Br. J. Dis.

Chest (1986) 80, 170

A COMPARISON OF METERED DOSE

INHALERS WITH NEBULIZERS FOR THE
DELIVERY OF IPRATROPIUM BROMIDE
IN DOMICILIARY PRACTICE

K. A. GUNAWARDENA, A. P. SMITH
AND J. SHANKLEMAN
Llandough Hospital, Penarth, South Clamorgan CF6 1XX

Summary

In a randomized, double-blind, crossover study consisting of three l-month periods, we

compared the effects of ipratropium bromide (IB) 120 lug delivered by a metered dose
inhaler (MDI) against two different doses of IB (125 lug and 500 pug) delivered by a gas
driven nebulizer.
Thirty-two patients (mean age 57.1 years, range 17-78) with severe airflow obstruction
(mean PEFR 192 litres/min, range 75-380 litres/min) were recruited to the study. They
had a maximum documented reversibility of over 20% (mean 55.2, range 25-200), and an
improvement of over 13% (mean 26.3, range 13-56) in the PEFR to a test dose of 120 ,ug
IB delivered by a MDI. In the 20 patients who completed the trial no significant differ-
ences were found between the treatment periods when comparisons were made of the
weekly averages for the morning PEFR, evening PEFR, reversibility, diurnal variation of
the PEFR, bronchodilator and steroid usage. The monthly assessments of FEV,, FVC,
VC, RV/TLC ratio and the single breath transfer factor showed all three treatments to be
better than the base-line assessment (P<O.OOl), but overall there was no significant
difference between treatments. The 6-minute walking distance did not show any improve-
ment over the base-line values with any of the treatments. Symptom scores also showed no
overall difference between treatments except for cough which was worse on the 500 ,ug
nebulizer solution (P<O.O5). The end of trial patient preferences and the proportion of
patients who dropped out of the trial on the different regimens were not statistically
significant. We could not demonstrate that in domiciliary practice the delivery of IB by a
nebulizer is of greater clinical benefit than its administration by a MDI.

INTRODUCTION
Many patients, especially those with severe obstruction, claim that the delivery of a
bronchodilator drug as a wet aerosol by a nebulizer driven by compressed air or oxygen
produces more relief than their normal metered dose inhaler (MDI). Such patients
sometimes use domiciliary oxygen equipment to deliver bronchodilator drugs, and some
Correspondence to: Dr A. P. Smith, Thoracic Outpatients Department, Llandough Hospital,
Llandough, Penarth, South Glamorgan CF6 1xX.
 GUNAWARDENA, SMITH, SHANKLEMAN: MDIs & NEBULIZERS 171

may purchase small compressors. The first is an inefficient and a wasteful way of producing
drug aerosols and, as the equipment is not available on the National Health Service Drug
Tariff, the second may involve the patient in personal expense.
Nebulized bronchodilators may be of benefit in childhood (Bacon 1978; Lenney 1978)
and in adults with asthma (Connelan & Wilson 1978) or emphysema (Connelan & Wilson
1979) but controlled trials of this type of treatment in domiciliary practice have not been
widely performed.
The object of our study was to compare the efficacy, both in terms of objective
measurements of lung function and symptomatic benefit of a frequently used bronchodila-
tor drug, ipratropium bromide (IB), given by a MD1 or a compressor driven nebulizer.

Methods
Patients
The clinical details of 32 patients who were recruited into the study are given in Table I. All had
episodic or chronic wheezing and breathlessness, and documented evidence of reversible airflow
obstruction. The duration of their symptoms varied from 1 to 60 years. Their maximal documented
reversibility in either FEV,, FVC or PEFR within the 2 years encompassing the period of the trial
ranged from 25 to 200% (mean 55.2, SD 36.9). In addition, on entry to the trial, they showed a

Table 1. Clinical details (mean and range)

On entry Completing the
trial
Total: 32 20
Sex (male/female) 2418 1614
Age (years) 57.1 59
(17-78) (3S-78)
Duration of symptoms (years) 21 20.4
(l-60) (1-51)
Maximum documented 55.2 52.6
reversibility (%) (25-200) (25-200)
Reversibility to 120 pg of 26.3 31.25
ipratropium bromide by (13-56) (13-55)
MD1 (%)
Per cent predicted FEVr 40.4 39.5
(litres) (15-81) (17-81)
PEFR at start of trial 192 196.6
(litres/min) (75-380) (100-300)
Treatment
Inhaled beta agonist 28 18
Inhaled ipratropium 11 6
bromide
Inhaled corticosteroids 24 14
Oral corticosteroids 18 12
Oral bronchodilators 18 10
Disodium cromoglycate 3 0
172 BR. J. DIS. CHEST: VOL. 80 NO. 2

response of 13% or more in the PEFR to a test dose of 120 ,ug IB delivered by a MD1 (range 13-56%)
mean 26.3, SD 9.1). Most patients had asthma, but 14 of the 32 had other conditions associated with
partially reversible airways obstruction, namely, eight with chronic bronchitis and emphysema, four
with bronchiectasis, one with bronchopulmonary aspergillosis and one with bronchiectasis and
pneumoconiosis. At the time of selection for the trial all patients were on inhaled bronchodilators,
mostly by MDIs; four patients were on nebulized salbutamol and IB as well. The majority were on
oral or inhaled steroids or both.
Trial design
The patients were assigned to receive the following treatments in random order, each treatment
being given for 4 weeks.
Treatment A=120 ,ug IB by MDIfplacebo by nebulizer.
Treatment B=placebo by MDI+12.5 pugIB by nebulizer.
Treatment C=placebo by MDI+SOO lug IB by nebulizer.
IB was provided in three forms: pressurized MD1 containing 40 pug/puff, and nebulizer solutions
containing either 250 pug/ml or lOOO~g/ml. Placebo MD1 contained the propellant and soya
lecithin. Placebo nebulizer solution was 0.9% saline.
At the beginning of each treatment period patients received a MDI, a bottle of nebulizer solution
and a bottle of diluent (0.9% saline). They were instructed to carry out four treatment sessionsdaily;
at each session they took 3 puffs from the MDI, added 0.5 ml of nebulizer solution to 1.5 ml of
diluent and inhaled it via an ‘Inspiron-Minineb’ compressor-nebulizer system using either a
mouthpiece or a face mask according to each patient’s choice. All trial material was prepared by the
manufacturer of IB, and was dispensed through the hospital pharmacy according to the randomiza-
tion schedule kept with the chief pharmacist. The trial was carried out double blind, and neither the
patients nor any of the investigators knew what treatment the patient received until the whole trial
was complete.
Assessments
Before the trial and at the end of each 4-week treatment period patients were seen at the clinic and
had their spirometry, static lung volumes and the transfer factor measured in the lung function
laboratory. Their exercise capacity was measured by the 6-minute walking test (Butland et al. 1982).
During each treatment period they recorded their symptoms, peak flow readings and drug usage on a
diary card. The symptoms recorded were ‘overall asthma severity’, ‘breathlessness on exertion’,
‘cough’ and ‘sleep difficulty due to asthma’. These were graded individually on a scale from 0 to 10
(O=no symptoms, lO=very severe symptoms). They also recorded whether or not they had a
productive cough and if so a grading was given on the scale of O-10 for the ‘difficulty coughing up
sputum’. The peak flow readings (the best of three consecutive blows on a standard mini-Wright
peak flow meter) were recorded morning and evening, before and half an hour after the inhalation of
the trial drugs. Additional treatments were recorded as the number of puffs of salbutamol inhaler
used for the day, the number of puffs of inhaled steroids and the total daily consumption of oral
steroids and oral bronchodilators.
When the patients were first seen for the trial they were given a full demonstration and instructed
by the research nurse (J.S.) about the use of the compressor-nebulizer equipment, the method of
diluting the nebulizer solution, the recording of peak flow rates and the filling in of the diary cards.
They were seen at home within the first few days of the trial to make sure that the instructions were
being adhered to. If the patient had any difficulty he was given a run-in period of about a week to get
used to the trial protocol before entry into the trial periods. Weekly home visits were subsequently
made by the research nurse to check on patient compliance, to collect the diary cards, to furnish new
supplies of drugs and to ascertain that the equipment was working properly.
 GUNAWARDENA, SMITH, SHANKLEMAN: MDIs & NEBULIZERS 173

Relapses and withdrawals

In the event of a relapse of asthma the patient was seen by one of the physicians in charge of the trial
and was treated with steroids and antibiotics asdeemed necessary. If there was no improvement or if
hospitalization was required the patient was withdrawn from the trial.

TREATMENT
A B C
7J
&.. ... .. .. ... .. o-o-o TLC

6-

v) 4-
z
3 vc
3- ~........0-i-: FVC
+........H
2-

b-A--a FEV,
4 .. .._..... ....
l-

26CP
‘I= PEFR
.c 240- . /
:’
-6 ,:’
g 220. .:’
2
200-

180-

16
m o TRANSFER
/ FACTOR
2
0-O
$ 16 ,,I’,/
,.../
-6 I
E
I
14 I

380

360
SIX MINUTE
g 340
z
r 320

300Beiore trial MDI

125pg
NEB
5oopg
NEB
Fig. 1. Lung function and walking distance before trial and at the end of each treatment period. All
three treatments improved these parameters (except TLC), but there is no significant difference
between treatments. Error bars indicate +SEM (n=20)
174 BR. J. DIS. CHEST: VOL. 80 NO. 2

Statistical analyses
Lung function variables and the walking distance were each subjected to a two-way analysis of
variance, with the patients and the treatment in the preceding 4 weeks as the main effects. Morning
and evening PEFR and symptom scores were condensed into weekly averages and subjected to a
three-way analysis of variance with patients, weeks and treatments as the main effects. In the event
of a significant difference being observed the analysisof variance (Morrison 1976) was supplemented
by Duncan’s multiple range test (Duncan 1955) to determine the source of the difference. For
bronchodilator and steroid usage, as the distributions were not ‘normal’, data medians and ranges
were examined and the analysis was by Friedman’s non-parametric two-way analysis of variance
(Friedman 1937). Treatment preferences and withdrawals were analysed by a weighted chi-squared
test.
All patients gave informed consent and the trial protocol was approved by the local ethical
committee.

RESULTS
Of the 32 patients entered, 20 completed the trial protocol satisfactorily (Table I). The
clinical characteristics of the patients remaining did not differ significantly from those of
the initial 32 who entered the trial. There were 10 patients with asthma, seven with chronic
bronchitis and emphysema, and one each with bronchiectasis with PMF, bronchopulmon-
ary aspergillosis and bronchiectasis. The reasons for the withdrawal of the remaining 12
patients are discussed below.

Lung function and exercise tolerance

Lung function and walking distance before the trial and after each of-the three periods on
IB are summarized in Fig. 1. Significant differences from the pretrial assessment were
observed for PEFR, FEV,, FVC, VC, RV/TLC ratio and the transfer factor (P<O.OOl),
whilst the difference for RV approached statistical significance (P<O. 1). With one excep-
tion these differences were accounted for by the fact that all three treatments were better
than the values before the trial (PcO.05 for FEV,, FVC, RV/TLC and transfer factor after
MDI; KO.01 for all other comparisons). There was no significant difference between
treatments. The only exception was the FVC which was higher after 500 pg nebulizer
solution than after the 120 pugMD1 (KO.05). RV after the 500 pg nebulizer solution was
significantly lower than before treatment (KO.05).

Diary card data

The weekly averages for the morning and evening PEFR before and after the trial drugs,
for each of the 4 weeks on the three treatment periods are shown in Fig. 2. Apart from one
exception there was no significant difference between the treatments at any time for the
morning and evening PEFR, diurnal variation or reversibility. The diurnal variation at
week 3 on the 125 pg nebulizer solution was greater than that on the 500 ,ug (PcO.05). The
weekly averages for the peak flow rates fluctuated by not more than +8 litres/min which
was well within the standard errors which ranged from 20 to 27 litres/min.
Analysis of the weekly average symptom scores disclosed no difference in breathless-
ness and sleep difficulty between treatments or between weeks within any treatment
period. The asthma severity score on the 500 lug nebulizer solution was just significantly
 GUNAWARDENA, SMITH, SHANKLEMAN: MDIs & NEBULIZERS 175

2004

1 i 3 4
&xi NCnb4er
12Opg MDI 125pg NEB 5OOpg NEB

Fig. 2. Weekly averages for the daily peak flow readings (n=20). The vertical arrow at each point
shows the improvement obtained after inhalation of the trial drugs. The morning and evening PEFR,
bronchodilator response and the diurnal variation of the different treatments are almost identical

greater than for the MD1 at 4 weeks (P~0.05). Cough scores on the 500 ,ug nebulizer
solution were higher at weeks 1 and 2 than for both other treatments (PcO.05) and at week
3 compared with the 125 lug (RO.05). There was a trend for the cough scores to fall
towards the end of each treatment period while the patients were on nebulizer solutions,
the score for week 4 being lower than for weeks 1 and 2 on the 500 pug (PcO.05) and the
score for week 4 being lower than for week 1 on the 125 pg (PeO.05).
There was no significant difference in the proportion of days that sputum was produced.
However, sputum was more difficult to cough up on the 500 pg nebulizer solution when
compared with the 125 ,ug nebulizer solution at weeks 2 and 3 (RO.01 and RO.05
respectively) and the 120 ,ug MD1 at week 2 (PcO.05). Also the difficulty score on the
500 ,ug nebulizer was higher in week 2 than in week 1 (KO.05).

Additional treatment
Additional treatment with inhaled salbutamol, inhaled steroids (Becotide, Bextasol) and
oral steroids (prednisolone) did not differ significantly according to the treatment period.

End of trial patient preference

Of the 20 patients who completed the trial seven had no preference, three preferred the
MDI, seven the 125 ,ug dose by nebulizer and one the 500 ,ug dose. Two patients preferred
either dose by nebulizer. If a weight was given for the order of preference (first pre-
ference=3, second preference=2, last preference=l, equal weights for no preference)
then the x2 of the observed preferences was not statistically significant.

Withdrawals and relapses

Twelve of the 32 patients recruited to the study failed to go through all three treatment
periods. Eight dropped out during the first month, one during the second and three during
the third. Four patients dropped out whilst on the MDI, two on the 125 pg dose by
nebulizer and six on the 500 pg dose. The reasons, for withdrawal were admission to
176 BR. J. DIS. CHEST: VOL. 80 NO. 2

hospital (one with myocardial infarct), relapse or side effects. One patient with hyperten-
sive heart disease died suddenly. This patient stopped his oral steroids on his own accord
and a post mortem examination revealed the cause of death as asthma and hypertensive
heart disease, This patient as well as the one who developed the myocardial infarct were on
the 500 lug nebulizer solution when these events occurred.
The differences in the proportions of patients who withdrew on different treatments
were not statistically significant when analysed by a weighted x2 test (weight for the
treatment on which patient withdrew= 1, equal weights for other two treatments unless the
patient had completed more than two periods of the trial and had expressed a preference
for one period over the other). A x2 test for the combined weights for treatment
preferences and treatment withdrawals was also non-significant.

DISCUSSION
Patients with chronic asthma and severe airflow obstruction pose a difficult management
problem particularly when they fail to obtain adequate relief from MDIs. Often such
patients are given nebulized bronchodilators in the hope that the different mode of
delivery of the drug would be more effective. In hospital practice nebulized bronchodila-
tors are practically always used in the treatment of acute severe airflow obstruction.
Possibly as a result of this practice patients seem to believe that nebulized bronchodilators
are the ‘state of art’ treatment for severe airflow obstruction in domiciliary practice also,
despite the absence of controlled trials showing that nebulizers are clearly of greater
benefit than MDIs.
We studied a group of patients with moderate to severe airflow obstruction who had
symptoms despite regular treatment with MDIs. On the evidence available up to this trial
we would have considered this type of patient for domiciliary nebulizer therapy. Although
the group was somewhat inhomogeneous as far as their primary chest disease was
concerned (some having predominant asthma and some predominant chronic bronchitis
and emphysema), they all had a demonstrable degree of reversible airflow obstruction and
a reasonably good response to the bronchodilator used in our study (Table I). With these
patients we failed to demonstrate that there is any clinically significant difference between
treatments when IB was given either via the MD1 in a dose of 120 ,ug or via the nebulizer in
a dose of 125 lug or 500 ,ug.
To estimate the type II error of this trial (that is the chance of missing a real difference
between the treatments), the 95% confidence limits for the observed differences were
calculated by means of a multivariate generalization of the t-test (Morrison 1976). This
showed that the trial would have been sufficiently powerful so as not to miss a 20% (40-50
litres/min) difference in the mean daily peak flow rates, a 15% difference in the total
symptom scores and a 15% difference in the walking distance. Smaller differences would
not have been of much clinical significance.
Either with a MD1 or a nebulizer only about lO-15% of the drug delivered actually
reaches the lung (Newman & Clark 1983). It is not surprising therefore, that there is no
difference in effect between 120 lug of IB delivered by a MD1 and 125 pg of IB delivered by
a nebulizer. The failure to demonstrate a difference between the 125 pg dose and the
500 ,ug dose is somewhat more difficult to understand. In a study of the dose response to IB
 GUNAWARDENA, SMITH, SHANKLEMAN: MDIs & NEBULIZERS 177

delivered by a MD1 and by jet nebulization, Gomm et al. (1983) have recently shown that
with either method of administration the bronchodilator response tends to plateau at a
dose of around 70-80 ,ug. The doses we used were larger and therefore would have
achieved near maximal bronchodilator response with any one of the three treatments, thus
explaining the failure to demonstrate a difference between the doses we used. Gomm et al.
also demonstrated that the dose-response curves for IB were similar for both the wet and
the dry aerosol and concluded that for patients with moderate airflow obstruction who are
experienced users of MDIs, dose for dose, there is no therapeutic advantage in the use of
IB by jet nebulization. Similar findings have also been reported for salbutamol (Tarala et
al. 1980; Christensson et al. 1981) and terbutaline (Cushley et al. 1983). The greater
efficacy of nebulizers reported in earlier studies (Choo-Kang & Grant 1975; Cayton et al.
1978) appears therefore to be dependent on the larger dose administered rather than on
the mode of delivery.
We found that the cough scores and the asthma severity were somewhat worse on the
500 ,ug dose. Patients found it more difficult to cough up sputum and they seem to have
used more oral steroids during this period although the latter difference was not
statistically significant. The monthly lung functions which appeared somewhat better on
the 500 pg dose may have improved due to the steroids rather than the larger dose of IB.
Only one patient gave a definite preference for the 500 ,ug dose and rather more patients
dropped out of the trial whilst on this dose. All this seems to indicate that on the average
the 500 ,ug dose is perhaps less beneficial than the lower doses. IB is known to cause
paradoxical bronchoconstriction, at least in patients with atopic asthma (Connolly 1982;
Howarth 1983; Pate1 & Tullet 1983) and this may be due to increased sputum viscosity
(Crompton 1982), a change in the reactivity of the bronchial smooth muscle to anti-
cholinergic drugs (Jolobe 1982)) sensitivity to the bromide radical (Pate1 & Tullet 1983), or
the hypotonicity of nebulizer solutions (Howarth et al. 1984). Whatever the explanation
the evidence merits close scrutiny of the use of large doses of IB.
There is little to be gained by administering a bronchodilator by a nebulizer instead of by
a MD1 to patients who show around 15% or more improvement in the PEFR when a test
dose of the drug is administered by a MDI. As these patients are unable to detect any
difference under double-blind conditions, and as there is no difference in the objective
tests, there seems little purpose in advising such patients to purchase compressor/
nebulizer equipment. Although we limited our study to IB, the findings of Christensson et
al. (1981), Tarala et al. (1980) and Cushley et al. (1983) suggest that similar conclusions
can be applied to sympathomimetic bronchodilators as well. Patients who do not respond
to small doses of a bronchodilator may, however, respond to larger doses and the correct
dose required should be identified by objective testing. Some patients may be unable to
use a MD1 for a number of reasons and a compressor driven nebulizer may be useful in
these cases.

ACKNOWLEDGEMENTS
We thank Dr Anne Eyre-Brook, Medical Adviser, Boehringer Ingelheim Ltd, for coor-
dinating the project, Mr Nicholas Praedy, MS Eleanor Allen and Mr Clive Moncrief for
their help with the statistics, Mr M. P. Mitchell for his help with the dispensation of the
178 BR. J. DIS. CHEST: VOL. 80 NO. 2

trial drugs, and Mr E. R. Buttfield for the supply of compressors and nebulizers. We are
grateful to Mrs Jean Williams for typing the manuscript and Mr K. Houston for perform-
ing the lung function tests. J.S. was supported by a grant frti”Boehringer Ingelheim Ltd.

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