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Comparative efficacy of inhaled albuterol between two handheld delivery devices in horses with recurrent airway obstruction

EQUINE VETERINARY JOURNAL Equine vet. J. (2011) •• (••) ••-••
doi: 10.1111/j.2042-3306.2010.00313.x
Comparative efficacy of inhaled albuterol between twohand-held delivery devices in horses with recurrentairway obstruction F. R. BERTIN, K. M. IVESTER and L. L. COUËTIL*
Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, Indiana, USA. Keywords: horse; recurrent airway obstruction; heaves; aerosol; delivery device; b2 agonist; bronchodilator; AeroHippus; Equine Haler
Reasons for performing study: Studies investigating the
Dynamic lung compliance clinical efficacy of albuterol administered with the same
Maximum change in transpulmonary pressure propellant and commercially available delivery devices
Pressurised metered-dose inhaler in horses with recurrent airway obstruction (RAO) are not
Recurrent airway obstruction Objectives: To determine the efficacy of aerosolised albuterol
administered to horses with RAO by means of 2 commercially
available, hand-held delivery devices.

Methods: Ten horses with RAO were kept in a dusty
Recurrent airway obstruction (RAO) is the most frequent obstruction. Lung mechanics were measured before and
cause of chronic respiratory tract disease in horses (Hotchkiss after the procedure. DPmax was measured 5 min after
et al.
administration of 180 mg of albuterol from a pressurised
bronchospasm with phases of remission when a horse's metered dose inhaler, using an aerosol delivery device chosen
environment is improved (Robinson et al. 1996). During disease randomly. This process was repeated every 5 min until
exacerbation, bronchoconstriction, airway wall oedema and maximal bronchodilation was achieved. After a 24 h washout
accumulation of mucus result in obstruction of the distal airways.
period, lung mechanics data were again collected using the
These mechanisms induce functional changes: maximum change in other aerosol delivery device.
transpulmonary pressure (DPmax) increases, pulmonary resistance Results: Aerosolised albuterol induced a significant and rapid
(RL) increases and dynamic lung compliance (Cdyn) decreases bronchodilation in the horses using both aerosol delivery
(Gillespie et al. 1966; Couëtil et al. 2001). Recurrent airway devices. No statistically significant difference in pulmonary
obstruction is believed to be an allergic reaction to organic dusts function was observed in response to albuterol therapy
and has many similarities with human asthma (Ghio et al. 2006; between the 2 devices. The dose required to achieve 50% of
Marti et al. 2008).
maximal bronchodilation was not statistically different
Inhaled short-acting b2-receptor agonists are the most effective between the 2 devices (173.35 ⫾ 78.35 mg with Device 1 and
medication for relieving acute bronchospasm (Anon 2007).
228.49 ⫾ 144.99 mg with Device 2, P = 0.26). The decrease in
Albuterol is the most commonly prescribed medication for asthma lung resistance tended to be more pronounced after albuterol
in man worldwide (Kelly 2005). Short-acting b2-receptor agonists, administration with Device 1 (P = 0.066).
amongst other actions, mediate vasodilation and bronchodilation (Weiss et al. 2006). In human medicine, nebulisers and spacer bronchodilator in horses with recurrent airway obstruction.
devices are popular means of delivering aerosols. Small volume There is no statistically significant difference between the
spacers, composed of a mouth piece and holding chamber with 2 commercially available aerosol delivery devices in terms
valves, have been developed for patients such as infants to avoid of efficacy.
having to precisely coordinate actuation of the pressurised metered-dose inhaler (pMDI) and inhalation. Spacers have been delivered using currently available devices leading to
shown to be clinically effective and result in fewer side effects from maximal bronchodilation in horses with RAO at an average
medication residue in the oral cavity (Clarke et al. 1993). Aerosol dose of 540 mg.
delivery to infants is more efficient from a pMDI via a small *Corresponding author email: [email protected][Paper received for publication 19.06.10; Accepted 16.08.10] Comparative efficacy of inhaled albuterol between two hand-held delivery devices volume spacer than from a nebuliser (Wildhaber et al. 1997).
of ⱖ12 was considered sufficient to warrant lung function testing.
In equine medicine, various aerosolised drugs have been used For inclusion in the study, a maximum change in transpulmonary successfully for the treatment of RAO (Rush et al. 1998; Derksen pressure (DPLmax) ⱖ15 cmH2O was required after the induction et al. 1999; Couëtil et al. 2005). Aerosolised bronchodilators period. If that pressure was achieved, lung mechanics were administered with pMDI are effective and associated with minimal measured at baseline and the horse was enrolled in the treatment trial side effects. In particular, aerosolised albuterol has been shown to using one of 2 aerosol delivery devices chosen at random. The horse be a valuable bronchodilator with rapid onset in the treatment of then returned to its stall in the dusty environment for a minimum RAO (Derksen et al. 1999; Rush et al. 1999). This type of therapy of 24 h washout period. The following day, if the horse met the requires specialised devices to optimise drug delivery in the equine inclusion criteria, lung mechanics data were again collected using lung. Convenient delivery devices have been described in horses the other aerosol delivery device. If the criteria were not met, the (Tesarowski et al. 1994; Derksen et al. 1996). Some of these horse was maintained in the dusty environment until inclusion devices use a nose piece, which fits inside the horse's nose, instead criteria were met. This protocol was approved by the Purdue Animal of a face mask to deliver a known dose of any given drug from a Care and Use Committee. Horses were to be removed from the pMDI into the equine lung (Derksen et al. 1996). The relative study if they became anorectic for >24 h.
percentage of a drug deposited in the lung varies based onthe device used and the type of propellant. However, data on the Aerosol delivery devices efficacy of inhaled albuterol using available delivery devices arenot available. Currently, 2 aerosol delivery devices that do not Two aerosol delivery devices, both commercially available, require a face mask are commercially available. A study using referred to as Devices 1 and 2 (Fig 1), were used for albuterol delivery Device 1 (Aerohippus)1 found that 18.2 ⫾ 9.3% of administration using a pMDI and HFA propellant. Both devices are administered beclomethasone dipropionate with hydrofluoroalkane hand-held chambers connected to a nose mask which is placed over (HFA) propellant is deposited in the lung (Hoffman et al. 2008).
one nostril. The pMDI was inserted into the back piece of the Another study, using delivery Device 2 (Equine Haler)2, reports chamber where the breathable particles were suspended until the that 8.2 ⫾ 5.2% of administered fluticasone propionate with horse breathed them through a one-way valve. The device was held chlorofluorocarbons (CFC) propellant is deposited in the equine on the nostril for 3 respiratory cycles to ensure complete inhalation lung (Funch-Nielsen et al. 2001). These 2 studies focused on lung of the dose. The breathing chamber of Device 1 was a cylinder deposition exploring 2 different drugs administered with 2 different whereas the breathing chamber of Device 2 was an ellipsoid.
propellants. In human medicine, it has been demonstrated that thechoice of a propellant considerably influences lung deposition Lung mechanics (Leach et al. 1998; Harrison 2002). However, CFCs have beenbanned from albuterol pMDI since 2008 in most countries Oesophageal pressure was measured using a balloon catheter and replaced by HFA. Studies investigating the clinical efficacy (internal diameter 4.8 mm; outside diameter 6.4 mm; 240 cm in of albuterol administered with the same propellant and the length), which was advanced to the mid-thoracic region and commercially available delivery devices in horses with RAO are connected to a pressure transducer. The balloon was a condom not currently available.
taped around the catheter tip and inflated with 3 ml of air. The The purpose of this study was to evaluate if aerosolised position of the balloon was recorded for each horse at the time albuterol administered to horses with RAO using aerosol delivery of baseline testing prior to induction of RAO exacerbation and devices currently commercially available have comparable efficacy used subsequently for all lung mechanics tests. Transpulmonary on lung function and to provide clinicians with guidelines for the pressure was defined as the difference between oesophageal selection of an aerosol delivery device.
pressure and atmospheric or mask pressure, depending on whetherthe horse was fitted with a facemask or not. When measuring Materials and methods
Device 2 (Equine Haler) Ten horses (5 mares and 5 geldings), age 7–29 years, with inducibleand reversible airway obstruction that are part of the RAO-affectedherd belonging to Purdue University were used in the study. Allhorses had been housed on pasture and fed a pelleted diet for atleast 3 months to ensure remission from disease. At the beginningof the study, abnormalities were not detected during physicalexamination of the horses. The horses were then exposed to a dustyenvironment by housing them in a barn and placing mouldy hay andstraw in their stall. In addition, mouldy hay was shaken twice a day for 5 min next to the horses' nose in order to increase dust exposure.
People shaking hay were protected from inhalation of dust by Device 1 (AeroHippus) wearing an N95 face mask. The horses remained in the confinedenvironment until they developed clinical signs of RAO. Clinicalscores were assigned to each horse once daily by use of a scaleadapted from Tesarowski et al. (1996) to screen for the onset of Fig 1: Delivery Devices 1 and 2 and albuterol metered-dose inhaler used in airway obstruction. The scale ranges from 0–21 and a clinical score the study.

F. R. Bertin et al.
airflow, a mask was fitted around the horse's nose with a TABLE 1: Mean ⫾ s.d. maximal changes in pleural pressure (DPLmax),
pneumotachometer coupled to a pressure transducer that generated dynamic compliance (Cdyn) and pulmonary resistance (RL) recorded
with the mask before (pre) and at the maximum effect after (post)

a signal proportional to airflow. Output signals were recorded by administration of aerosolised albuterol
computer software as previously reported (Couëtil et al. 2001). Atleast 10 respiratory cycles from breaths devoid of artefacts were selected for analysis.
For each trial, baseline measurements of lung mechanics DPLmax post (cmH2O) including airflow, change in transpulmonary pressure (DPLmax) were Cdyn pre (l/cmH2O) recorded. Values for resistance (R L) and compliance (Cdyn) were dyn post (l/cmH2O) computed in accordance with the method described by Amdur and RL pre (cmH2O/l/s) Mead (1958). The mask was then removed and another baseline L post (cmH2O/l/s) DPLmax measured. The horse was then given 2 puffs (180 mg) ofalbuterol (Ventolin)3 using one of the 2 delivery devices and DPLmaxwas measured again 5 min later. This process was repeated until maximal bronchodilation was achieved (ⱕ10% difference between 2 consecutive doses) or a maximum of 10 puffs had been administered. After the last measurement, the mask was replaced and lung mechanics measured again. A dose-response-curve was constructed by plotting DPLmax vs. albuterol dose.
Calibration of flow and pressure transducers was performed once a day before each experiment using a 3 l calibrated syringe and a water manometer, respectively.
Mean ⫾ s.d. were calculated for data that followed normal Fig 2: Mean s.d. maximal changes in pleural pressure (DP distribution and median (range) for data with non-normal Lmax) recorded without the mask before (0) and after subsequent administrations of distribution. Comparison of normally distributed data between aerosolised albuterol with Devices 1 and 2 (P = 0.26). treatment groups (Device 1 vs. Device 2) was made using a pairedt test. Other data were compared using a Wilcoxon signed ranktest. In particular, the albuterol dose that resulted in a 50% and maximum decrease in DPLmax from baseline and absolute and relative difference in RL before and after the last dose of albuterolwere compared between the 2 aerosol delivery devices. Changes in lung function variables (DPLmax, RL, Cdyn) between baseline and at the time of maximal bronchodilation were compared between treatment groups (Device 1 vs. Device 2) using repeated measuresANOVA. Post hoc tests were used when appropriate. Significance was defined as P<0.05.
All the horses met the inclusion criteria within 3 weeks of exposure to the dusty environment. The median clinical score before lung Fig 3: Mean s.d. percentage of reduction of initial maximal changes in function test was 16/21 (9–19). Lung mechanics (DPLmax, RL and pleural pressure (DPLmax) after subsequent administrations of aerosolised Cdyn) before administration of albuterol were not statistically albuterol with Devices 1 and 2 (P = 0.39). different between the 2 treatment trials (P = 0.51, P = 0.88, P = 0.79,respectively). Lung mechanics (DPLmax, RL and Cdyn), after the significant further reduction of mean DPLmax was observed by maximum effect on DPLmax was reached by administration of increasing the dose beyond 540 mg. However, the response was albuterol with either spacer, were not statistically different very variable from one horse to another. Among the 20 tests (P = 0.27, P = 0.20, P = 0.46, respectively; Table 1).
performed, maximum reduction of DPLmax was achieved after 2 Albuterol administered by both delivery devices induced a puffs in 4 tests (3 with Device 1 and one with Device 2), after 4 significant decrease in DPLmax (P<0.001), a significant increase puffs in 2 tests (one with each device), after 6 puffs in 8 tests in Cdyn (P<0.001) and a significant decrease in RL (P<0.001).
(2 with Device 1 and 6 with Device 2), after 8 puffs in 4 tests Albuterol administered by both delivery devices induced a dose- (all with Device 1) and after 10 puffs in 2 tests (all with Device 2).
dependent response and the responses were not statistically The absolute and relative reduction in RL following different between devices (P = 0.26; Fig 2). There was no statistical administration of the last albuterol dose tended to be higher difference between the maximal reduction of DPLmax observed with with Device 1 (1.10 [-0.07–3.31] cmH2O/l/s; 65.1 [7.9–89.0]%; albuterol administered with either mask, either in absolute value (P P = 0.066) than with Device 2 (0.68 [0.61–1.99] cmH2O/l/s; = 0.44) or in percentage of reduction (P = 0.39; Fig 3). The mean 53.7 [20.0–79.1]%). The absolute decrease in RL post albuterol dose required to reach the plateau effect was 540 mg (6 puffs). No challenge was greater with Device 1 in 6 horses but greater with

Comparative efficacy of inhaled albuterol between two hand-held delivery devices administration was higher with Device 2 than with Device 1especially for DPLmax (Table 1). The large standard deviation in DPLmax post albuterol for Device 2 is mainly due to one horse, which responded poorly to treatment with Device 2 (DPLmax = 65.7 cmH2O at baseline and DPLmax = 47.5 cmH2O after 10 puffs) but responded well to treatment administered with Device 1 (DPLmax = 45.9 cmH2O at baseline and DPLmax = 7.1 cmH2O after 10 puffs).
Data analysis was repeated after excluding data from this horse andresults indicated that post albuterol DPLmax = 14.0 ⫾ 6.5 cmH2O with Device 2. Previous studies reported lung deposition of 18.2 ⫾ 9.3% and 8.2 ⫾ 5.2% using Devices 1 and 2, respectively (Funch-Nielsen et al. 2001; Hoffman et al. 2008). These results should be interpreted with caution because the studies were not peer-reviewed. Nevertheless, based on these data we would expect the Fig 4: Mean s.d. dose of aerosolised albuterol required to observe 50% dose of albuterol required to achieve 50% of the maximum effect of reduction of maximal changes in pleural pressure (DPLmax) with Devices on DPLmax with Device 1 to be approximately half that required with 1 and 2 (P = 0.31). Device 2. In fact, the dose required with Device 1 was only 24% Device 2 in 2 horses. In one horse RL increased after albuterol lower and that difference was not statistically significant. The administration with both devices and RL measurement was higher lung deposition reported with Device 1 was obtained with unavailable prealbuterol in one horse.
beclomethasone dipropionate and an HFA propellant while the The dose of albuterol required to reach 50% of the maximum lower deposition was with fluticasone propionate and a CFC effect on DPLmax was not statistically different between Device 1 propellant (Funch-Nielsen et al. 2001; Hoffman et al. 2008).
(173.35 ⫾ 78.35 mg) and Device 2 (228.49 ⫾ 144.99 mg, P = 0.31; Human clinical trials indicate that relative drug deposition in the lungs is approximately 2-fold higher with HFA than with CFCpropellant for drugs such as beclomethasone and flunisolide (Richards et al. 2001; Harrison 2002). Therefore, lung depositionof beclomethasone-HFA in horse's lungs using Device 2 would be The 10 horses completed the study protocol and they inhaled the expected to be around 16.4% which is similar to the 18.2% reported medication with ease. They did not exhibit any adverse effects of for Device 1 delivering the same drug formulation. This b2-agonist therapy and no horse exhibited anorexia throughout extrapolation is consistent with the present study findings.
the study duration.
The study revealed that albuterol delivered with Device 1 During exposure, the 10 horses exhibited clinical signs of RAO resulted in a 34% greater improvement in RL than with Device 2 but and experienced altered DPLmax, RL and Cdyn as previously reported this difference did not reach statistical significance. Conducting (Tesarowski et al. 1996; Rush et al. 1998; Derksen et al. 1999).
additional studies with a larger number of horses would be helpful Administration of albuterol significantly improved pulmonary to confirm if the 2 devices achieve significantly different drug function parameters in all the tested horses. These findings are delivery levels and require different dose recommendation for the consistent with published studies (Derksen et al. 1999; Rush treatment of RAO.
et al. 1999).
Pulmonary function is traditionally quantified using DPLmax, No statistically significant difference was noted in DPLmax, RL RL and Cdyn. In this study, only DPLmax has been measured between and Cdyn before the treatment trial using delivery device. These individual administrations of albuterol. In other reports, DPLmax results indicate that a 24 h washout period between the 2 trials was and RL appeared to be the most sensitive markers of improved adequate and are consistent with the fact that during exacerbation airway obstruction in horses with RAO (Robinson et al. 1993; of the disease, a horse's pulmonary function remains relatively Tesarowski et al. 1994; Derksen et al. 1996; Rush et al. 1998).
stable (Jean et al. 1999).
Measurement of DPLmax does not require a mask fitted around All doses of albuterol induced a significant decrease in the horse's nose with a pneumotachometer coupled to a pressure DPLmax within 5 min of administration, which indicates a rapid transducer. However, DPLmax is also influenced by voluntary improvement of airway obstruction. These results are similar to breathing efforts and may vary with excitement or tachypnoea.
those reported using fenoterol (Tesarowski et al. 1994) and albuterol In this study, RL was also measured before and after the last dose (Derksen et al. 1999; Rush et al. 1999) delivered by pMDIs of albuterol confirming the fact that improvement in lung function combined with other delivery devices. However, in this study, the was due to reduced airway obstruction and not just changes in mean dose required to reach the plateau effect was 540 mg (6 puffs).
breathing strategy.
No significant further bronchodilation was observed by increasing Bronchodilation induced by albuterol lasts for 30–60 min the dose beyond 540 mg. This dose is higher than the dose of 360 mg (Derksen et al. 1999). During the study we chose to administer previously reported (Derksen et al. 1999). Since the same HFA albuterol 2 puffs at a time in order to reduce the time elapsed propellant was used in both studies, the difference may be explained between the first administration of albuterol and the last by the higher percentage of drug deposited in the lungs using the measurement. Using this method, the time required to administer device that is no longer commercially available.
the maximal dose (900 mg or 10 puffs) and perform the No statistically significant difference was noted in DPLmax, RL last measurement was 32 min on average. If the mask were and Cdyn after the treatment trial using either delivery device. These repositioned to perform a complete measurement of the lung results suggest that the 2 devices achieved a similar amount of drug function between each administration, the incremental dose- response curve would not have been accurate for the last F. R. Bertin et al.
measurements. Using this protocol, it was considered that the bronchodilator effect induced by the first administration ofalbuterol was still present when the last measurement of pulmonary 1Trudell Medical International, London, Ontario, Canada.
2 function was performed. This assumption was reinforced by the Equine Health Care Aps, Horsholm, Denmark.
3GlaxoSmithKline, Brentford, Middlesex, UK.
fact that DPLmax either continued to decrease or reached a plateauas increasing dosages were delivered but it never increased by thetime the last dose was administered.
A large variation was observed between horses. Some horses reached maximal bronchodilation with as little as 2 puffs (180 mg) Amdur, M. and Mead, J. (1958) Mechanics of respiration in unanesthetized guinea while others required 10 (900 mg). Also, most of the improvement pigs. Am. J. Physiol. 192, 364-368.
in DPLmax was seen within the first few puffs after which the effect Anon (2007) Expert Panel Report 3: Guidelines for the Diagnosis and Management of levelled off. As reported in other studies (Derksen et al. 1996), Asthma. Department of Health and Human Services, National Institutes of Health:National Heart, Lung, and Blood Institute. National Asthma Education Prevention small airways of horses with RAO are occluded by mucus, airway Program. Bethesda.
wall thickening and bronchospasm, thus resulting in unpredictable Clarke, J.R., Aston, H. and Silverman, M. (1993) Delivery of salbutamol by metered amount of inhaled drug deposition. Furthermore, horses did not dose inhaler and valved spacer to wheezy infants: Effect on bronchial reach the same clinical score or degree of airway obstruction based responsiveness. Arch. Dis. Child. 69, 125-129.
on lung function testing. It is likely that some horses were more Couëtil, L.L., Rosenthal, F.S., DeNicola, D.B. and Chilcoat, C.D. (2001) Clinical affected and therefore produced more mucus and experienced signs, evaluation of bronchoalveolar lavage fluid, and assessment of pulmonary more severe bronchospasm resulting in decreased lung deposition function in horses with inflammatory respiratory disease. Am. J. vet. Res. 62,
of albuterol. However, all the horses had an improved lung Couëtil, L.L., Chilcoat, C.D., DeNicola, D.B., Clark, S.P., Glickman, N.W. and function test after repeated administration, possibly because an Glickman, L.T. (2005) Randomized, controlled study of inhaled fluticasone initial bronchodilation aided drug deposition during the subsequent propionate, oral administration of prednisone, and environmental management of horses with recurrent airway obstruction. Am. J. vet. Res. 66, 1665-1674.
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Management of Asthma (Anon 2007), short-acting b2-agonists are and Ruth, D.T. (1999) Aerosolized albuterol sulfate used as a bronchodilator in
horses with recurrent airway obstruction. Am. J. vet. Res. 60, 689-693.
the most effective medication for relieving acute bronchospasm; Derksen, F.J., Olszewski, M.A., Robinson, N.E., Berney, C., Lloyd, J.W., Hakala, J., however, increasing the use of short-acting b2-agonists treatment Matson, C. and Ruth, D. (1996) Use of a hand-held, metered-dose aerosol delivery or using short-acting b2-agonists >2 days/week for symptom device to administer pirbuterol acetate to horses with ‘heaves'. Equine vet. J. 28,
relief indicates an inadequate control of asthma in addition to the need for initiating or intensifying anti-inflammatory therapy.
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albuterol is only recommended as rescue medication, as a Gillespie, J.R., Tyler, W.S. and Eberly, V.E. (1966) Pulmonary ventilation and diagnostic test for RAO or as therapy in combination with inhaled resistance in emphysematous and control horses. J. appl. Physiol. 21, 416-422.
corticosteroids. In addition, the emphasis should be placed on the Ghio, A.J., Mazan, M.R., Hoffman, A.M. and Robonson, N.E. (2006) Correlates need to improve the environment of a horse affected by RAO by between human lung injury after particle exposure and recurrent airway limiting antigen inhalation, particularly thermophilic moulds and obstruction in the horse. Equine vet. J. 38, 362-367.
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Hotchkiss, J.W., Reid, S.W. and Christley, R.M. (2007a) A survey of horse owners in However, the primary therapy for horses affected by RAO should Great Britain regarding horses in their care. Part 1: Horse demographic focus on managing and controlling their environment.
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Hotchkiss, J.W., Reid, S.W. and Christley, R.M. (2007b) A survey of horse owners in Great Britain regarding horses in their care. Part 2: Risk factors for recurrent Conflict of interest
airway obstruction. Equine vet. J. 39, 301-308.
Jean, D., Vrins, A. and Lavoie, J.P. (1999) Monthly, daily, and circadian variations of The authors declare no conflict of interest.
measurements of pulmonary mechanics in horses with chronic obstructive
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Kelly, H.W. (2005) What is new with the b2-agonists: Issues in the management of Sources of funding
asthma. Ann. Pharmacother. 39, 931-938.
Leach, C.L., Davidson, P.J. and Bourdeau, R.J. (1998) Improved airway targeting with Supported by Trudell Medical International, London, Ontario, the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC- Canada, the state of Indiana and the Purdue University School beclomethasone. Eur. Respir. J. 12, 1346-1353.
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(2008) Report of the 3rd Havemeyer workshop on allergic diseases of the horse,
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a nebulizer and two small volume spacers. Pediatr. Pulmonol. 23, 212-216.


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