ORIGINAL ARTICLE

Effect of Single Inhalation of a Salbutamol, Ipratropium

Bromide and Beclomethasone on Mucociliary Clearance in
Patients With Chronic Obstructive Airway Disease

R. Guleria, Th. Rajendra Singh, Sanjeev Sinha, K. Padhy1, K. Gupta1 and J.N. Pande

Departments of Medicine and Nuclear Medicine 1, All India Institute of Medical Sciences, New Delhi, India

ABSTRACT
Background. Chronic obstructive airway disease (COAD) is associated with hyperplasia and
hypertrophy of the mucus producing glands. The beneficial effect of inhaled drug may be due
to improved mucociliary function. The present study was done to evaluate the effect of
salbutamol, ipratropium bromide and beclomethasone dipropionate inhalation on mucociliary
clearance in patients with COAD.
Methods. Ten patients of COAD were taken up, two patients however did not complete the
study. Salbutamol, ipratropium bromide, beclomethasone dipropionate and placebo inhalation
were given randomly to each patient on four separate days. Radioaerosol inhalation lung cine-
scintigraphy after inhalation of the different drugs was followed up to two hours and than after
24 hours.
Results. There was no significant visually noticeable increased mucociliary clearance on any of
the days. Two patients showed definite steep slope in the time activity curves with salbutamol
as compared to other drugs or placebo. All the quantitative indices analysed at the end of one
hour and two hours for the three drugs were comparable to placebo.
Conclusions. A single dose of inhaled salbutamol, ipratropium bromide and beclomethasone
dipropionate has no appreciable effect on mucociliary clearance in patients with COAD.

Key words : Mucociliary clearance, Chronic obstructive airway disease.

[Indian J Chest Dis Allied Sci 2003; 45 : 241-246]

INTRODUCTION principal mechanisms, i.e. mucociliary clearance

and coughing 2-4. Impairment of mucociliary
Chronic bronchitis is a condition associated clearance function may play a role in chronic
with excessive tracheobronchial mucus bronchitis5. It is not uncommon for patients with
production sufficient to cause cough with irreversible airway obstruction to report
expectoration for at least three months of the subjective benefit from the use of beta-
year for more than two consecutive years 1 . adrenergic therapy despite a lack of
Clearance of airway secretion occur by two improvement in tests reflecting the airway
[Received : March 20, 2002; accepted after revision : August 26, 2002]
Correspondence and reprints request : Dr Randeep Guleria, Additional Professor, Department of Medicine, All
India Institute of Medical Sciences, New Delhi-110 029, India; Tele. : 91-11-6593676; Telefax : 91-11-6862663;
E-mail : <randeepg@hotmail. com>.
242 Mucociliary Clearance in COAD R. Guleria et al

caliber. One possible explanation may be the the study was obtained from all the patients.
stimulation of mucociliary clearance indepen- Detailed history and physical examination was
dent of bronchodilation6. done and recorded on a proforma. Chest
radiograph (PA view) was also obtained.
Few studies of mucociliary clearance have
Spirometry and lung volume estimation was
been done until the recent introduction of
done on electronic lung function machine (PK
radioaerosol lung scintigraphy as a new tool.
Morgam, UK). Patients were advised to stop all
This tool is useful in dynamically demonstrating
the drugs 12 hours before the study. On each
the deposition pattern of inhaled radioaerosol in
day, on a random basis, patients were either
the lungs and how the deposited radioactivity is
given salbutamol 2 puffs (100 µg/puff),
cleared from the lungs with time. Thus,
ipratropium bromide 2 puffs (20 µg/puff),
mucociliary clearance can be assessed.
beclomethasone 2 puffs (100 µg/puff) or placebo
The effect of pharmacological agents on the 2 puffs through a MDI as described.
clearance of airway secretions has been
Radioaerosol inhalation lung cine-
debatable. In vivo studies have indicated that
scintigraphy using the study drugs was carried
beta-2 stimulators increase ciliary beat
out in the Department of Nuclear Medicine as
frequency 7,8. However, whether beta-agonists
follows : On day 1, after a preliminary physical
increase mucociliary clearance in the lungs is
examination to make sure that the patient did
still an unanswered question. Similarly
not have symptomatic bronchospasm, he was
ipratropium bromide, an anticholinergic drug,
made to sit comfortably in a chair and relax for
has been used effectively in the treatment of
10 minutes. Then Technetium 99m phytate
chronic obstructive airway disease (COAD).
radioaerosol generated through BARC (Bhaba
One study 9 has demonstrated facilitated
Atomic Research Center) nebuliser was given
clearance following administration of the drug
through a mouth piece during tidal breathing.
in healthy subjects. The effect of ipratropium
The radioaerosol solution used contained 20
bromide on mucociliary clearance in chronic
micro curie (mci) of radioactivity. The size of
bronchitis is unclear. Also there is little data on
aerosol produced by the BARC nebuliser was
whether inhaled steroids, by virtue of their anti-
0.84 micron in activity median aerodynamic
inflammatory action, have any affect on
diameter (AMAD) with geometric standard
mucociliary clearance in patients with COAD.
deviation of 1.73. The patient was asked to
The present study was carried out to evaluate inhale the aerosol for about three minutes so
and compare the effect of a single inhalation of that about 2 mci, i.e. one-tenth of total
salbutamol, ipratropium bromide and preparation was deposited inside the thorax.
beclomethasone on mucociliary clearance in Immediately later, the test one puff of the
patients of COAD. chosen drug was given from a MDI in the same
position. About 10 seconds of breath holding
was observed after inhalation. A second dose of
MATERIAL AND METHODS the drug administered after five minutes.
The patient was then made to lie comfortably
Ten patients of COAD, attending the
in the supine position on the examination table
Medicine out-patient's department and chest
under a gamma camera. Radioactivity in the
clinic were included in the study. These were
thorax was continuously measured in sequential
chronic smokers who met the Medical Research
frame mode anteriorly for two hours. One
Council (UK) 1 criteria of chronic bronchitis.
hundred and twenty, 60 seconds frames were
Patients were excluded from the study if they
stored in the computer. At the end of the
had associated right ventricular failure,
recording period, a static transmission image
arrhythmia, valvular disease, and respiratory
was obtained. During the procedure, two
failure or associated acute illness.
observations were made. First, aerosol
Informed written consent for participation in deposition patterns in the lungs was inspected
2003; Vol. 45 The Indian Journal of Chest Diseases & Allied Sciences
and secondly, for quantitative analysis, the 120
frames were sequentially divided into 8 parts,
each representing a sequential 15 minutes
process consisting of 15 original frames. These
sequential 15 frames were then lumped together
to make one frame. Thus, eight new frames
were made out of 120 frames in all. Radio-
activity in the first new frame covering the
initial 15 minutes after radioaerosol inhalation
was the basis for the subsequent calculation and
comparison. The patient was called the next day
to measure the radioactivity that remained in
the thorax at the end of 24 hours to determine
the alveolar deposition ratio. Similar study was
performed on four days. The different parame-
ters were calculated as explained below.
Data Analysis
Following correction for radioactivity
background and obtaining a physically half-life-
corrected time activity curve from the right
lung, time activity curve was visually inspected
and the following quantitative parameters to
assess mucociliary clearance were calculated for
each 15 minutes period for the ciliated airways
in the right lung. The left lung was excluded
because of possible contamination of
radioactivity from the stomach. Data analysis
was done using the following equations:
A = Radioactivity in the extrapulmonary
ciliated airway
B = Radioactivity in the intrapulmonary
ciliated airways.
C = Radioactivity in the poorly ciliated or non
ciliated airways and/or the alveoli.
T = Total radioactivity.
The total radioactivity at ‘0’ time will be,
T0 = A0 + B0 + C0
In actual calculation the radioactivity in the
compartment A was not taken into consi-
deration by obviating measurement of
radioactivity over the mediastinum. Thus,
T0 = B0 + C0
The radioactivity present in the alveolar
compartment does not clear and remains till 24
243
hours. Therefore, the radioactivity remaining in
the lungs at 24 hours (Ct), which is defined as
the alveolar deposition, would be equal to Co.
C0 will thus be equal to Ct at 24 hours. Hence,
the modified equation is :
T0 = B0 + C0
= B0 + Ct
The various parameters and equations used to
evaluate intrapulmonary mucociliary clearance
are discussed in table 1.
Statistical Analysis
Statistical analysis was done using statistical
package Statistics 4.0 (an analytical form of
statistics). Two-way ANOVA test was used to
look for any significant difference in the
mucociliary effect between placebo and the
three different drugs at the end of 1 hour and
2 hour, respectively. Wilcoxon sign rank test was
used to look for any significant difference
between the 1 hour and 2 hour observations for
drugs.
RESULTS
Demographic Profile
Eight patients completed the study. Their
mean age was 52 years. All were males. The
mean duration of symptoms was 2.5 years. The
mean FEV 1 , expressed as a percentage of
predicted, was 66.71 ± 25.45 and the mean FEV1
FVC% was 68.9 ± 15.3.
Radioaerosol Inhalation Lung Cine-scinti-
graphy
On visual inspection, the radioaerosol
deposition was mainly in the central large and
medium sized airways. However, the deposi-
tion tended to be slightly peripheral when
salbutamol was given. There was no significant
visually noticeable increased cine-scintigraphic
mucociliary clearance with any of the drugs.
With salbutamol two patients showed a definite
steep slope in the time activity curves as
244 Mucociliary Clearance in COAD R. Guleria et al

Table 1. The various parameters are to evaluate intrapulmonary mucociliary clearance

1. Lung Retention Ratio = Tt
× 100
(LRR) (%) T0

= amount of radioactivity remaining in the lungs at the time

‘t’ relative to the total radioactivity initially deposited.

2. Airway Deposition Ratio = Bt Tt – C0

(ADR) (%) × 100 = × 100
T0 T0
= percentage of radioactivity initially deposited that has
occupied the ciliated airways by time ‘t’. In another words,
amount of radioactivity throughout the ciliated airways
relative to the total radioactivity initially deposited in the
lungs.

3. Airway Retention Ratio = Bt Tt – C0

(ARR) (%) × 100 = × 100
B0 T0 – C 0
= percentage of radioactivity initially deposited on the
ciliated airways that has been retained by time ‘t’.

4. Airways Clearance Efficiency = B0 – Bt × 100

(ACE) (%) B0
= percentage of radioactivity deposited on the ciliated
airways that has already been cleared by time ‘t’.

5. Alveolar Deposition = C0 × 100

(AIDR) (%) T0
= Percentage of the total initial radioactivity deposited in the
non-ciliated alveolar space relative to the total radioactivity
deposited in the lung.
Tt – amount of radioactivity in the lung at time t.
To – total amount of radioactivity initially deposited in the lung, i.e. at time 0.
Bt – amount of radioactivity present in the intra, pulmonary ciliated airways at time t.
B0 – amount of radioactivity initially deposited in the pulmonary ciliated airways at time 0.
C0 – amount of radioactivity initially deposited in the non-ciliated alveolar space, i.e. at time 0.

compared to the other drugs. The time activity are provided in table 2. However, the temporal
curve with other drugs was not different from difference in mucociliary clearance was not
that of placebo. significant among these drugs and placebo.

Quantitative Indices
All the quantitative indices analysed by two-
way ANOVA at the end of one hour and two
hour with the three drugs were not significantly
different when compared with placebo (Table 2).
The mucociliary clearance was better during the
first one hour with all the three drugs as well as
with placebo as determined from the airways
clearance efficiency (2 hr – 1 hr). These results
DISCUSSION
The main objective of our study was to find
out whether salbutamol, beclomethasone and
ipratropium bromide given through MDI as a
single dose enhanced mucociliary clearance in
patients with COAD. Our present study is
largely comparable in methodology to the
recent studies by Isawa et al10 and Claudio et al11.
2003; Vol. 45 The Indian Journal of Chest Diseases & Allied Sciences 245

Table 2. Radioaerosol lung scintigraphy quantitative parameters in COAD at 1 and 2 hours (mean ± SD)
Parameter Placebo Salbutamol Ipratropium Beclomethasone
LRR
1st hourns 85.21 ± 6.63 79.63 ± 14.32 84.52 ± 8.11 85.68 ± 12.98
2nd hourns 76.35 ± 8.72 69.73 ± 16.21 75.47 ± 14.60 76.32 ± 15.02
Change 8.8 ± 4.04* 9.9 ± 6.4* 9.02 ± 8.2* 9.3 ± 4.2*
ADR
1st hourns 51.96 ± 26.42 45.52 ± 25.02 59.51 ± 20.61 52.57 ± 27.57
2nd hourns 43.13 ± 26.67 36.33 ± 26.18 51.72 ± 23.33 43.68 ± 29.00
Change 8.8 ± 4.07* 9.2 ± 6.7* 7.8 ± 5.3* 9.32 ± 4.2*
ARR
1st hourns 72.40 ± 20.48 67.32 ± 18.46 77.86 ± 12.57 75.45 ± 21.23
2nd hourns 17.56 ± 29.48 51.02 ± 22.33 66.02 ± 20.78 59.23 ± 27.72
Change 16.2 ± 11.7* 16.3 ± 12.1* 11.8 ± 9.4* 16.9 ± 10.8*
ACE
1st hourns 27.22 ± 19.94 36.83 ± 21.11 20.90 ± 11.35 24.48 ± 21.26
2nd hourns 43.82 ± 29.48 48.98 ± 22.33 33.97 ± 20.78 41.38 ± 28.32
Change –16.2 ± 11.7* –15.9 ± 12.4* –13.1 ± 11.7* –16.9 ± 10.8*

ns: The p values are not significant (p>0.05) by two-way ANOVA; 1 and 2 hour readings compared with
each group by Wilcoxon sign rank test.
LRR; Lung retention ratio, ADR; Airway deposition ratio, ARR; Airway retention ratio, ACE: Airway
clearance efficiency.
* : Change between 1st and 2nd hour (p<0.05)

We also carried out continuous recording of
radioaerosol clearance for the test period that
alleviates any discrepancies in the result that
might arise from repositioning of the patients
before the gamma camera. Unlike previous
workers, we examined the clearance effect of the
drug on separate days with the placebo. This is
because of the assumption that giving placebo
and test-drug on the same day would take
longer time and hence increase the chances of
getting an error due to inadvertent movement of
the patients. Secondly, as there were three test-
drugs the whole study consisting of the
combinations of test drug and placebo would
become more cumbersome.
It has been suggested that β 2 -agonists
accelerate mucociliary clearance7,8. This should
lead to a faster transport of the radioactive
mucus in radioaerosol inhalation lung-
scintigraphy leading to a steeper change in the
slope of the time activity curve and a significant
change in the quantitative parameters. This was
not seen in our study when salbutamol was
used. In two patients, however, a steep curve
was noticed and it is possible that some
improvement in mucociliary clearance occurred
in these patients. It could be due to the reason
that salbutamol improves mucociliary clearance
in a subset of patients with COAD. A larger
sample size would, thus, be needed to answer
this question. We used 200 micrograms of
salbutamol in the present study as this is the
dose routinely used to achieve broncho-
dilatation. It has been suggested that significant
mucociliary clearance may occur with a dose
500 micrograms. This remains to be confirmed.
In humans, ipratropium is believed not to
alter the volumetric and rheologic properties of
secretion12,13. Different studies have demons-
trated no impairment in clearance of lung
secretion following the inhalation of
ipratropium aerosol in healthy subjects9,14 and
patients with bronchial asthma15,16 and chronic
bronchitis17,18. However, one study19 demons-
trated an enhancement of clearance in healthy
subjects. In the present study, we were not able
246 Mucociliary Clearance in COAD
to find any improvement in mucociliary
clearance after ipratropium bromide inhalation
in the dose used.
Anti inflammatory drugs like corticosteroids
decrease inflammation and edema and may
thus improve mucociliary clearance. This action
may manifest after use of inhaled steroids for a
prolonged period. We did not find any
immediate improvement in mucociliary
clearance after inhalation of a single dose of
inhaled corticosteroids.
In summary, salbutamol seemed to improve
mucociliary clearance in some patients with
COAD, although not in the group as a whole.
Further, neither ipratropium bromide nor
beclomethasone inhalation showed any
immediate improvement in mucociliary
clearance over placebo in patients with COAD.
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