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Keywords:

  • Anticholinergic therapy;
  • Bronchodilatation;
  • Heaves;
  • RAO

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Background

Equine recurrent airway obstruction (RAO) is characterized by airway inflammation, bronchoconstriction, and increased mucus production in the airways. Anticholinergic drugs like atropine induce bronchodilatation and rapid improvement in lung function. N-butylscopolammonium bromide (NBB) is an anticholinergic drug used to relieve spasmodic colic in horses, but its effect on airway smooth muscle is unknown.

Objective

To evaluate the effect of NBB on clinical signs and lung function of RAO-affected horses.

Animals

Nine horses diagnosed with RAO.

Methods

Double-blind, placebo-controlled, randomized crossover trial. Horses were challenged with moldy hay until a maximum change in transpulmonary pressure (∆PLmax) > 15 cmH2O was achieved. NBB (0.3 mg/kg) or placebo (0.9% saline) was administered IV. Clinical scores and lung function were recorded at baseline and then periodically after treatment administration. Horses were allowed a 6-week washout before administration of opposite treatments.

Results

Clinical score at 10 and 30 minutes (8.7 ± 2.8 and 8.7 ± 3.2, respectively) after NBB administration was significantly lower than baseline (10.8 ± 2.4). NBB administration resulted in a significant decrease in ∆PLmax (baseline: 35.1 ± 6.9 cmH2O) starting 2 minutes after administration (16.3 ± 6.6 cmH2O) with a maximum decline observed at 10 minutes (13.5 ± 7.1 cmH2O). ∆PLmax values between 60 and 120 minutes after NBB administration were not different from placebo.

Conclusion and Clinical Importance

N-butylscopolammonium bromide is a potent bronchodilator, reaching maximum effect 10 minutes after intravenous administration. This effect dissipates within 1 hour of drug administration.

Abbreviations
PLmax

maximum change in transpulmonary pressure

C dyn

dynamic lung compliance

NBB

N-butylscopolammonium bromide

RAO

recurrent airway obstruction

R L

pulmonary resistance

Recurrent airway obstruction (RAO) or heaves is a chronic distal airway inflammatory disease commonly seen in adult horses stabled in wet, cool climates. This condition has similar features to human asthma, which includes distal airway inflammation, reversible airway obstruction, and bronchial hyperresponsiveness.[1-3] Clinical signs associated with RAO include chronic intermittent coughing, nasal discharge, increased respiratory effort at rest, and exercise intolerance. When exposed to dust or molds found in hay or straw, horses affected by RAO develop an exacerbation of clinical signs leading to an acute RAO crisis,[4] characterized by signs of respiratory distress because of bronchoconstriction, distal airway inflammation, and mucus plugging of the airways. Diagnosis of RAO can be made based on characteristic clinical signs, cytological analysis of lower respiratory tract secretions, and pulmonary function testing. Horses diagnosed with RAO show an increase in maximum change in transpulmonary pressure (∆PLmax) and lung resistance (RL) and a decrease in dynamic lung compliance (Cdyn).[5, 6]

Medical management of an RAO crisis is directed at controlling bronchoconstriction that is caused by airway smooth muscle contraction mediated via vagal activation of muscarinic receptors.[7] Clinical improvement has been observed with the use of anticholinergic drugs, β2–adrenergic agonists, and methylxanthines, with the intravenous administration of atropine being the most effective at decreasing ∆PLmax and alleviating clinical signs of respiratory distress.[8] Atropine is a parasympatholytic medication and it competitively binds to the muscarinic receptors on airway smooth muscle, blocking the effects of acetylcholine. Despite the rapid and effective bronchodilatation achieved with intravenous atropine, it is not used commonly in equine practice because of its undesirable adverse effects such as prolonged decrease in gastrointestinal motility (ileus) or colic.[9]

The anticholinergic N-butylscopolammonium bromide1 (NBB) is a quaternary ammonium compound that has been approved in the United States for use in horses experiencing colic caused by gas, spasms, or mild impactions. Adverse effects associated with NBB are minimal and include a transient tachycardia, decreased borborygmi, and transient pupillary dilatation.[10, 11] The effect of NBB administration on lung function of horses with RAO during clinical exacerbation has not been reported.

The purpose of this study is to determine if NBB administered at the dose approved for horses with colic can be used as a bronchodilator for horses acutely affected with RAO. We hypothesized that NBB at a dose of 0.3 mg/kg IV will improve clinical signs and lung function of horses experiencing an acute RAO crisis.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Experimental Design

Nine horses, 6 mares and 3 geldings, ranging from 8 to 29 years of age owned by Purdue University were used in this randomized double-blind placebo-controlled study. The horses had been previously diagnosed with RAO based on inducible and reversible airway obstruction. They were all considered otherwise healthy based on a physical examination when entering the study. For the duration of the study, horses were housed in 12 by 12 foot box stalls bedded with straw and fed good quality grass hay ad libitum and complete pelleted feed. To induce exacerbation of active disease, they were also fed with moldy hay that was shaken in front of each horse's nose for 2 minutes twice daily. A physical exam and assignment of a clinical score were performed daily. Horses were kept in this environment until they developed signs compatible with RAO determined by a clinical score ≥10,[6] which prompted performance of standard lung mechanics. Horses were included in the study once ∆PLmax ≥ 15 cmH2O was achieved. Clinical scores were assigned at baseline and at 10, 30, and 60 minutes after administration of a one-time dose of NBB (0.3 mg/kg, IV) or placebo (0.9% saline, isovolume). Standard lung mechanics were measured at baseline and 2, 10, 20, 30, 60, 90, and 120 minutes after medication administration. Upon completion of the 1st phase of the study, horses were turned out on pasture for 6 weeks and then returned to the barn for another hay challenge before entering the second phase of the study with the opposite treatment being administered. The order of the treatments was chosen at random for each horse. The Purdue Animal Care and Use Committee approved this protocol.

Clinical Scoring

Two previously adopted clinical scoring systems[6, 12] were used to assess respiratory compromise during the moldy hay challenge and after administration of the treatment. A clinical score adopted from Tesarowski et al (long score) ranging from 0 to 21 was assigned based on respiratory rate, nasal discharge, respiratory effort, tracheal sounds, crackles, wheezes, cough, and abdominal effort on exhalation. A clinical score adopted from Rush et al (short score) ranging from 2 to 8 was assigned based on nostril flaring and abdominal effort. In both scoring systems, a higher score indicates more severe clinical disease. Clinical scores were assigned by an observer (JH) who was masked to treatment allocation and lung function values.

Standard Lung Mechanics

Horses were restrained in stocks without sedation. An esophageal balloon catheter (inner diameter, 4.8 mm; outer diameter, 6.4 mm; length, 240 cm) was advanced through the nose to mid-thorax. The exact position of the catheter was recorded for each horse at baseline testing and used in the subsequent measurements. A mask was placed over the nose of each horse with a pneumotachometer coupled to a differential pressure transducer that measured a signal proportional to airflow. A 2nd catheter of same length and diameter was used to measure pressure within the mask. Both catheters were connected to a differential pressure transducer. Maximum change in transpulmonary pressure was defined as the difference between esophageal and mask pressures during peak inspiratory and expiratory effort. Signals produced by the pneumotachometer and the pressure transducer were recorded by computer software.[2] Resistance (RL) was measured using the isovolume 50% method. Dynamic compliance (Cdyn) was computed by dividing tidal volume by the difference in ∆PLmax between points of zero flow. Other parameters measured included respiratory rate, tidal volume, and minute ventilation. The sampling time was approximately 2 minutes and the average of 10 representative breaths was used for analysis.

Statistical Analysis

Data were evaluated by commercially available statistical software.2 Normality of data distribution was assessed by the Kolmogorov-Smirnov test. Results were expressed as mean ± SD. The effect of treatment (NBB or placebo) on the primary variables of interest (clinical score, lung function) overtime was evaluated using analysis of variance for repeated measures. Posthoc tests (Tukey HSD) were used as indicated. Associations between clinical score and pulmonary function variables were evaluated using the Pearson correlation coefficient for the long score and Spearman rank for the short score. Results were considered significantly different at < .05.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Horses

All horses met the inclusion criteria to be involved in the study during the 1st moldy hay challenge, whereas only 7 horses met the inclusion criteria during the 2nd moldy hay challenge (1 horse in the treatment group and 1 horse in the placebo group). All horses remained otherwise healthy during the experiments and no adverse effects of the NBB were noted.

Clinical Scoring

There was no statistically significant difference in the mean clinical scores between the groups before administration of the intervention (Table 1). No effect was noted on respiratory rate, nostril flare score, and respiratory effort score caused by treatment with NBB when these outcome measures were analyzed individually or together as the short score. However, horses in the NBB group showed a significant decrease in the long score at 10 minutes (= .01) and 30 minutes (= .01) after NBB administration when compared with baseline. Clinical scores beyond 30 minutes were not different between the groups.

Table 1. Clinical signs and clinical scores obtained immediately before (baseline) and at various times after intravenous administration of N-butylscopolammonium (NBB) or placebo
 Baseline10 Minutes30 Minutes60 MinutesP Valueb
  1. Measurements expressed as mean ± SD.

  2. a

    Statistically different from baseline (< .05).

  3. b

    P-value for the main treatment effect.

Respiratory rate (breaths/minute)NBB26.3 ± 5.624.6 ± 9.424.0 ± 7.727.4 ± 6.3.14
Placebo23.0 ± 5.621.3 ± 4.923.4 ± 4.922.3 ± 3.9
Nostril flare scoreNBB3.5 ± 0.82.9 ± 0.82.8 ± 0.73.0 ± 0.5.2
Placebo3.4 ± 0.53.1 ± 1.03.1 ± 0.63.1 ± 0.6
Respiratory effort scoreNBB3.5 ± 0.53.3 ± 0.73.3 ± 0.73.3 ± 0.71.0
Placebo3.6 ± 0.53.4 ± 0.53.4 ± 0.53.4 ± 0.5
Long scoreNBB10.9 ± 2.48.8 ± 2.8a8.8 ± 3.2a10.4 ± 3.2.02
Placebo10.3 ± 2.19.4 ± 2.810.4 ± 2.79.8 ± 2.1
Short scoreNBB7.0 ± 1.26.1 ± 1.56.0 ± 1.36.3 ± 1.2.35
Placebo7.0 ± 0.96.5 ± 1.46.5 ± 1.16.5 ± 1.1

Standard Lung Mechanics

Lung mechanics variables (∆PLmax, RL, and Cdyn) before administration of the treatment were not significantly different between the 2 groups. Tidal volume increased significantly at 2 minutes after NBB administration (= .03) but values after 10 minutes were not statistically different between groups. NBB administration resulted in a significant decrease in breathing frequency 10 minutes after drug administration (17.8 ± 7.0 breaths/minute) when compared with baseline (22.1 ± 8.1 breath/minute; = .04), but NBB had no significant effect on minute ventilation. A rapid and statistically significant improvement in ∆PLmax was noted in horses administered NBB, but not in horses given placebo. NBB administration induced a significant decrease in ∆PLmax starting at 2 minutes (16.3 ± 6.6 cmH2O; P < .001), with maximal effects at 10 minutes (13.5 ± 7.1 cmH2O; < .001; range, 4.5–28.4 cmH2O) when compared with baseline (35.1 ± 6.6 cmH2O; range, 20.2–43.2 cmH2O). Values after 60 minutes of NBB administration were not different from placebo (Fig 1). Administration of NBB resulted in a rapid and statistically significant decrease in total pulmonary resistance (RL) starting at 2 minutes after administration that lasted until 30 minutes posttreatment (Fig 2). Pulmonary resistance 60 minutes after NBB administration was not different from placebo. Increase in dynamic compliance (Cdyn) in response to NBB administration was noted between 2 and 20 minutes after NBB administration (< .02; Fig 3). Finally, ∆PLmax was significantly correlated with both the short (r = 0.54, < .05) and long clinical scores (r = 0.40, = .002).

image

Figure 1. Maximum change in transpulmonary pressure (∆PLmax) after intravenous administration of N-butylscopolammonium (solid squares) or placebo (open squares) at time 0. See Table 1 for keys.

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image

Figure 2. Change in lung resistance (RL) after intravenous administration of N-butylscopolammonium (solid circles) or placebo (open circles) at time 0. See Table 1 for keys.

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image

Figure 3. Change in lung dynamic compliance (Cdyn) after intravenous administration of N-butylscopolammonium (solid triangles) or placebo (open triangles) at time 0. See Table 1 for keys.

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Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Our study demonstrates that NBB at a dose of 0.3 mg/kg given IV is capable of reversing signs of airway obstruction in horses during an acute RAO crisis as evidenced by rapid improvement in clinical score, ∆PLmax, and RL. While the onset of improvement is fast (2 minutes after intravenous administration) the effect is fairly short in duration, with no significant difference in clinical scores and lung function measurements at 60 minutes post administration, when compared with baseline values.

One of the characteristic features of equine RAO is the fast improvement in lung function that occurs with the administration of bronchodilators such as anticholinergics or β2-adrenergic receptor agonists, providing rapid confirmation of the diagnosis of RAO.[1] Atropine has been proven to be the most effective in achieving maximal bronchodilatation in clinically affected cases,[8] with improvement in lung function lasting for 1–2 hours after intravenous administration.[13] Due to its rapid onset of action and ease of administration, atropine had been used for the bronchodilator test in the past, but it has fallen out of favor because of the adverse effects associated with the gastrointestinal and nervous systems seen in horses.[9] Aerosolized bronchodilators such as anticholinergic drugs ipratropium bromide and glycopyrrolate or the β2-adrenergic receptor agonist albuterol have been proven to be effective in alleviating signs of airway obstruction measured by lung mechanics during an acute RAO crisis.[14-16] Their main advantage is the deposition of high concentrations of medications in the peripheral airways without development of the adverse effects commonly associated with systemic therapy. Despite the favorable therapeutic effects, their use is often limited because of the expense associated with the delivery system (nebulizer or mask) and drugs (pressurized metered-dose inhaler) required for their administration. Another disadvantage of inhalation therapy is the unpredictable drug deposition in the lung due to the mucus accumulation and bronchoconstriction preventing equal amounts of active drug reaching the small airways.[15]

N-butylscopolammonium bromide, similar to atropine and glycopyrrolate, is a nonspecific antagonist at the muscarinic receptor subtypes, inducing blockade of the parasympathetic nervous system.[17] The clinical signs associated with the parasympathetic blockade are transient and dose-related[18] and include decreased production of salivary and bronchial secretions, tachycardia, decreased intestinal motility, and transient pupillary dilatation.[10, 11, 18] While atropine has a narrow therapeutic window and readily crosses the blood-brain barrier, the quaternary ammonium structure of NBB results in poor penetration into the central nervous system,[17] therefore it has not been associated with neurologic side effects. NBB has also been shown to produce only minimal and transient (less than 2 hours) changes in the motility pattern of small and large intestines in horses[19, 20] and to result in a less pronounced tachycardia when compared to atropine for the reversal of detomidine-induced bradycardia in horses.[21] Based on the minimal side effects associated with NBB, we can conclude that it is safer when compared to atropine when anticholinergic therapy is indicated.

Pulmonary function testing is a valuable diagnostic tool available at some equine referral practices and research centers, which allows clinicians to evaluate the severity and the reversibility of airway obstruction in horses with RAO. Our results indicated that administration of NBB resulted in a significant decrease in RL and ∆PLmax and increase in Cdyn, confirming the reversibility of airway obstruction shortly after drug administration, and with maximal beneficial effect occurring 10 minutes after treatment. Similar results were reported in a study where aerosolized ipratropium bromide was evaluated in the treatment of acute airway obstruction, and the magnitude of improvement in Cdyn lagged behind the improvement in RL and ∆PLmax.[7] As the increase in RL is mainly because of obstruction of the trachea and large bronchi (ie, central airways), and the decrease in Cdyn is principally because of obstruction of the peripheral airways during an acute RAO crisis,[22] these parameters represent different regions within the lung. It has been shown previously that the trachea and the main bronchi have a greater response to anticholinergic therapy than the peripheral airways in horses with RAO,[23] which is likely the reason why the improvement in Cdyn did not reach maximum until 10 minutes in our study whereas RL was minimal already at 2 minutes.

While there are multiple reports on the effects of bronchodilator therapy on lung mechanics in an acute RAO crisis in horses,[12, 14-16] to the authors' knowledge there is only 1 study evaluating the change in clinical signs associated with bronchodilator therapy during an acute RAO crisis.[24] As pulmonary function testing is neither widely available nor practical for everyday use, the ability of a drug to rapidly alleviate signs of respiratory distress remains to be determined by clinical improvement after bronchodilator administration in the clinical setting. We used 2 previously adopted clinical scoring systems to evaluate the effect of NBB on clinical signs associated with airway obstruction.[6, 12] The scoring systems were applied by a masked observer providing an objective assessment of respiratory compromise. The long score results in our study correlated with the pulmonary function testing results, confirming the validity of the scoring system. Interestingly, none of the components of the clinical score, including respiratory rate or respiratory effort, showed a statistically significant difference in response to NBB administration when they were individually analyzed. These findings are in contrast with the breathing frequency results determined via measurements of lung mechanics, as breathing frequency decreased significantly 10 minutes after NBB administration when compared to baseline. The explanation to this discrepancy is likely due to the method of counting the breaths of the horse. Breathing frequency was computed by exact measurements of the number of breaths taken over a 2-minute period, whereas respiratory rate taken by the masked observer was determined by counting the number of breaths in 15 seconds then multiplied by 4 as commonly done in clinical settings. However, the decrease in respiratory frequency recorded 10 minutes after NBB administration was small (3–4 breaths on average) corresponding to 1 less breath per 15 seconds, therefore a clinician is unlikely to detect such a small difference or it can be easily missed. This observation emphasizes the importance of counting the number of breaths for 60 seconds rather than only 15 seconds when evaluating the effects of bronchodilator therapy. Based on our results, we conclude that respiratory rate counted for 60 seconds alone or in combination with the long respiratory score should be used as objective measurements of clinical improvement during bronchodilator therapy in horses experiencing an acute RAO crisis.

The effect of NBB in horses experiencing an acute RAO crisis lasted less than 1 hour. However, we only tested the effect of a single administration of the drug. Repeated administration of NBB would be interesting to attempt as it may help relieve some of the lung hyperinflation and airway mucus accumulation and provide longer lasting improvement in clinical signs and lung function. According to NBB safety information filed with the FDA,3 administration of the drug at the recommended dose (0.3 mg/kg) every hour for 3 hours is not associated with clinically significant adverse events.

Based on our results and the previous studies evaluating the safety of NBB, we conclude that NBB has the potential to serve as a safer alternative to atropine and be used to test reversibility of airway obstruction in horses with respiratory distress to confirm a presumptive diagnosis of RAO. The effects are relatively short lived, therefore NBB is not recommended to be used for the long-term management of RAO affected horses, but should be considered as a rescue medication during an acute crisis. Future studies should investigate the efficacy and safety of repeated administration of NBB and dose-effect relationship in horses with RAO.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Special thanks to Donna Griffey, RVT, Margo Kasting, and Randy Wilson for their technical help.

Conflict of Interest: The study was conducted at Purdue University College of Veterinary Medicine. This work was supported in part by a gift from Boehringer Ingelheim Vetmedica, Inc and by the state of Indiana, the Purdue University School of Veterinary Medicine Research account funded by the total wager tax.

Footnotes
  1. 1

    Buscopan® injectable solution, Boeringher-Ingelheim Vetmedica Inc, St. Joseph, MO

  2. 2

    STATISTICA, StatSoft Inc, Tulsa, OK

  3. 3

    Buscopan® injectable solution, Freedom of information summary, NADA 141–228, http://www.fda.gov/downloads/animalveterinary/products/approvedanimaldrugproducts/foiadrugsummaries/ucm118039.pdf

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References