Download Comparative efficacy of inhaled albuterol between two handheld

EQUINE VETERINARY JOURNAL
Equine vet. J. (2011) •• (••) ••-••
doi: 10.1111/j.2042-3306.2010.00313.x
1
Comparative efficacy of inhaled albuterol between two
hand-held delivery devices in horses with recurrent
airway 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
Summary
Reasons for performing study: Studies investigating the
clinical efficacy of albuterol administered with the same
propellant and commercially available delivery devices
in horses with recurrent airway obstruction (RAO) are not
currently available.
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
environment and fed mouldy hay to induce airway
obstruction. Lung mechanics were measured before and
after the procedure. DPmax was measured 5 min after
administration of 180 mg of albuterol from a pressurised
metered dose inhaler, using an aerosol delivery device chosen
randomly. This process was repeated every 5 min until
maximal bronchodilation was achieved. After a 24 h washout
period, lung mechanics data were again collected using the
other aerosol delivery device.
Results: Aerosolised albuterol induced a significant and rapid
bronchodilation in the horses using both aerosol delivery
devices. No statistically significant difference in pulmonary
function was observed in response to albuterol therapy
between the 2 devices. The dose required to achieve 50% of
maximal bronchodilation was not statistically different
between the 2 devices (173.35 ⫾ 78.35 mg with Device 1 and
228.49 ⫾ 144.99 mg with Device 2, P = 0.26). The decrease in
lung resistance tended to be more pronounced after albuterol
administration with Device 1 (P = 0.066).
Conclusions: Aerosolised albuterol is an effective
bronchodilator in horses with recurrent airway obstruction.
There is no statistically significant difference between the
2 commercially available aerosol delivery devices in terms
of efficacy.
Potential relevance: Aerosolised albuterol is effectively
delivered using currently available devices leading to
maximal bronchodilation in horses with RAO at an average
dose of 540 mg.
Abbreviations
Cdyn:
DPmax:
pMDI:
RAO:
RL:
evj_313
Dynamic lung compliance
Maximum change in transpulmonary pressure
Pressurised metered-dose inhaler
Recurrent airway obstruction
Pulmonary resistance.
1..6
Introduction
Recurrent airway obstruction (RAO) is the most frequent
cause of chronic respiratory tract disease in horses (Hotchkiss
et al. 2007a), characterised by airway inflammation and
bronchospasm with phases of remission when a horse’s
environment is improved (Robinson et al. 1996). During disease
exacerbation, bronchoconstriction, airway wall oedema and
accumulation of mucus result in obstruction of the distal airways.
These mechanisms induce functional changes: maximum change in
transpulmonary pressure (DPmax) increases, pulmonary resistance
(RL) increases and dynamic lung compliance (Cdyn) decreases
(Gillespie et al. 1966; Couëtil et al. 2001). Recurrent airway
obstruction is believed to be an allergic reaction to organic dusts
and has many similarities with human asthma (Ghio et al. 2006;
Marti et al. 2008).
Inhaled short-acting b2-receptor agonists are the most effective
medication for relieving acute bronchospasm (Anon 2007).
Albuterol is the most commonly prescribed medication for asthma
in man worldwide (Kelly 2005). Short-acting b2-receptor agonists,
amongst other actions, mediate vasodilation and bronchodilation
(Weiss et al. 2006). In human medicine, nebulisers and spacer
devices are popular means of delivering aerosols. Small volume
spacers, composed of a mouth piece and holding chamber with
valves, have been developed for patients such as infants to avoid
having to precisely coordinate actuation of the pressurised
metered-dose inhaler (pMDI) and inhalation. Spacers have been
shown to be clinically effective and result in fewer side effects from
medication residue in the oral cavity (Clarke et al. 1993). Aerosol
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]
© 2011 EVJ Ltd
2
Comparative efficacy of inhaled albuterol between two hand-held delivery devices
volume spacer than from a nebuliser (Wildhaber et al. 1997).
In equine medicine, various aerosolised drugs have been used
successfully for the treatment of RAO (Rush et al. 1998; Derksen
et al. 1999; Couëtil et al. 2005). Aerosolised bronchodilators
administered with pMDI are effective and associated with minimal
side effects. In particular, aerosolised albuterol has been shown to
be a valuable bronchodilator with rapid onset in the treatment of
RAO (Derksen et al. 1999; Rush et al. 1999). This type of therapy
requires specialised devices to optimise drug delivery in the equine
lung. Convenient delivery devices have been described in horses
(Tesarowski et al. 1994; Derksen et al. 1996). Some of these
devices use a nose piece, which fits inside the horse’s nose, instead
of a face mask to deliver a known dose of any given drug from a
pMDI into the equine lung (Derksen et al. 1996). The relative
percentage of a drug deposited in the lung varies based on
the device used and the type of propellant. However, data on the
efficacy of inhaled albuterol using available delivery devices are
not available. Currently, 2 aerosol delivery devices that do not
require a face mask are commercially available. A study using
delivery Device 1 (Aerohippus)1 found that 18.2 ⫾ 9.3% of
administered beclomethasone dipropionate with hydrofluoroalkane
(HFA) propellant is deposited in the lung (Hoffman et al. 2008).
Another study, using delivery Device 2 (Equine Haler)2, reports
that 8.2 ⫾ 5.2% of administered fluticasone propionate with
chlorofluorocarbons (CFC) propellant is deposited in the equine
lung (Funch-Nielsen et al. 2001). These 2 studies focused on lung
deposition exploring 2 different drugs administered with 2 different
propellants. In human medicine, it has been demonstrated that the
choice of a propellant considerably influences lung deposition
(Leach et al. 1998; Harrison 2002). However, CFCs have been
banned from albuterol pMDI since 2008 in most countries
and replaced by HFA. Studies investigating the clinical efficacy
of albuterol administered with the same propellant and the
commercially available delivery devices in horses with RAO are
not currently available.
The purpose of this study was to evaluate if aerosolised
albuterol administered to horses with RAO using aerosol delivery
devices currently commercially available have comparable efficacy
on lung function and to provide clinicians with guidelines for the
selection of an aerosol delivery device.
Materials and methods
Horses
Ten horses (5 mares and 5 geldings), age 7–29 years, with inducible
and reversible airway obstruction that are part of the RAO-affected
herd belonging to Purdue University were used in the study. All
horses had been housed on pasture and fed a pelleted diet for at
least 3 months to ensure remission from disease. At the beginning
of the study, abnormalities were not detected during physical
examination of the horses. The horses were then exposed to a dusty
environment by housing them in a barn and placing mouldy hay and
straw 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
wearing an N95 face mask. The horses remained in the confined
environment until they developed clinical signs of RAO. Clinical
scores were assigned to each horse once daily by use of a scale
adapted from Tesarowski et al. (1996) to screen for the onset of
airway obstruction. The scale ranges from 0–21 and a clinical score
© 2011 EVJ Ltd
of ⱖ12 was considered sufficient to warrant lung function testing.
For inclusion in the study, a maximum change in transpulmonary
pressure (DPLmax) ⱖ15 cmH2O was required after the induction
period. If that pressure was achieved, lung mechanics were
measured at baseline and the horse was enrolled in the treatment trial
using one of 2 aerosol delivery devices chosen at random. The horse
then returned to its stall in the dusty environment for a minimum
of 24 h washout period. The following day, if the horse met the
inclusion criteria, lung mechanics data were again collected using
the other aerosol delivery device. If the criteria were not met, the
horse was maintained in the dusty environment until inclusion
criteria were met. This protocol was approved by the Purdue Animal
Care and Use Committee. Horses were to be removed from the
study if they became anorectic for >24 h.
Aerosol delivery devices
Two aerosol delivery devices, both commercially available,
referred to as Devices 1 and 2 (Fig 1), were used for albuterol
administration using a pMDI and HFA propellant. Both devices are
hand-held chambers connected to a nose mask which is placed over
one nostril. The pMDI was inserted into the back piece of the
chamber where the breathable particles were suspended until the
horse breathed them through a one-way valve. The device was held
on the nostril for 3 respiratory cycles to ensure complete inhalation
of the dose. The breathing chamber of Device 1 was a cylinder
whereas the breathing chamber of Device 2 was an ellipsoid.
Lung mechanics
Oesophageal pressure was measured using a balloon catheter
(internal diameter 4.8 mm; outside diameter 6.4 mm; 240 cm in
length), which was advanced to the mid-thoracic region and
connected to a pressure transducer. The balloon was a condom
taped around the catheter tip and inflated with 3 ml of air. The
position of the balloon was recorded for each horse at the time
of baseline testing prior to induction of RAO exacerbation and
used subsequently for all lung mechanics tests. Transpulmonary
pressure was defined as the difference between oesophageal
pressure and atmospheric or mask pressure, depending on whether
the horse was fitted with a facemask or not. When measuring
Device 2 (Equine Haler)
Albuterol HFA
Device 1 (AeroHippus)
Fig 1: Delivery Devices 1 and 2 and albuterol metered-dose inhaler used in
the study.
F. R. Bertin et al.
TABLE 1: Mean ⫾ s.d. maximal changes in pleural pressure (DPLmax),
dynamic compliance (Cdyn) and pulmonary resistance (RL) recorded
with the mask before (pre) and at the maximum effect after (post)
administration of aerosolised albuterol
DPLmax pre (cmH2O)
DPLmax post (cmH2O)
Cdyn pre (l/cmH2O)
Cdyn post (l/cmH2O)
RL pre (cmH2O/l/s)
RL post (cmH2O/l/s)
ΔPLmax cm H20
airflow, a mask was fitted around the horse’s nose with a
pneumotachometer coupled to a pressure transducer that generated
a signal proportional to airflow. Output signals were recorded by
computer software as previously reported (Couëtil et al. 2001). At
least 10 respiratory cycles from breaths devoid of artefacts were
selected for analysis.
For each trial, baseline measurements of lung mechanics
including airflow, change in transpulmonary pressure (DPLmax) were
recorded. Values for resistance (RL) and compliance (Cdyn) were
computed in accordance with the method described by Amdur and
Mead (1958). The mask was then removed and another baseline
DPLmax measured. The horse was then given 2 puffs (180 mg) of
albuterol (Ventolin)3 using one of the 2 delivery devices and DPLmax
was 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.
3
Device 1
Device 2
P value
31.92 ⫾ 11.44
12.73 ⫾ 3.83
0.53 ⫾ 0.30
0.92 ⫾ 0.37
1.86 ⫾ 1.07
0.58 ⫾ 0.58
36.36 ⫾ 17.62
20.20 ⫾ 20.54
0.49 ⫾ 0.37
0.79 ⫾ 0.42
1.95 ⫾ 1.53
1.42 ⫾ 1.99
0.51
0.27
0.79
0.46
0.88
0.20
50
45
40
35
30
25
20
15
10
5
0
Device 1
Device 2
0
Statistical analysis
200
400
600
800
1000
Albuterol (μg)
Results
Fig 2: Mean ⫾ s.d. maximal changes in pleural pressure (DPLmax) recorded
without the mask before (0) and after subsequent administrations of
aerosolised albuterol with Devices 1 and 2 (P = 0.26).
80
70
60
% of reduction
Mean ⫾ s.d. were calculated for data that followed normal
distribution and median (range) for data with non-normal
distribution. Comparison of normally distributed data between
treatment groups (Device 1 vs. Device 2) was made using a paired
t test. Other data were compared using a Wilcoxon signed rank
test. 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 albuterol
were 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 measures
ANOVA. Post hoc tests were used when appropriate. Significance
was defined as P<0.05.
50
40
Device 1
Device 2
30
20
10
0
All the horses met the inclusion criteria within 3 weeks of exposure
to the dusty environment. The median clinical score before lung
function test was 16/21 (9–19). Lung mechanics (DPLmax, RL and
Cdyn) before administration of albuterol were not statistically
different between the 2 treatment trials (P = 0.51, P = 0.88, P = 0.79,
respectively). Lung mechanics (DPLmax, RL and Cdyn), after the
maximum effect on DPLmax was reached by administration of
albuterol with either spacer, were not statistically different
(P = 0.27, P = 0.20, P = 0.46, respectively; Table 1).
Albuterol administered by both delivery devices induced a
significant decrease in DPLmax (P<0.001), a significant increase
in Cdyn (P<0.001) and a significant decrease in RL (P<0.001).
Albuterol administered by both delivery devices induced a dosedependent response and the responses were not statistically
different between devices (P = 0.26; Fig 2). There was no statistical
difference between the maximal reduction of DPLmax observed with
albuterol administered with either mask, either in absolute value (P
= 0.44) or in percentage of reduction (P = 0.39; Fig 3). The mean
dose required to reach the plateau effect was 540 mg (6 puffs). No
Device
Fig 3: Mean ⫾ s.d. percentage of reduction of initial maximal changes in
pleural pressure (DPLmax) after subsequent administrations of aerosolised
albuterol with Devices 1 and 2 (P = 0.39).
significant further reduction of mean DPLmax was observed by
increasing the dose beyond 540 mg. However, the response was
very variable from one horse to another. Among the 20 tests
performed, maximum reduction of DPLmax was achieved after 2
puffs in 4 tests (3 with Device 1 and one with Device 2), after 4
puffs in 2 tests (one with each device), after 6 puffs in 8 tests
(2 with Device 1 and 6 with Device 2), after 8 puffs in 4 tests
(all with Device 1) and after 10 puffs in 2 tests (all with Device 2).
The absolute and relative reduction in RL following
administration of the last albuterol dose tended to be higher
with Device 1 (1.10 [-0.07–3.31] cmH2O/l/s; 65.1 [7.9–89.0]%;
P = 0.066) than with Device 2 (0.68 [0.61–1.99] cmH2O/l/s;
53.7 [20.0–79.1]%). The absolute decrease in RL post albuterol
challenge was greater with Device 1 in 6 horses but greater with
© 2011 EVJ Ltd
4
Comparative efficacy of inhaled albuterol between two hand-held delivery devices
400
Albuterol (μg)
350
300
250
200
Device 1
Device 2
150
100
50
0
Device
Fig 4: Mean ⫾ s.d. dose of aerosolised albuterol required to observe 50%
of reduction of maximal changes in pleural pressure (DPLmax) with Devices
1 and 2 (P = 0.31).
Device 2 in 2 horses. In one horse RL increased after albuterol
administration with both devices and RL measurement was
unavailable prealbuterol in one horse.
The dose of albuterol required to reach 50% of the maximum
effect on DPLmax was not statistically different between Device 1
(173.35 ⫾ 78.35 mg) and Device 2 (228.49 ⫾ 144.99 mg, P = 0.31;
Fig 4).
Discussion
The 10 horses completed the study protocol and they inhaled the
medication with ease. They did not exhibit any adverse effects of
b2-agonist therapy and no horse exhibited anorexia throughout
the study duration.
During exposure, the 10 horses exhibited clinical signs of RAO
and experienced altered DPLmax, RL and Cdyn as previously reported
(Tesarowski et al. 1996; Rush et al. 1998; Derksen et al. 1999).
Administration of albuterol significantly improved pulmonary
function parameters in all the tested horses. These findings are
consistent with published studies (Derksen et al. 1999; Rush
et al. 1999).
No statistically significant difference was noted in DPLmax, RL
and Cdyn before the treatment trial using delivery device. These
results indicate that a 24 h washout period between the 2 trials was
adequate and are consistent with the fact that during exacerbation
of the disease, a horse’s pulmonary function remains relatively
stable (Jean et al. 1999).
All doses of albuterol induced a significant decrease in
DPLmax within 5 min of administration, which indicates a rapid
improvement of airway obstruction. These results are similar to
those reported using fenoterol (Tesarowski et al. 1994) and albuterol
(Derksen et al. 1999; Rush et al. 1999) delivered by pMDIs
combined with other delivery devices. However, in this study, the
mean dose required to reach the plateau effect was 540 mg (6 puffs).
No significant further bronchodilation was observed by increasing
the dose beyond 540 mg. This dose is higher than the dose of 360 mg
previously reported (Derksen et al. 1999). Since the same HFA
propellant was used in both studies, the difference may be explained
by the higher percentage of drug deposited in the lungs using the
device that is no longer commercially available.
No statistically significant difference was noted in DPLmax, RL
and Cdyn after the treatment trial using either delivery device. These
results suggest that the 2 devices achieved a similar amount of drug
deposition in the lungs. Data variability post albuterol
© 2011 EVJ Ltd
administration was higher with Device 2 than with Device 1
especially 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 and
results 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 (FunchNielsen et al. 2001; Hoffman et al. 2008). These results should be
interpreted with caution because the studies were not peerreviewed. Nevertheless, based on these data we would expect the
dose of albuterol required to achieve 50% of the maximum effect
on DPLmax with Device 1 to be approximately half that required with
Device 2. In fact, the dose required with Device 1 was only 24%
lower and that difference was not statistically significant. The
higher lung deposition reported with Device 1 was obtained with
beclomethasone dipropionate and an HFA propellant while the
lower deposition was with fluticasone propionate and a CFC
propellant (Funch-Nielsen et al. 2001; Hoffman et al. 2008).
Human clinical trials indicate that relative drug deposition in the
lungs is approximately 2-fold higher with HFA than with CFC
propellant for drugs such as beclomethasone and flunisolide
(Richards et al. 2001; Harrison 2002). Therefore, lung deposition
of beclomethasone-HFA in horse’s lungs using Device 2 would be
expected to be around 16.4% which is similar to the 18.2% reported
for Device 1 delivering the same drug formulation. This
extrapolation is consistent with the present study findings.
The study revealed that albuterol delivered with Device 1
resulted in a 34% greater improvement in RL than with Device 2 but
this difference did not reach statistical significance. Conducting
additional studies with a larger number of horses would be helpful
to confirm if the 2 devices achieve significantly different drug
delivery levels and require different dose recommendation for the
treatment of RAO.
Pulmonary function is traditionally quantified using DPLmax,
RL and Cdyn. In this study, only DPLmax has been measured between
individual administrations of albuterol. In other reports, DPLmax
and RL appeared to be the most sensitive markers of improved
airway obstruction in horses with RAO (Robinson et al. 1993;
Tesarowski et al. 1994; Derksen et al. 1996; Rush et al. 1998).
Measurement of DPLmax does not require a mask fitted around
the horse’s nose with a pneumotachometer coupled to a pressure
transducer. However, DPLmax is also influenced by voluntary
breathing efforts and may vary with excitement or tachypnoea.
In this study, RL was also measured before and after the last dose
of albuterol confirming the fact that improvement in lung function
was due to reduced airway obstruction and not just changes in
breathing strategy.
Bronchodilation induced by albuterol lasts for 30–60 min
(Derksen et al. 1999). During the study we chose to administer
albuterol 2 puffs at a time in order to reduce the time elapsed
between the first administration of albuterol and the last
measurement. Using this method, the time required to administer
the maximal dose (900 mg or 10 puffs) and perform the
last measurement was 32 min on average. If the mask were
repositioned to perform a complete measurement of the lung
function between each administration, the incremental doseresponse 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 of
albuterol was still present when the last measurement of pulmonary
function was performed. This assumption was reinforced by the
fact that DPLmax either continued to decrease or reached a plateau
as increasing dosages were delivered but it never increased by the
time 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)
while others required 10 (900 mg). Also, most of the improvement
in DPLmax was seen within the first few puffs after which the effect
levelled off. As reported in other studies (Derksen et al. 1996),
small airways of horses with RAO are occluded by mucus, airway
wall thickening and bronchospasm, thus resulting in unpredictable
amount of inhaled drug deposition. Furthermore, horses did not
reach the same clinical score or degree of airway obstruction based
on lung function testing. It is likely that some horses were more
affected and therefore produced more mucus and experienced
more severe bronchospasm resulting in decreased lung deposition
of albuterol. However, all the horses had an improved lung
function test after repeated administration, possibly because an
initial bronchodilation aided drug deposition during the subsequent
administration.
According to the third Expert Panel Report on Diagnosis and
Management of Asthma (Anon 2007), short-acting b2-agonists are
the most effective medication for relieving acute bronchospasm;
however, increasing the use of short-acting b2-agonists treatment
or using short-acting b2-agonists >2 days/week for symptom
relief indicates an inadequate control of asthma in addition to the
need for initiating or intensifying anti-inflammatory therapy.
Similarly in horses, the use of short-acting b2-agonists such as
albuterol is only recommended as rescue medication, as a
diagnostic test for RAO or as therapy in combination with inhaled
corticosteroids. In addition, the emphasis should be placed on the
need to improve the environment of a horse affected by RAO by
limiting antigen inhalation, particularly thermophilic moulds and
actinomycetes that grow in mouldy hay (Robinson et al. 1996;
Hotchkiss et al. 2007b).
In conclusion, aerosolised albuterol from a pMDI administered
with either of 2 commercially available delivery devices is an
effective bronchodilator in horses experiencing RAO crises.
However, the primary therapy for horses affected by RAO should
focus on managing and controlling their environment.
Conflict of interest
The authors declare no conflict of interest.
Sources of funding
Supported by Trudell Medical International, London, Ontario,
Canada, the state of Indiana and the Purdue University School
of Veterinary Medicine Research account funded by the total
wager tax.
Acknowledgements
The authors thank Donna Griffey, Jessica Squires, Mitchell
Jessup, Christina Carey and Caroline Chauché for their technical
assistance.
5
Manufacturers’ addresses
1
Trudell Medical International, London, Ontario, Canada.
Equine Health Care Aps, Horsholm, Denmark.
GlaxoSmithKline, Brentford, Middlesex, UK.
2
3
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