Efficacy of Inhaled Levalbuterol Compared to Albuterol in Horses with Recurrent Airway Obstruction

Abstract

Background

The (R)‐enantiomer of racemic albuterol (levalbuterol) has bronchodilatory properties whereas the (S)‐enantiomer causes adverse effects in human airways, animal models, and isolated equine bronchi. Levalbuterol is commercially available and improves pulmonary function of asthmatic patients with a longer duration of effect than albuterol.

Objective

To determine the dose at which inhaled levalbuterol produces maximal bronchodilatory effect (EDmax) and determine its duration of action in recurrent airway obstruction (RAO)‐affected horses in comparison to racemic albuterol.

Animals

Nine horses with inducible and reversible RAO.

Methods

Randomized, crossover trial. Horses were challenged with moldy hay to induce airway obstruction. Horses were treated with nebulized albuterol or levalbuterol chosen randomly. Pulmonary function testing (PFT) was measured before and for up to 3 hours after bronchodilatation challenge. Maximum change in transpulmonary pressure (DP _max) was measured to assess the dose effect and duration of action of each drug. After a 24 hours washout period, the bronchodilatation challenge was repeated with the second bronchodilator.

Results

The duration of effect was 60 minutes for albuterol and 120 minutes for levalbuterol. The dose of bronchodilator EDmax was not significantly different between albuterol and levalbuterol (EDmax = 125.0 [125–125 μg] and EDmax = 188 [125–188 μg] respectively; P = .068). The magnitude of bronchodilatation was not significantly different between the 2 treatments (61.1 and 59.9% decrease in DP _max for albuterol and levalbuterol respectively; P = .86).

Conclusions and clinical importance

Levalbuterol is as effective a bronchodilator as albuterol; although levalbuterol lasts twice as long as albuterol, its duration of action is still too short to make it practical for RAO treatment.

Abbreviations

C_dyn

dynamic lung compliance

DP_max

maximum change in transpulmonary pressure

ED50%

dose producing 50% decrease in DP_max

ED_max

dose producing maximum bronchodilation

IL‐4

interleukin‐4

IQR

interquartile range

PFT

pulmonary function testing

RAO

recurrent airway obstruction

R_L

lung resistance

Recurrent airway obstruction (RAO), also known has “heaves”, is an inducible and reversible chronic inflammatory airway disease commonly encountered in older horses in the northern hemisphere. An episode of acute RAO can be triggered by inhalation of dust from hay and the disease in horses has many similarities to asthma in humans.1, 2 Functional changes include increases in maximum transpulmonary pressure change (DP_max) and pulmonary resistance (R _L) and a decrease in dynamic lung compliance (C _dyn).3

Equine RAO is a disease that cannot be cured but can be managed with medical treatment (systemic or inhaled corticosteroids and bronchodilators) and environmental changes (decreasing dust exposure by modifying housing and diet). Some horses need continuous medical management because of the challenge of achieving appropriate environmental control. Aerosol treatment is considered the best approach because of its rapid onset of action and deposition of high concentration of medication in the peripheral airways while minimizing systemic adverse effects.

Bronchodilators are used commonly in horses with acute exacerbation of RAO as a rescue medication, as treatment in combination with corticosteroids or as a diagnostic tool.4 Albuterol, a short acting β₂‐adrenergic receptor agonist, is an effective bronchodilator that relieves acute airway obstruction by relaxing airway smooth muscle.5 Within 5 minutes after administration, pulmonary function is improved maximally. The effect, however, lasts only 30–60 minutes on average, making long‐term control of RAO impractical.4, 5 Albuterol is a racemic mixture containing equal concentrations of (R) – and (S)‐enantiomers. The (R)‐enantiomer, called levalbuterol, is responsible for the rapid bronchodilatory effect, decrease in wall edema, inhibition of mast cells, and decrease in eosinophilic migration to airways.6 The (S)‐enantiomer has been shown to have adverse effects in the human respiratory tract such as inducing airway hyper‐responsiveness, increasing production of histamine and interleukin‐4 (IL‐4) in mast cells and promoting activation of eosinophils.6, 7, 8 The (S)‐ enantiomer also causes airway hyper‐responsiveness and bronchoconstriction in isolated equine bronchi in vitro9, but, there is no report regarding the clinical effect of levalbuterol in horses. Levalbuterol is commonly used in human medicine because it improves pulmonary function and provides up to 6 hours of bronchodilatation.6, 10, 11, 12 However, recent evidence has shown no clinical benefit of levalbuterol versus albuterol in adult patients with asthma and chronic obstructive pulmonary disease (COPD).13 The purpose of our study was to compare the bronchodilatory effect as well as the duration of action of levalbuterol and albuterol in horses with an acute episode of RAO.

Materials and Methods

Study Design

All methods were approved by the Purdue University Animal Care and Use Committee.

Nine horses (3 geldings, 6 mares; age range, 9–24 years) owned by Purdue University and with a history of inducible and reversible RAO were involved in this randomized, crossover trial. All of the horses remained on pasture on a complete pelleted feed for at least 2 months before the trial to achieve clinical remission. The animals were transported to the research facilities and resided there for the duration of the trial. On arrival, a physical examination and pulmonary function testing (PFT) were performed.

The horses were housed in individual stalls bedded with wood shavings and fed complete pelleted feed as well as free choice hay placed in a hay net. In addition, they were exposed to moldy hay which was shaken 2 times a day for 3 minutes next to the horse's nose to increase dust exposure.4 A daily physical examination was performed, and a clinical score was assigned to every horse based on a scale that ranges from 0 to 21 as previously described.14 When the clinical score reached ≥10, PFT was performed. The horse was enrolled in the study if DP_max ≥ 15 cm H₂O. The PFT was performed at baseline followed by administration of the bronchodilator challenge, randomly chosen (racemic albuterol or levalbuterol). The bronchodilator was given in a stepwise fashion until maximum dilatation was achieved. The PFT was performed 5 minutes after each dose. The horse then was returned to the stall for a washout period of at least 24 hours. The second treatment was administered the next day if the same inclusion criteria were achieved and testing was repeated.

Pulmonary Function Test (PFT)

An esophageal balloon catheter¹ was placed to obtain measurements analogous to pleural pressure. The position of the catheter was estimated by measuring the distance between the horse's nostrils to mid thorax. The horse was placed in stocks with no sedation and an air‐tight mask² was fitted around the horse’ muzzle with the port of the mask holding the pneumotachometer³ to measure airflow. Esophageal pressure and airflow output signals from both devices were recorded simultaneously by computer software⁴ for 2 minutes to average the measurement of DP_max and calculation of pulmonary R _L and C _dyn over 10 adequate breaths.4, 15

Bronchodilator Challenge

A first dose (62.5 μg) of albuterol sulfate⁵ or levalbuterol hydrochloride⁶ solution was chosen randomly by flipping a coin. This low dose corresponded to 0.15 mL of the bronchodilator solution as measured with a 1‐mL syringe and given nondiluted. The bronchodilator was administered using an ultrasonic nebulizer⁷ and DP_max measured 5 minutes later. The doses were repeated and the DP_max was measured 5 minutes after each dose to evaluate the effects of cumulative bronchodilator administration and the dose at which maximal bronchodilatation was achieved. If the DP_max reached a plateau consisting of a difference ≤10% between 2 successive doses, the air‐tight mask was repositioned and PFT repeated 10, 20, 30, 40, 60, 90, 120, 180 minutes after the last dose of bronchodilator to determine the duration of the treatment effect, as previously described.4 After a washout period of 24 hours, physical examination and clinical scores were obtained to ensure that enrollment criteria were met again, and measurements were repeated after switching treatment drug.

The dose of bronchodilator that resulted in a 50% decrease in DP_max (ED50%) was calculated by linear interpolation and the dose resulting in maximum bronchodilatation (ED_max) was determined as the first dose of the plateau effect.

Statistical Analysis

Clinical scores and PFT data were compared between treatments using the Wilcoxon Matched Paired Test.⁸ The dose that resulted in a 50% and maximum decrease in DP_max from baseline was compared between both drugs administered. Changes in PFT variables between baseline and subsequent time points were compared using Friedman ANOVA. Post‐hoc tests were conducted using Wilcoxon matched pairs test when appropriate. Association between DP_max at baseline and ED_max was assessed by Spearman's rank correlation. Data were summarized as median and interquartile range (IQR) and significance was defined as P < .05.

Results

All 9 horses met the inclusion criteria and responded to the moldy hay during 2 weeks of exposure. None of them developed anorexia or clinically relevant weight loss throughout the study. Results of baseline PFT (DP_max, R _L and C _dyn) before administration of bronchodilators were not statistically different between the 2 treatment groups (P = .76).

The mean duration of bronchodilator effect was 60 minutes for albuterol and 120 minutes for levalbuterol (Fig 1). A comparable response was observed with R _L data whereby albuterol effect lasted 40 minutes and levalbuterol effect was significant up to 120 minutes (Fig 2). Bronchodilator effect on C _dyn followed a similar trend but was only statistically significant for 10–40 minutes. Two of the 9 horses continued to experience decreased DP_max 3 hours after levalbuterol administration. The effects on PFT were noted after the first dose (63 μg) of either albuterol or levalbuterol and resulted in average decreases of 50 and 56% in DP_max respectively. The calculated ED50% and ED_max of the doses were not significantly different between albuterol (ED50% = 43.6 [38.2–47.3 μg] and ED_max = 125.0 [125–125 μg]) and levalbuterol (ED50% = 39.7 [35.0–52.5 μg; P = .40] and ED_max = 188 [125–188 μg; P = .068]; Fig 3). Similarly, the relative magnitude of bronchodilatation was not significantly different between the 2 treatments (61.1 [43.1–67.9] and 59.9 [52.2–63.6] % decrease in DP_max for albuterol and levalbuterol respectively; P = .86). There was no significant correlation between DP_max at baseline and ED_max.

Figure 1.

Mean ± standard deviation of the maximum change in transpulmonary pressure (DP _max) recorded with the mask before (0) and after completion of the bronchodilator challenge with albuterol (solid squares) and levalbuterol (open diamonds). *: significantly different from baseline (P < .05).

Figure 2.

Mean ± standard deviation of the lung resistance (R _L) recorded with the mask before (0) and after completion of the bronchodilator challenge with albuterol (solid squares) and levalbuterol (open diamonds). *: significantly different from baseline (P < .05).

Figure 3.

Mean ± standard deviation of the maximum change in transpulmonary pressure (DP _max) recorded without the mask before (0) and following each dose of nebulized albuterol (solid squares) and levalbuterol (open diamonds). *: significantly different from baseline (P < .05).

Discussion

Levalbuterol, a β‐agonist containing only the (R)‐enantiomer of racemic albuterol, has been developed for human asthmatic patients to avoid the adverse effects of the (S)‐enantiomer.6, 11, 12, 16, 17 To our knowledge, no previous studies have compared the use of levalbuterol and racemic albuterol for the treatment of horses with an acute episode of RAO.

Our results suggest that there are no significant differences in the magnitude of improvement in pulmonary function achieved by both bronchodilators, although the effects of levalbuterol lasted twice as long as those of albuterol (2 versus 1 hour respectively). No adverse effects were noted with this single short‐term treatment with either bronchodilatator, but future studies using daily treatment over several days would be needed to further assess this possibility. Despite this longer duration of action, the return of pulmonary pressures to baseline values by 180 minutes limits the use of levalbuterol to a rescue medication for horses with an acute RAO crisis or as a diagnostic method to confirm reversibility of airway obstruction.

Before the bronchodilator challenge, there was no significant difference in pulmonary function (DP_max, R _L, and C _dyn) between each arm of the study, demonstrating that a washout period of 24 hours was adequate, as previously reported.4

The average albuterol dose that induced a maximum bronchodilatory effect (125 μg) is markedly lower than the dose reported in previous studies (360–540 μg).4, 5 This difference suggests that a higher proportion of drug was deposited in the lung using the ultrasonic nebulizer, presumably because of the smaller particle size delivered with the nebulizer compared to the hand‐held device used in the previous studies.4 The nebulizer was easy to place and it took approximately 1 minute to administer each dose. The horses showed no adverse behavior throughout the bronchodilator challenge, similar to reports in previous studies.18 Bronchodilatation was significant after the first dose (63 μg) of either albuterol or levalbuterol, which corresponded to 0.15 mL of solution. We did not attempt to start the bronchodilator challenge with a lower dose because of the difficulty in accurate measurement of small volumes.

The deposition of the aerosol reaching the lungs in horses with ultrasonic nebulizers (5.09 ± 0.66%) is lower than the average 10% of aerosol deposition achieved in human patients.18 This difference is likely attributed to horses being nasal breathers, causing higher filtration. In addition, the deposition of small‐sized aerosol particles in the human lung is augmented by deep inhalation, followed by a period of breath‐holding at total lung capacity. This maneuver is not possible in horses.19, 20, 21 Horses experiencing an acute RAO episode tend to have rapid and shallow breaths that would be expected to decrease lung deposition of the bronchodilator. However, the doses of albuterol and levalbuterol resulting in ED_max in horses (125 and 188 μg, respectively) were very small compared to ED_max reported in human patients with severe asthma exacerbation (7.5 and 3.25 mg respectively).22 An additional effect from oral absorption of drugs deposited in the nasopharynx is unlikely because it would be expected to result in a delayed therapeutic effect, but this phenomenon was not observed in our study. Furthermore, there is evidence that oral albuterol is poorly absorbed in the horse⁹ and a closely related compound, terbutaline, also is not bioavailable orally in horses.23 Therefore, nebulized albuterol and levalbuterol are highly potent bronchodilators in horses with acute RAO exacerbation.

The effect of levalbuterol lasted 2 hours in RAO horses compared to 6 hours in human asthmatic patients.12, 24 This decreased duration of action of levalbuterol in the horse is similar to that observed with another bronchodilator, salmeterol xinafoate.25 Salmeterol in human asthmatic patients has a duration of action of 12 hours and only 6 hours in horses with RAO. We hypothesized that the difference might be attributed to rapid drug clearance from the lung because of enhanced alveolar and bronchial absorption secondary to increased airway epithelial permeability25 or a species‐specific pharmacokinetic difference in disposition of the drug. There are no validated explanations of why the duration of action of these bronchodilators is shorter in horses than in people.

Our results suggest that levalbuterol is effective to treat acute RAO in horses but, the only benefit of levalbuterol is the slightly longer duration of bronchodilatory effect compared to albuterol. There was no statistically significant difference in PFT after ED_max using either bronchodilator. These results suggest that both bronchodilators achieve a similar degree of bronchodilatation in horses, as opposed to humans in whom levalbuterol is more efficient at improving pulmonary function in addition to having a longer acting bronchodilatory effect than albuterol.6

In conclusion, unlike findings in human asthmatic patients, administration of levalbuterol to horses with RAO did not result in greater bronchodilatation compared to albuterol. Levalbuterol is an effective bronchodilator, but the short duration of action makes this drug nonpractical for treatment of RAO.

Funding

The United States Equestrian Federation and the state of Indiana, the Purdue University College of Veterinary Medicine Research account funded by the Total Wager Tax.