vacuum would not alter appreciably the valve could serve the purpose.
urpose. The hazards bureau, Health and Welfare Can-
speed of the draw, nor would it in-
crease hemolysis of the blood or the
probability of vein occlusion, for these
effects depend upon the pressure dif-
ference between the vein and the
unfilled tube and this would increase
by only about 10%.
Still another approach might be to
incorporate a check valve into the sys-
tem to permit flow in one direction
only. Such a mechanism would be ef-
fective even if the sampling technique
were faulty. Various designs of check
Beclomethasone dipropionate in asthma
PAUL CHAMPIQN,* MB, PH D. LONIA MACLEAN; MOIRA CHAN-YEUNG, MB, MRCP, FRCP[C], FACP
Summary: Beclomethasone dipropionate
aerosol therapy can replace or diminish
systemic corticosteroid therapy in
the majority of asthmatics. In a
clinical trial of 41 patients with
perennial asthma, the 10 who had not
required long-term corticosteroid
therapy improved symptomatically
and in pulmonary function. Of the
31 who had required prolonged
systemic corticosteroid therapy 12
were able to discontinue oral prednisone
therapy, 15 were able to decrease
the maintenance dose of prednisone
and only 4 were unable to decrease the
dose; all maintained satisfactory lung
function and some showed improvement.
Discontinuation of systemic
corticosteroid therapy was accomplished
more readily in patients whose daily
maintenance dose was less than
15 mg and who had been taking
the drug for less than 3 years. Side
effects consisted of a "dry throat"
in seven patients, two of whom had
throat infections with Candida albicans.
Recurrence of rhinitis after
discontinuation or reduction of systemic
corticosteroid therapy was noted
in 11 patients.
R6sum6: La dipropionate de
b6cIom.thasone dans I'asthme
Chez Ia majoritA des asthmatiques
le dipropionate de b6clom6thasone
donne en a6rosol peut remplacer ou
diminuer Ia posologie de Ia
corticoth6rapie par voie g6n6rale.
Au cours d'un essai clinique sur 41
From the University of British Columbia,
department of medicine, Vancouver General
Hospital
This work was supported by the Canadian
Thoracic Society.
*Re.arch fellow, BC Tuberculosis and
Christmas Seal Society
Reprint requests to: Dr. M. Chan-Yeung, UBC
department of medicine, Vancouver General
Hospital, Vancouver, BC V5Z 1M9
valve could be located in the needle,
on the inner surface of the stopper, or
in the tube itself.
Pending a technologic solution, it is
hoped that this analysis of the back-
flow problem will alert clinicians to the
hazards of evacuated blood-collection
tubes and the necessity for strict adher-
ence to proper technique in their use.
We thank Drs. R.H. Elder and B.C. Mor-
ton of Ottawa Civic Hospital, Mr. Nelson
Dune of the National Research Council
and Dr. H.A. Pivnik of the microbial
malades souffrant d'asthme chronique,
los 10 malades dont l'6tat n'avait pas
exige une corticoth6rapie prolong6e
ont vu leur 6tat s'am6lioror au point
de vue symptomatique ainsi que leur
fonction pulmonaire. Chez los 31
autres qui avaient d. rocevoir une
corticoth6rapie do longue dur6e par
voje g6n6ralo, 12 ont Pu abandonner
Ia prednisone orale, 15 sont parvenus
a r6duire Ia dose d'ontretien do
prednisone ot 4 seulemont n'ont Pu
r6duire cette dose; chez tous, Ia
fonction pulmonaire s'est maintonue
do fa9on satisfaisante et cortains
malades ont 6t6 am6lior6s. L'abandon
do Ia corticoth6rapie par vole gbn6ralo
a pu so faire plus facilement chez
los malados dont Ia posologie
d'entretion quotidionne 6tait inf6rioure
a 15 mg ot qui avalont pris lo
medicament pendant moms do 3 ans.
Chez sept malades los r6actions
secondairos consistajent on "gorge
s.che", mais ii faut remarquor quo
deux do coux-ci souffraient d'infections
do Ia gorge causee par Candida
albicans. Chez 11 malades on a not6
do Ia rhinite apres abandon ou
r6duction do Ia corticoth6rapie par
voie g6n6rale.
Beclomethasone dipropionate has re-
cently been used as an aerosol in the
treatment of patients with chronic per-
ennial asthma, particularly as a replace-
ment for oral corticosteroid therapy.
Several studies14 have shown that the
drug is effective and has few side
effects.
The following is a report of a clinical
trial of beclomethasone dipropionate
aerosol therapy in 41 patients with asth-
ma. The major aim of this trial was
to study the extent to which this ther-
apy could replace systemic cortico-
steroid therapy.
CMA JOURNAL/AUGUST 9, 1975/VOL. 113 213
ada. The valued assistance of Dr. A.K.
DasGupta, director, bureau of medical
devices, is gratefully acknowledged.
References
1. MENDELSSOHN K, Wsrrs LI: Transmission of
infection during withdrawal of blood. Br Med
1 1: 625, 1945
2. SHACKLE JW: Technique of venepuncture.
Ibid, p 749
3. MENDELSSOHN K, Wsrrs U: Technique of
venepuncture. Ibid, p 852
4. FUST JA: letter. A SCP Summary Rep 9:
Jan 1972
5. MEDREK TJ: Eliminating vacutainer hazard.
ASCP Summary Rep 10: Apr 1973
6. MCLEISH WA, CORRIGAN EN, ELDER RH, et
al: Contaminated vacuum tubes. Can Med
Assoc 1 112: 682, 1975
Patients and methods
Patients
Two groups of patients with peren-
nial asthma were studied: a non-steroid-
dependent group - 10 patients who
had never received, or only occasionally
required, intermittent courses of sys-
temic corticosteroids; and a steroid-
dependent group - 31 patients who
had received systemic corticosteroids
for a long period. Six of the 41 patients
were using disodium cromoglycate at
the time of the study; another 21 had
tried it in the past but had not found it
helpful.
Methods
The patients were observed for 4 to
6 weeks before the commencement of
aerosol beclomethasone therapy, during
which period they were stabilized on
their usual medication and baseline
measurements of respiratory function
were made. In steroid-dependent pa-
tients the lowest dose of steroids re-
quired to keep them free from symp-
toms and maintain satisfactory lung
function was established. Patients were
instructed to record on special diary
cards the severity of symptoms relating
to asthma, cough and sputum volume
for each day and night (scores are
shown in Appendix 1) and the frequen-
cy with which they used oral (Tedral,
Amesec or Choledyl) or aerosol (Ven-
tolin or Alupent) bronchodilators and
other medications.
Beclomethasone dipropionate therapy
was then begun. The drug was admin-
istered as a metered aerosol delivering
50 ,.tg per puff. Patients were asked to
inhale 100 p.g four times daily. After
1 week of beclomethasone therapy
those who were steroid-dependent were
asked to reduce their prednisone dosage
at a maximum rate of 1 mg/d. The six
patients who were using disodium cro- methasone therapy the following de¬ aerosol bronchodilator therapy (at least
moglycate were asked not to alter its terminations were performed in all a 20% increase in FEVi). The steroid-
dose while they were using beclo- patients: hemoglobin concentration, dependent patients had, in general, a
methasone. leukocyte count and concentrations of lesser degree of airway obstruction be¬
Every 2 weeks throughout the trial blood urea nitrogen and serum crea¬ cause they had been taking systemic
the patients were seen and their tinine, total bilirubin and glutamic corticosteroids; some showed little re¬
symptoms and diary cards assessed. oxaloacetic and pyruvic transaminases. sponse to aerosol bronchodilators be¬
One-second forced expiratory volume Plasma cortisol (at 9 am) was also de¬ cause their FEVi had been close to
(FEVi), forced vital capacity (FVC) termined in most of the patients who the predicted normal value.
and maximum midexpiratory flow rate were steroid-dependent. The average daily symptom scores
(MMFR) were measured by spirometer When results of the trial were anal¬ and the frequency of use of aerosol
(Warren E. Collins, Inc, Braintree, ysed all patients had had at least 3 and oral bronchodilators are shown in
Massachusetts). months of beclomethasone therapy and Table II, and the results of lung func¬
Before and after 3 months of beclo- some had had 6 to 8 months. Analysis tion tests in non-steroid-dependent pa¬
was based on (a) daily record of symp¬ tients before and after beclomethasone
Table I.Clinical details of 41 patients toms, (b) requirement for aerosol bron¬ dipropionate therapy, in Table III.
chodilator and (c) spirometric measure¬ All patients showed symptomatic im¬
with asthma ments. The findings during the 4 weeks provement; the increase in symptom
Non-steroid- Steroid- before beclomethasone therapy were score was significant for asthma and
dependent dependent compared with those during the last cough. Patients who used aerosol or
Feature (n 10) (n 31)
= =
4 weeks of therapy for each patient. oral bronchodilators, or both, showed
Sex reduction in the frequency of their use.
Male 4 16 Results The symptomatic improvement was as¬
Female 6 15 The clinical details of the 41 patients sociated with improvement in lung
Age (yr) 51.5 53.9 are summarized in Table I. The non- function in all patients; the degree of
Mean
Range 30-68 8-70 steroid-dependent patients had a mod¬ improvement in FEVi, FVC and
Duration of asthma (yr) erate degree of airway obstruction and MMFR was significant.
Mean 12.9 13.9 showed an appreciable response to Of the 31 steroid-dependent patients
Range 1-28 1-60
Smoking history Table lll.Results* of lung function tests before and after beclomethasone
Nonsmoker 4
6
14
13
therapy
Exsmoker in non-steroid-dependent patients
Smoker 0 4
Duration of continuous FEVi (% of predicted) FVCf (% of predicted) MMFRt (% of predicted)
systemic corticosteroid Patient
therapy (yr) 4.95
no. Before After Before After Before After
Mean
Range 0.5-18 1 45 103 62 105
FEVi* (%of predicted) 2 45 59 64 73
Before bronchodilator 3 31 53 67 88 11 22
Mean 40.6 59.6 4 42 69 58 79 17 34
Range 31-97 27-104 5 87 113 94 105 49 54
After bronchodilator 6 78 91 90 103 40 46
Mean 56.4 75.5 7 58 73 68 79 31 43
Range 33-106 36-120 8 56 75 82 97 21 31
% response to 9 97 91 104 98 67 64
bronchodilator 10 64 68 81 84 23 23
Mean 42.7 36.0
Range 23-75 2-200 Mean 60.3 79.5 77.0 91.0 32.4 39.6
Disodium cromoglycate t 3.71 3.76 3.22
therapy Probability < 0.01 < 0.01 < 0.01
Not tried 8
In effective 18 *The average results of lung function tests in the 4 weeks before beclomethasone therapy were compared
Helpful 5 with those of the last 4 weeks of beclomethasone therapy.
fForced vital capacity.
*One-second forced expiratory volume. tMaximum midexpiratory flow rate.
Table II.Average* daily symptom scores and bronchodilator use before and after beclomethasone dipropionate therapy in
non-steroid-dependent patients

Patient no.
"12
3
4
5
6
7
8
9
10
Mean
t
Probability
*The average daily symptom scores and bronchodilator use in the 4 weeks before beclomethasone therapy were compared with the values for the last 4 weeks
of beclomethasone therapy.
tMaximum daily scores (absence of symptoms): asthma, 6; cough, 4; sputum, 7.
216 CMA JOURNAL/AUGUST 9, 1975/VOL. 113
12 were able to discontinue prednisone
and 15 were able to reduce the dose
after beclomethasone therapy; the other
4 patients were unable to reduce the
dose. The findings in this group of
patients are presented in Table IV. Of
the patients who were able to discon¬
tinue prednisone those with symptoms
before beclomethasone therapy reported
symptomatic improvement. The pul¬
monary function of these patients did
not deteriorate; surprisingly, there was
slight improvement in FEVi and
MMFR. Patients who were able to
reduce their dose of prednisone while
on beclomethasone therapy showed
marginal improvement in their symp¬
tom scores and spirometric measure¬
ments. In those patients who had side
effects from systemic corticosteroid
therapy such as moon face, cushingoid
features or weight gain, such effects
disappeared when the prednisone was
discontinued or the dose reduced ap-
preciably. The reasons for the inability
of four patients to decrease the dose
of prednisone while taking beclometha¬
sone included the occurrence of severe
rhinitis in one patient, depression when
an attempt was made to reduce the
dose in two patients, and myocardial
ischemia during the trial in the fourth
patient.
There was no apparent correlation
between plasma cortisol value before
beclomethasone therapy and the dura¬
tion and maintenance dose of predni¬
sone in these patients. The plasma cor¬
tisol value was below the lower limit
of normal « 5 /ug/dl) in 8 of 21
patients before beclomethasone therapy;
it increased to more than 5 /xg/dl in all
3 patients in whom prednisone was
discontinued and in 2 of the 4 patients
in whom reduction in dose of predni¬
sone was achieved.
However, the response to beclome¬
thasone therapy in these patients was
correlated with the duration and main¬
tenance dose of prednisone and the
severity of the airway obstruction be¬
Table IV.Mean values* of prednisone dose, plasma cortisol, daily symptom score, bronchodilator
function before and after beclomethasone therapy in steroid-dependent patients
?See footnotes to Tables II and lll.
fore the trial. Patients who were able
to discontinue prednisone had a shorter
duration of steroid therapy (mean, 2.8
years; range, 0.5 to 8 years) and a
smaller daily maintenance dose (mean,
11 mg; range, 2.5 to 15 mg). The de¬
gree of airway obstruction before the
trial was less severe in this subgroup
(mean FEVi, 81.7%; range, 50 to
112%). Patients who were only able to
reduce the prednisone dose had a long¬
er duration of steroid therapy (mean,
6.5 years; range, 0.5 to 18 years) and a
larger daily maintenance dose (mean,
16 mg; range, 7.5 to 30 mg). The de¬
gree of airway obstruction before the
trial was more severe in this subgroup
(mean FEVi, 60.9%; range, 24 to
89%).
Seven patients complained of "dry
throat" and huskiness of voice in the
initial phase of beclomethasone ther¬
apy; cultures of throat swabs grew
Candida albicans in two instances.
These symptoms usually subsided spon¬
taneously without treatment. Eleven
patients had a recurrence of rhinitis
after the discontinuation or reduction
of prednisone therapy. There was no
notable change in hematologic or blood
chemistry values after beclomethasone
therapy.
Discussion
Bronchial asthma varies in intensity,
and ideally any trial of a new meth¬
od of treatment should include a
placebo and be conducted in a double-
blind manner. However, most patients
in this trial had been taking systemic
corticosteroids for long periods and at¬
tempts to wean them from this medica¬
tion were unsuccessful, so the use of
a placebo is not justified for them. We
therefore decided to observe them
closely for at least 4 weeks, during
which period the lowest dose of corti¬
costeroids required was established.
Beclomethasone dipropionate has
been reported to be effective in' the
treatment of asthma, with little evid¬
CMA JOURNAL/AUGUST 9, 1975/VOL. 113 217
ence of suppression of adrenal func¬
tion.1"6 This clinical trial has confirmed
these findings. All 10 patients who had
never received steroids or occasionally
required intermittent courses of sys¬
temic steroids responded well to this
drug not only symptomatically but also
with an improvement in pulmonary
function. Of the 31 steroid-dependent
patients 12 were able to discontinue
prednisone therapy and, surprisingly,
some of them showed further improve¬
ment in lung function. Fifteen of the
31 were able to decrease considerably
the maintenance dose of prednisone
without deterioration of lung function.
Only four patients were unable to de¬
crease the dose of prednisone. Patients
who had been taking systemic cortico¬
steroids for less than 3 years and whose
daily maintenance dose of prednisone
was relatively low (less than 15 mg/d)
were able to discontinue the drug.
Those who had been taking systemic
corticosteroids longer and whose daily
maintenance dose was high had to con¬
tinue the drug during beclomethasone
therapy although the dose could be
reduced. The main reasons for inability
to reduce the maintenance dose of sys¬
temic corticosteroids in four patients
were development of depression, severe
exacerbation of allergic rhinitis and
myocardial ischemia.
There was no evidence of adrenal
suppression with beclomethasone at the
dose (400 fjig/d) used in this study.
The plasma cortisol value returned to
normal in all the patients who were
able to discontinue prednisone therapy
and in two of four patients who were
able to reduce the dose of prednisone.
Moon face and cushingoid features also
disappeared then. These observations,
together with the fact that previously
suppressed allergic symptoms such as
rhinitis were unmasked, suggest that
the systemic absorption of beclometha¬
sone dipropionate is negligible and that
the site of action of the drug is local.
Experimental work on volunteers con-
use and pulmonary
 firmed that adrenal suppression is min-
imal until doses of about 2 mg/d are
Side effects, however, are frequent;
their incidence is directly proportional
Hygroton
inhaled.7 It is important to warn pa- to the maintenance dose.9 Beclometha-
tients who are able to discontinue or sone dipropionate aerosol can replace Dosage
Edema - 100 to 200 mg daily may be
reduce the dose of prednisone while oral steroid therapy in some patients required initially to produce the desired
taking beclomethasone to resume tak- and can reduce the maintenance dose response in severe cases of edema.
ing or increase the dose of systemic in others. It appears to be useful in When "dry" weight is reached, average
- corticosteroids during any acute exa- many patients who have failed to re- maintenance doses of 100 mg daily
cerbation of asthma even though the spond to disodium cromoglycate ther- should suffice.
plasma cortisol value may have re- apy. This new form of treatment has 50 to 100 mg daily will usually control
returned to normal. much to offer in the management of mild to moderate cases of edema. Dos-
Fungal infection of the respiratory chronic asthma. age level should be adjusted individually
tract is the most important side effect We thank Dr. S. Grzybowski for his criti- as it is often dependent on the patient's
of inhaled steroid therapy. McAllen, cism of the manuscript and Glaxo Canada salt intake.
Kochanowski and Shaw8 reported can- Ltd. for the supply of beclomethasone
didiasis of the pharynx in 13% and of dipropionate for the trial. Hypertension - 100 mg daily will usually
the larynx in 5% of patients taking produce the desired response. Once re-
duction of blood pressure has been at-
beclomethasone. They also found that tained, mild cases are often controlled
these patients were immunologically References on 50 mg daily, while more severe cases
normal and that the incidence of can- may require a higher maintenance dos-
didal infection was dose-related, for 1. BROWN HM, STOREY G, GEORGE WHS: age. Dosage level should be adjusted
such infections were not seen in pa- Beclomethasone dipropionate aerosol in chil-
dren. Br Med 1 1: 585. 1972
individually as it is often dependent on
tients who were taking less than 400 2. BROWN HM, STOREY G: Beclomethasone di. the patient's salt intake.
propionate steroid aerosol in treatment of
.g/d. However, in this study we found perennial allergic asthma in children. Br Med Note: Divided doses are unnecessary
J 2. 161 1973
two patients with C. albicans infection 3. GADDIE I, REm 1W, SKINNER G, et al: Aero- and a single daily dose given in the
who were taking 400 .g/d. sol beclomethasone dipropionate in chronic morning with food is recommended.
bronchial asthma. Lancet 1: 691, 1973
Other long-term side effects of aero- 4. Idem: Aerosol beclomethasone dipropionate:
a dose-response study in chronic bronchial The therapeutic effect of Hygroton oc-
sol beclomethasone therapy have not asthma. Lancet 2: 280, 1973
been reported. Atrophy of the skin is 5. CLARK IJH: Effect of beclomethasone di- curs even without strict salt restriction
a well known complication of excessive
propionate delivered by aerosol in patients
with asthma. Lancet 1: 1361, 1972
and is well-sustained during continued
6. LAs 5, HAIuus DM, BHALLA KG, et al: use. Its saluretic effect is sufficiently
use of topical steroids. There is as yet Comparative double blind trial of beclo- distinct from that of other sulfonamide
no information on the histologic methasone dipropionete aerosol and oral diuretics so that it may be employed suc-
prednisone in the treatment of reversible
changes of the mucosa of the human airways obstruction. Br Med 1 3: 314, 1972 cessfully in a high proportion of patients
respiratory tract exposed to steroid 7. HARRIS DM, MARTIN LE, HARRI5ON C, et al:
The effect of oral and inhaled beclometha-
who are intolerant of other agents or
aerosols. Further investigation should sone dipropionate on adrenal function. Clin who become refractory to them.
Allergy 3: 243. 1973
be directed to this area. 8. MCALLEN MK, KOCHANOWSKI SJ, SHAW KM:
Contraindications
There is no doubt that long-term sys- Steroid aerosols in asthma: an assessment of
betamethasone valerate and a 12-month study Complete renal shutdown.
temic corticosteroid therapy improves of patients on maintenance treatment. Br
Med 1 1: 171, 1974
the quality of life in many patients 9. MAUNSELL K, BRUCE PEARSON RS, LIvING- Precautions
STONE JL: Long term corticosteroid treat- Maintain moderate sodium intake, unless
disabled with chronic perennial asthma. ment of asthma. Br Med 1 1: 661, 1968
inadvisable, and consider dietary or
other potassium supplement. Close ob-
Appendix 1-Scores for asthma symptoms, cough and sputum volume servation should be maintained in the
presence of cirrhosis, diabetes, gout and
digitalis therapy. There is the possibility
Asthma score Cough score* Sputum score of hyperuricem ia or hyperglycemia.
As with any drug, Hygroton should not
Score By day By night Score Grade Score Colour Volume be used during the first trimester of preg-
nancy unless in the opinion of the pre-
scribing physician, the potential benefits
1 Unable to move about Kept awake 1 Distressing cough 1 Yellow Copious (more outweigh the possible risks.
In bed or chair most most of the night most of the time. than 2 egg
of the day. Very by asthma. cups) Side Effects
breathless. Rarely serious. Occasionally, transient
2 Able to walk slowly Woken by 2 Distressing cough 2 Yellow Moderate ('A symptoms such as nausea, headache,
about the house but asthma about in attacks only. to 2 egg cups) weakness or dizziness are observed.
becomes very hourly.
breathless.
3 Able to walk slowly Woken by 3 Occasional cough, 3 Yellow Scanty (a few
or climb stairs very asthma four to not distressing. blobs) Hygroton 100 mg Each white scored tab-
slowly but cannot keep six times. let engraved . contains 100 mg chlor-
up a normal walking thalidone Geigy Standard.
speed. 4 Grey Copious (more
4 Able to walk at normal Woken by 4 No cough. than 2 egg Hygroton 50mg Each yellow scored tab-
speed or climb stairs asthma two to cups) let engraved . contains 50 mg chlor-
slowly but cannot three times. thalidone Geigy Standard.
hurry without distress. 5 Grey Moderate ('A
5 Able to hurry for short Woken by to 2 eggs cups)
periods but unable to asthma only Supplied in bottles of 50 and 500 tablets.
keep it up for as long once.
as others of similar 6 Grey Scanty (a few Full information is available on request.
ageand build. blobs)
6 Able to keep pace Sleeps through
with others of similar the night. 7 - None
age and build.
Geigy
Dorval 780, Que. G-3165
*Scores for cough and sputum are the same for day and night.
218 CMA JOURNAL/AUGUST 9, 1975/VOL. 113