for delivery of saline nebulization but result in inefficient delivery of nebulized medications.

MDIs

MDIs are designed for at-home administration of aerosolized drugs and are the preferred devices to deliver maintenance glucocorticoid and bronchodilator medications in people with asthma or chronic obstructive pulmonary disease (COPD). Particles delivered by MDIs are larger than those created by nebulization and, thus, do not penetrate as deeply into the respiratory tract.1

How they work. A traditional pressurized MDI consists of a mouthpiece and an actuator (holder) into which a canister of medication is inserted. Manually depressing the canister (actuation) releases a single dose of medication (sometimes called a puff). People shake the canister, exhale deeply, insert the mouthpiece, 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 expectorate to remove most of the drug deposited in the oropharynx (only about 10% of each dose reaches the airways). Since dogs and cats cannot use a MDI in this way, spacer devices designed to fit MDIs have allowed MDIs to be adapted for use in animals.

Equipment needed. Several types of spacers are available, from simple tubes inserted between the MDI and the mouth and nose to holding chambers with one-way valves activated by inhalation. Spacers were designed for young children or debilitated adults with less than ideal coordination, so simultaneous canister depression and inhalation is not necessary. The spacer also has the advantage of allowing the largest particles to fall out and not enter the patient's mouth. In people, spacers improve drug delivery by about 10%, nearly doubling the amount of drug reaching the target site.1,2

Some spacer devices are made specifically for veterinary patients, such as Aerokat and NebulAir Small Animal Chamber. Other devices for people can be adapted for veterinary use, such as OptiChamber Advantage Valved Holding Chamber (Philips Respironics) (Figure 3). The devices for people can be purchased inexpensively over-the-counter from any pharmacy. Face masks can be purchased (anesthetic masks are about $40) or fashioned. The MDI fits directly in one end of the spacer.

3. Propellant-driven MDIs can be adapted for use in cats or dogs by attaching a spacer device and a face mask. Spacers made for people can be adapted (as seen here), but spacer and mask combinations are also available specifically for use in cats or dogs.

Recent developments. Until the last several years, most MDIs used chlorofluorocarbons as propellants. Chlorofluorocarbons are being phased out because of concerns about the ozone layer. The drugs previously used in MDIs must be reformulated either to use alternative, ozone-safe propellants or new technologies including breath-actuated inhalers.

Breath-actuated inhaler devices contain no propellant but instead rely on the patient's inhalation through a reservoir containing the drug dose. The most common types include dry powder inhalers, such as disk inhalers and turbohalers (Figure 4). These breath-actuated inhalers do not use a spacer device and require a voluntary inhalation of a minimum force to deliver the drug, so they are not readily adapted for dogs or cats.

4. Many drugs designed for inhalant delivery in people are available in breath-actuated delivery systems not readily adapted for administration to pets.

Because breath-actuated inhalers are not readily used by all people (e.g. infants) either, some drugs are still available in pressurized MDIs using alternative propellants such as hydrofluoroalkanes. The recent change to newer formulations of MDIs has dramatically increased the cost of some medications formerly available as inexpensive generic preparations.

WHEN AND HOW TO USE NEBULIZATION

Indications

In small-animal medicine, nebulizers have predominantly been used to treat respiratory infections. Nebulizers have long been used to humidify the airway or administer antimicrobials directly into the respiratory tract. Mucolytic agents (e.g. N-acetylcysteine) have also been nebulized to treat animals with respiratory infection but are not generally recommended because of irritation and bronchoconstriction after such therapy.3 Sterile saline nebulization administered three or four times a day is safe to treat animals with bronchopneumonia. Although no scientific studies demonstrate utility, it is my impression that saline nebulization is beneficial.

In people, it is common to include antimicrobials in nebulized solutions to treat severe bacterial pneumonia, particularly in patients with compromised defenses such as patients with cystic fibrosis.4 Some drugs that are made especially for delivery by this route do not contain potentially reactive additives or preservatives (e.g. tobramycin inhalation solution [Tobi—Novartis]), but these preparations are prohibitively expensive for dogs and cats. Veterinarians have used drugs made for parenteral administration in nebulized solutions to treat pneumonia or other respiratory infections, including infection with Bordetella bronchiseptica. Not all liquid antibiotics are suitable for nebulization. Aminoglycosides are the most frequently used class of antibiotics for nebulization.

Dosing

There are no well-established guidelines for dosing or administering drugs not made specifically for aerosol administration in veterinary patients. Typically, the total daily systemic dose of a drug such as gentamicin or amikacin is diluted in saline solution to be delivered in a single daily session with the nebulizer.

Rarely, patients may experience bronchoconstriction in response to such therapies. Pretreatment with bronchodilators may minimize potential reaction to drug carriers and improve aerosolized drug delivery. Bronchodilators may be administered parenterally 15 minutes before nebulization or by an initial nebulization period, with the bronchodilator added directly to the nebulized fluid before the antimicrobial drug is added. Common bronchodilator choices for nebulization are albuterol 0.5% solution for inhalation (5 mg/ml) or the premixed 2.5 mg/3 ml solutions. The concentrated drug should be diluted in about 3 ml sterile saline solution before administration. While a dose has not been established for nebulized albuterol in dogs and cats, the dose for children is 0.1 to 0.15 mg/kg with a maximum dose of 2.5 mg given up to a maximum of four times daily. Delivery of nebulized antimicrobials should never replace systemic antimicrobials in animals with pneumonia. Instead, nebulization should be regarded as a complementary therapy.

Prevent iatrogenic infections

When nebulizers are used to treat 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 discarded. Nebulization of a nosocomial Pseudomonas species, for instance, could have devastating consequences for an animal with compromised respiratory function.

WHEN AND HOW TO USE MDIS

Indications

MDIs are the preferred delivery device for most asthma and COPD medications in people, and they have been advocated for use in treating feline bronchopulmonary diseases, including asthma, as well as for treating chronic bronchitis or related airway disease in dogs.

The use of inhaled corticosteroids may be particularly helpful in minimizing the systemic effects of glucocorticoids in asthmatic cats with comorbid conditions such as diabetes mellitus or congestive heart failure. For any patient, concomitant use of inhaled and systemic corticosteroids may allow decreased systemic drug dosages. Keep in mind that inhaled corticosteroids take days or weeks to be maximally effective and, thus, should not be relied on for emergent treatment of asthmatic cats.

Albuterol delivery by MDI can be useful during exacerbations of asthma but will not always successfully replace parenteral administration of bronchodilators for cats in asthmatic crisis.

A variety of respiratory drugs are available as MDIs, including corticosteroids (e.g. fluticasone [Flovent—GlaxoSmithKline]), short-acting bronchodilators (e.g. albuterol [Ventolin—GlaxoSmithKline; Proventil—Schering-Plough]), and nonsteroidal anti-inflammatory drugs such as cromolyn or nedocromil. Some inhaled medations—including most long-acting bronchodilators and combination corticosteroid/bronchodilators (e.g. salmeterol [Serevent—GlaxoSmithKline], fluticasone and salmeterol combination [Advair—GlaxoSmithKline], formoterol [Foradil—Schering-Plough])—come as breath-actuated inhalers instead of MDIs and are, thus, not useful in dogs and cats. Even when the drug is available as an MDI, not all MDIs fit the spacers typically used for dogs and cats. For example, triamcinolone acetonide (Azmacort—Abbott Laboratories) has a built-in spacer, so it cannot be adapted to commercial feline spacer devices. Be certain that the drug you prescribe comes in an MDI that will work with the spacer device used by the client.

Dosing

To administer a dose, turn the animal so that its head faces away and its tail faces into the person delivering the drug. Shake the MDI and fit it into the spacer device, fit the mask at the other end of the spacer device over the animal's face, and depress the canister (Figure 3). When using some types of valved spacers, you can depress the canister immediately before placing the mask if the noise scares the pet. Then allow the animal to breathe into the mask for seven to 10 breaths. In my experience, few owners have trouble administering the inhaled medication in this fashion.

Appropriate dosage regimens have not been clearly established for drug delivery by MDI in dogs and cats. Commonly used medications include albuterol (108 μg albuterol sulfate/puff) for acute signs of bronchoconstriction. A single puff may be effective, or it can be given up to four times daily during an acute exacerbation. More than occasional use of albuterol can lead to paradoxic bronchoconstriction, and the need for frequent treatment (> three times a week) should prompt re-evaluation of other aspects of treating the disease.5 The most commonly used MDI corticosteroid is fluticasone propionate, available in 44-, 110-, and 220-μg/puff strengths. Although no evidence demonstrates the most effective dose, it is often used in the 110- or 220-μg strength as one puff twice daily.

EFFICACY OF AEROSOL DRUG DELIVERY IN SMALL ANIMALS

Few scientific studies report on the safety or efficacy of these aerosol therapies in companion animals. Although there are plentiful descriptions of aerosol therapy in textbooks and at continuing education meetings, there are few controlled published studies of animals with naturally occurring disease. The information that has been published about aerosol drug delivery in dogs or cats includes the following:

• Bordetella bronchiseptica was shown to be susceptible to aminoglycosides delivered directly onto the respiratory epithelium,6 and such administration of aminoglycosides resulted in little if any systemic drug absorption.7

• A preliminary study suggested better recovery in dogs with kennel cough treated with nebulized aminoglycosides, but this study lacked a control population, and bacterial infection was not confirmed.8

• One study demonstrated the ability to deliver particles by nebulization to the lower airways in conscious, unsedated cats by aerosol.9

• An inhaled corticosteroid (flunisolide 250 μg b.i.d.) reduced eosinophil percentage in bronchoalveolar lavage fluid in cats with experimentally induced asthma but did not affect allergen-specific IgE, airway hyperresponsiveness, or blood lymphocyte phenotype.10

• A dose of 250 μg fluticasone propionate given once a day for two weeks diminished airway inflammation and reactivity in a group of cats with mild chronic bronchitis.11

• A recent study found that much lower doses of a corticosteroid (44 μg fluticasone b.i.d.) were as effective as higher doses (either 110 or 220 μg fluticasone b.i.d.) in reducing experimentally induced allergic eosinophilic airway inflammation without measurable suppression of the hypothalamic-adrenal axis.12 Airway reactivity was not assessed.

• A positive response to corticosteroids delivered by MDI was reported in a small retrospective study of dogs with bronchitis.13

• Other studies demonstrate reduced suppression of the hypothalamic-pituitary-adrenal axis in dogs and cats treated with inhaled vs. oral corticosteroids, but these studies did not evaluate the therapeutic efficacy of the corticosteroids for the treatment of any disease.14,15

• A combination of ipratropium (an anticholinergic bronchodilator) with salbutamol reduced airflow limitation in cats with experimentally induced asthma.16

Because of the questions still surrounding the efficacy of drug delivery by aerosol, these drugs should generally be used as adjuncts in treating animals with moderate to severe signs of disease. Once signs have improved, inhalant therapy may replace medications traditionally administered by other routes.

AEROSOL DELIVERY OF OTHER THERAPIES

Other uses for inhalation therapy include treating lung cancer or systemic disease. Several reports describe the use of aerosolized drug delivery with chemotherapeutic or immunomodulating drugs in treating spontaneous primary and metastatic cancers in dogs.17-19 Dogs have also been used as a model in the development of insulins to be delivered via needle-free aerosol.20 Such an insulin product was FDA-approved for use in people (Exubera—Nektar) but was withdrawn from the U.S. market because of a lack of consumer demand. Recently, nebulized regular insulin was demonstrated to effectively lower blood glucose concentrations in five healthy domestic cats.21

Small animals have been used as models for other aerosol therapies, including treatment aimed at cardiovascular and hemodynamic perturbations (e.g. inhaled nitric oxide for pulmonary hypertension), vaccination, and even gene therapy.22 As delivery systems are developed specifically for animals and as our knowledge of the efficacy of this system of drug delivery grows, we are likely to use more inhalational therapy in small-animal patients.

Leah A. Cohn, DVM, PhD, DACVIM

Department of Veterinary Medicine and Surgery

College of Veterinary Medicine

University of Missouri

Columbia, MO 65211

REFERENCES

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