Inhalation Therapy for Equine Airway Disease

Editor's Note: N. Edward Robinson, BVetMed, PhD, is the Matilda Wilson professor in large animal clinical sciences at Michigan State University. He is one of the world's leading researchers in equine airway disease, and he has lectured on this topic around the world. Following is information from Robinson on the latest in inhalation therapy for equine airway disease.

In horses, inhalation therapy is suitable for treating heaves (recurrent airway obstruction) and inflammatory airway disease (IAD). Heaves is an allergic response to organic dusts in the environment. Usually these dusts originate in poorly cured or dusty hay, but horses can also respond to dusts in pastures or tree pollens. Like people, some horses are more susceptible to these antigens than others. When the heaves-susceptible horse inhales dusts, his airways become inflamed and neutrophils invade the airway lumen, or cavity. Neutrophils are the warriors of the white blood cells. They evolved to respond rapidly to infection and "eat" things the horse's body considers invaders. The role they play in heaves is not clear.

However, neutrophil products initiate over-proliferation of the mucus cells in heaves-susceptible horses, and that can lead to excessive mucus secretion. At the same time, the airway smooth muscle becomes hyperresponsive to stimuli (such as allergens and dusts) so that if the particulate (dust) load is high enough, bronchospasm develops. Bronchospasm is constriction of the smooth muscles around the small airways that restricts airflow and oxygen exchange; this tightening of the airways means that not enough air gets through. This leads to the respiratory distress that is typical of heaves.

Many heaves-susceptible horses can have significant airway inflammation even without signs of respiratory distress. This inflammation might be enough to maintain excess mucus secretion, but not to cause bronchospasm. So, the absence of obvious distress in a horse with a history of heaves doesn't mean his disease is under control.

The airway epithelium (lining) can stay in a pro-inflammatory (easily irritated) condition even when the horse is taken from the stable and put in pasture. The horse with heaves is therefore very like an asthmatic human.

The term IAD refers to a syndrome in which the horse does not show respiratory distress at rest, but on examination of the respiratory system, accumulations of mucus and inflammatory cells are found within the trachea. If intense exercise is demanded from affected horses, such as racehorses, IAD can be associated with reduced performance. In pleasure horses, IAD might be undetected or simply cause bouts of coughing at the start of exercise.

The cause of IAD is a subject of investigation. In racehorses, there is increasing evidence that IAD is associated with recurrent infections by Gram-positive organisms (bacteria identified by a particular laboratory stain test), particularly Streptococcus bacteria. In the older performance or pleasure horse, the cause of IAD is unknown, but environmental causes are suspected. The connection between IAD and heaves is currently unknown.

Why Inhalation Therapy?

Inhalation therapy delivers a high concentration of drug where it is needed--in the airway. Achieving similar concentrations in the lung by systemic administration (i.e., intravenously) requires that the whole body be exposed to relatively high concentrations of drugs that can cause side effects. This is particularly true with the two groups of drugs generally used for inhalation therapy--bronchodilators and corticosteroids.

Anticholinergic (block acetylcholine released from parasympathetic nerves) bronchodilators can't be given repeatedly by
systemic administration because they cause immobility of the gut (possibly leading to colic) and rapid heartbeat. Beta 2-adrenergic agonists (the most effective bronchodilators available) at high doses cause excitement, sweating, and tachycardia. The untoward effects of systemic corticosteroids include increased susceptibility to infections, and possibly laminitis.

When inhalation therapy is used, the total dose delivered to the body is only a fraction of that given during systemic therapy. In addition, some of the drugs used for inhalation are designed to be poorly absorbed out of the lung or are metabolized by the liver very rapidly and thus excreted rapidly, so they don't affect the rest of the body.

Administration

Medications approved for inhalation therapy in humans are packaged in metered dose canisters and generally marketed in some sort of device such as a metered dose inhaler (MDI) that can be used for inhalation through the mouth. The MDI contains drug in a propellant that when activated releases a standard dose in a particle size that reaches the lower airways.

To administer inhalation therapy to horses, one must couple the MDI to a delivery device attached to the horse's nostrils or face. Two devices currently are available, the Equine Aeromask and the EquineHaler. The Equine Aeromask has been available for several years, but the EquineHaler is a new device for administration of aerosol drugs to horses.

In horses, it is impossible to coordinate release of medication with inhalation, so the spacer provides a reservoir in which medication is held until a horse takes his next breath. Another advantage of the spacer is that it lets larger particles sediment out so that the horse inhales only the small particles that reach the distal airways.

To give drugs with the Aeromask, the mask is strapped to the horse's face and drug is administered into the spacer. In contrast, the EquineHaler does not have to be attached to the horse's face. It consists of a flexible cone designed to cover one nostril of the horse. The cone is attached to a plastic spacer with valves through which the horse can inhale. The MDI attaches to the spacer. The nose cone is placed over the left nostril and a puff of medication is released into the spacer. After the horse has inhaled, additional puffs can be administered, but no more than one per breath. If the horse is shy about the noise made when the MDI is triggered, the device can be removed and the medication puffed into the spacer away from the horse, then the EquineHaler can be placed over the horse's nose. Delivery of medication is more effective if the opposite nostril is temporarily covered so that all inhalation occurs through the spacer device.

Studies in Newmarket have demonstrated the efficacy of the EquineHaler in delivering medications deep into the lung.

What Medications are Used?

Bronchodilators and corticosteroids are the medications usually delivered by inhalation. Bronchodilators relax airway smooth muscle and relieve bronchospasm, which is the main cause of airway obstruction in heaves. Corticosteroids reduce the inflammatory response that is the basis of the structural and functional abnormalities associated with heaves and IAD.

There are two classes of bronchodilator drugs, anticholinergics and beta 2-adrenergic agonists. The anticholinergic drug designed for administration by inhalation is ipratropium, which is designed to be poorly absorbed out of the lung. In human medicine, its use is not associated with the usual systemic effects of anticholinergic administration. A single dose of ipratropium is very effective for four to six hours in horses with heaves, but there have been no studies of the side effects associated with long-term administration.

Beta 2-adrenergic agonists are available in short-acting (albuterol, pirbuterol) and long-acting (salmeterol) forms. Short-acting bronchodilators take effect within minutes, but the duration of their effect is only one to two hours. The long-acting salmeterol does not take effect for 15-30 minutes, but it causes bronchodilation for up to 12 hours. Unfortunately, in the United States salmeterol is marketed as an inhaled powder, and there is no device available to deliver such powders to horses.

Anticholinergics and beta 2 agonists tend to work at different levels of the airways. Anticholinergics dilate primarily the larger airways, and beta 2 agonists are more effective in the peripheral airways. For this reason, combinations of ipratropium and albuterol are commercially available.

Corticosteroids available for inhalation include beclomethasone dipropionate, fluticasone propionate, triamcinolone acetonide, and budesonide. The efficacy of beclomethasone and fluticasone has been shown in horses with heaves. At therapeutic doses, beclomethasone administration is associated with a decrease in plasma cortisol, indicating feedback inhibition of the adrenal gland. However, there is no long-term effect on the adrenal gland because the adrenal response to ACTH is not affected.

Fluticasone is more potent and appears to cause less adrenal suppression than beclomethasone. This means that fluticasone can be used more safely for long-term use. A very recent investigation from Purdue University showed that fluticasone treatment speeded up the recovery of horses with heaves when they were taken away from their dusty environment.

Using Bronchodilators and Corticosteroids Together

Bronchodilators open airways and relieve airway obstruction. Generally, they do little to reduce the inflammation at the base of the structural and functional changes. For this reason, use of a bronchodilator alone is not ideal. Bronchodilators might need to be used in the following situations:

1. To rescue a horse with severe distress.

2. Just before exercise to dilate the airways and improve exercise tolerance in a horse with mild airway disease.

3. Immediately before administration of an inhaled corticosteroid. This will dilate the airways and allow more effective distribution of the inhaled corticosteroid.

While environmental management to reduce dust exposure generally removes the particulates that are the cause of airway inflammation, low-grade inflammation can persist even in the horse on pasture, eating soaked hay, or eating silage. Corticosteroids might be necessary under the following circumstances:

1. To control airway inflammation until environmental management can be effective.

2. To reduce the persistent low-level inflammation that can occur even with excellent environmental management.

3. To control exacerbations or airway inflammation that can occur seasonally.

How Much, and When?

The inhaled bronchodilators and corticosteroids available for use in people can be used for treatment of horses. If the dose for a horse has not been reported, do not simply adjust the dose based on the difference in body weight between a human and a horse. Humans inhale medications through their mouths, and a lot of drug is lost on the tongue and in the throat.
Because horses inhale the drug through their noses, less drug is lost. A good rule of thumb is to begin treatment with three times the human dose, then gradually increase the dose until the necessary effect is obtained.

Frequency of administration depends on the drug used. Inhaled corticosteroids are generally administered twice daily. As the horse responds to treatment, the dose can be reduced or given once daily. The horse owner must work with the veterinarian to tailor the dose to the individual horse's situation.

Short-acting bronchodilators are given as needed, but no more than every two to four hours. With beta agonists, excessive dosing will result in sweating and trembling. Salmeterol is given twice daily, and ipratropium every four to six hours.

Risks of Inhalation Therapy?

The therapeutic index of drugs given by inhalation is large (there little chance of overdosing the horse) and there is therefore little risk of untoward effects.

In humans, oral candidiasis (fungal infection) can occur when inhaled corticosteroids are given. This has not been reported in horses.

Racehorses and Show Horses

Although inhalation therapy delivers a much lower dose of medication than systemic treatment, inhaled drugs are detectable in blood and urine. Check the regulations of your racing or show jurisdiction before administering aerosol medications to horses that are racing or being exhibited.

Take-Home Message

Research into inhalation therapy for respiratory problems including IAD and heaves has advanced very rapidly in the past few years. While there are some problems associated with this type of treatment, including possible drug positives in competition horses, the ability to quickly and effectively alleviate respiratory distress in horses prone to these conditions should be considered the humane and right thing to do. 
Kimberly S. Herbert and N. Edward Robinson, BVetMed, PhD


References

Anon (2001) Chairperson's introduction: International Workshop on Equine Chronic Airway Disease, Michigan State University, 16-18 June 2000. Equine Veterinary Journal 33, 5-19.

Couetil, L.L.; Chilcoat, C.D.; DeNicola, D.B.; Clark, S.P.; Glickman, N.W.; Glickman, L.T. (2005) Randomized, controlled study of inhaled fluticasone propionate, oral administration of prednisone, and environmental management of horses with recurrent arirway obstruction. American Journal of Veterinary Research 66, 1665-1674.

Anon (2003) Workshop report: Inflammatory airway disease: defining the syndrome. Equine Veterinary Education 5, 81-82.

Derksen, F.J.; Olszewski, M.; Robinson, N.E.; Berney, C.; Lloyd, J.W.; Hakala, J.; Matson, C.; and Ruth, D. (1996) Use of a hand-held, metered-dose aerosol delivery device to administer pirbuterol acetate to horses with `heaves.' Equine Veterinary Journal 28, 306-310.

Derksen, F.J.; Olszewski, M.A.; Robinson, N.E.; Berney, C.E.; Hakala, J.E.; Matson, C.J.; and Ruth, D.T. (1999) Aerosolized albuterol sulfate used as a bronchodilator in horses with recurrent airway obstruction. American Journal of Veterinary Research 60, 689-693.

Henrikson, S.L.; and Rush, B.R. (2001) Efficacy of salmeterol xinafoate in horses with recurrent airway obstruction. Journal of the American Veterinary Medical Association 218, 1961-1965.

Lavoie, J.P. (2003) Heaves (recurrent airway obstruction): Practical management of acute episodes and prevention of exacerbations. In: Current Therapy in Equine Medicine 5, Ed: N.E. Robinson, Saunders, Philadelphia, 417-421.

Robinson, N.E.; Derksen, F.J.; Berney, C.; and Goossens, L. (1993) The airway response of horses with recurrent airway obstruction (heaves) to aerosol administration of ipratropium bromide. Equine Veterinary Journal 25, 299-303.

Rush, B.R.; Raub, E.S.; Rhoads, W.S.; Matson, C.J.; Hakala, J.E.; and Gillespie, J.R. (1998a) Pulmonary function in horses with recurrent airway obstruction after aerosol and parenteral administration of beclomethasone dipropionate and dexamethasone, respectively. American Journal of Veterinary Research 59, 1039-1043.

Rush, B.R.; Raub, E.S.; Thomsen, M.M.; Davis, E.G.; Matson, C.J.; and Hakala, J.E. (2000) Pulmonary function and adrenal gland suppression with incremental doses of aerosolized beclomethasone dipropionate in horses with recurrent airway obstruction. Journal of the American Veterinary Medical Association 217, 359-364.

Rush, B.R.; Worster, A.A.; Flaminio, M.J.; Matson, C.J.; and Hakala, J.E. (1998b) Alteration in adrenocortical function in horses with recurrent airway obstruction after aerosol and parenteral administration of beclomethasone dipropionate and dexa-methasone, respectively. American Journal of Veterinary Research 59, 1044-1047.

--Kimberly S. Herbert and N. Edward Robinson, BVetMed, PhD

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