Clinical Science and Molecular Medicine (1974) 47, 105-1 17.
THE TIME-COURSE OF RESPONSE TO P R E D N I S O L O N E
I N C H R O N I C BRONCHIAL ASTHMA
R. ELLUL-MICALLEF,") R. C. B O R T H W I C K
AND
G. J . R. M c H A R D Y
Department of Respiratory Diseases, University of Edinburgh
(Received 30 January 1974)
SUMMARY
1. In six patients with stable chronic bronchial asthma, the effect of a single oral
dose of 0.11 mmol (40 mg) of prednisolone was studied by carrying out repeated
measurements of dynamic and static lung volumes, thoracic gas volume and airway
resistance and maximum expiratory flow-volume curves.
2. No significant diurnal variation in the measurements performed was demonstrated on the 2 days before prednisolone was given. The administration of placebo
tablets produced no significant change.
3. A statistically significant improvement was detectable 3 h after administration
of the drug in the group of patients studied. The maximum effect was reached within
9-12 h, after which there was a return towards pretreatment values.
4. The improvement in specific conductance and maximum expiratory flow rate
as well as in mid-expiratory flow rate suggests that the relief in airway obstruction
occurred in both the large and the smaller airways.
5. The peak expiratory flow rate as measured by a Wright's peak flow meter proved
to be as sensitive an index of change as any of the other tests employed.
Key words : asthma, corticosteroids, spirometry, lung volumes, flow-volume curves,
body plethysmography.
Clinical observation suggests that in patients with bronchial asthma there is a time-lag between
the administration of corticosteroids and the onset of improvement.The extent of this time-lag
has never to our knowledge been systematically investigated. This study was designed to follow the alteration in various aspects of pulmonary function during the period from 48 h before
to 36 h after the administration of a single dose of prednisolone to patients with chronic
(I) Present address: Department of Physiology, The Royal University, Msida, Malta G.C.
Correspondence: Dr R. C. Borthwick, Department of Respiratory Diseases, City Hospital, Greenbank
Drive, Edinburgh EHlO 5SB.
105
106
R. Ellul-Micallef, R. C. Borthwick and G . J. R. McHardy
bronchial asthma. A short account of the work has already been given (Ellul-Micallef, Borthwick & McHardy, 1971).
PATIENTS A N D METHODS
For the purpose of this study chronic bronchial asthma was defined as a condition in which
widespread reversible airway obstruction is present for a prolonged period with or without brief
spontaneous remissions.
Nine patients were studied in whom the definition of chronic asthma was fulfilled on
clinical grounds. The duration of their disease ranged between 6 months and 34 years. Their
illness could no longer be controlled by bronchodilator drugs and they had been admitted to
hospital for a trial of corticosteroid therapy. In this Department such a trial consists of the
administration of placebo tablets for 2 days followed by prednisolone given in a daily
divided dose of 0-11 mmol (40 mg) for a further 7 days. In none of the patients had corticosteroids been used previously. For the purposes of our study we used the initial days of the
trial before regular corticosteroid therapy was instituted by the patients’ physicians. At the
time of admission the nature and purpose of the study were explained to the patients and informed consent was obtained. However, the patients were not aware that the study involved
the use of placebo tablets, as well as the active drug.
A chest X-ray film and an electrocardiogram were taken, and sputum examination for
bacterial infection and tests of hepatic and renal function were carried out. In addition,
sputum and blood specimens were examined for eosinophils, and skin tests to a control
solution and to house-dust mite, grass pollen and AspergiZZusfumigatus were carried out.
One patient became extremely wheezy and dyspnoeic on the second pretreatment day and
immediate therapy for acute asthma was instituted. Two other patients improved spontaneously shortly after admission to the trial. These three patients were therefore excluded on
grounds of instability. Table 1 shows the clinical details and physiological data on the remaining six patients, whose airway obstruction remained stable throughout the pretreatment
period.
Plan of study
The study was carried out over 4 days. In order to obtain repeated pretreatment baseline
measurements, to ensure that patients were in a stable state and to assess any pre-existing
diurnal variation in the tests to be performed after the drug was given, placebo tablets indistinguishablein appearance from the actual drug were given at 09.00 hours on the first 2 days
of the trial. On the third day 0.1 1 mmol(40 mg) of prednisolone was administered as a single
oral dose at 09.00 hours, and on the fourth day placebo tablets were again given. The measurements made and the times at which they were performed throughout the study are shown in
Fig 1.
Procedures
The forced expiratory volume in 1 s (FEV,) and the forced vital capacity (FVC) were
measured by means of a water-filled spirometer (Gaensler, 1951), and peak expiratory flow
rate (PEFR) was measured with a Wright’s peak flow meter (Wright & McKerrow, 1959).
Total lung capacity (TLC), vital capacity (VC), functional residual capacity (FRC) and
2
3
4
5
6
1
73
62
76
39
43
41
Patient Age
no.
(years)
F
M
F
F
F
M
(m)
Height
800
1500
800
1250
800
800
lo00
k302
1800
2700
1700
1550
2100
2100
1992
k411
Duration
FEV,
FVC
of disease (mlBTPS) (ml BTPS)
1.62
5years
1.75
2years
1-59
6months
1.62 13years
1-73 12years
1.75 34years
Group mean values k SEM
Sex
125
225
165
180
120
75
148
? 52
(I/min)
PEFR
5.45
8.01
5.62
k1.40
5.36
4.38
6.30
4.20
TLC
(I ATPS)
2.90
4.28
2-65
4.31
3.92
715
420
k1.61
2-53
3.20
2.30
3.41
3-12
5.59
3.36
k1.17
FRC
RV
(I ATPS) (1 ATPS)
425
33.4
51-8
577
58.9
52.2
49.4
k3.14
Pa
s-ll-l
vi,
k0.32
5.04
434
3.40
5.28
589
6-01
5.32
7.56
4.48
tl-64
2-91
429
4.22
3-22
464
cm water (1 ATPS)
s-ll-l
Raw
TABLE
1. Clinical and physiological data of patients studied
All measurements are immediate pretreatment values, used in statistical analyses and graphic representations. BTPS, Body temperature and pressure,
saturated; ATPS, atmospheric temperature and pressure, saturated.
%
B
%3a
(D
2
s'
Y
4
&
3
$;'
108
R. Ellul-Micallef, R. C. Borthwick and G. J. R. McHardy
residual volume (RV) were measured by the closed-circuit helium-dilution technique, the final
reading being taken when helium concentration had been stable for at least 3 min. A constantvolume body plethysmograph was used to obtain thoracic gas volume (VJ, airway resistance
(Raw)and conductance (G,J, the method first described by Dubois, Botelho, Bedell, Marshall
& Comroe (1956) being used. Specific conductance (SG,,,,)was calculated by dividing G,, by
Vt,. It has been shown that a deep inspiration may temporarily alter airway resistance (Nadel &
Tierney, 1961;Lloyd, 1963) and body plethysmographic measurements were therefore carried
out before the other tests were undertaken, on each occasion when they were done. Volume and
flow during a maximal expiratory manoeuvre from TLC were measured at the mouth with a
Wedge spirometer (model 170, Med-Science Electronics Incorp., St Louis, Missouri) and
FIG.1. Plan of study. Placebo tablets were given at 09.00 hours on the first, second and fourth days.
On the third day 0.1 I rnrnol(40rng) of prednisolone was given as a single oral dose at 09.00 hours.
Hatched areas represent times at which tests were done.
recorded against time on a multichannel direct writing recorder (Mingograf 81, ElemaSchonander, Stockholm). Maximum expiratory flow-volume curves (Fry, Ebert, Stead &
Brown, 1954; Fry, 1958; Hyatt, Schilder & Fry, 1958) were then constructed from this record
by using the flow rate at 20,40, 50,60 and 80% of VC and also the maximum flow rate.
All tests were carried out before or at least 2 h after meals and all measurements were made
with the patient seated. When the FEV,, FVC, PEFR and maximum expiratory flow-volume
curves were measured, the best of three successive, technically acceptable attempts was
chosen (Hutchinson, 1846 ;Freedman & Prowse, 1956).When plethysmographic measurements
were made, five separate sets of angles, from which V,, and R,, could be derived, were measured
on each occasion. The first result was discarded and the average of the next four was taken.
All plethysmographic measurements were carried out by one observer (R.E.-M.). Statistical
significance was tested in all instances by means of Student’s paired t-test (Snedecor & Cochran, 1971).
RESULTS
Minor fluctuations in all the measurements were observed during the first 2 days of the trial
109
Corticosteroid response in asthma
but no consistent pattern was seen. No significant diurnal variation was observed nor could
any response to placebo tablets be demonstrated. The mean values of measurements made on
these 2 days were not significantlydifferent from measurements made immediately before drug
administration on the third day. For the purpose of statistical analysis the results obtained
after administration of prednisolone have been compared with those obtained immediately
--.
-I--,
..---€
..
'\\
3
6
"'1
6 - 14
2
Time (h)
9
FIG.2. Effect of a single oral dose of 0.11 mmol (40 mg) of prednisolone on FENI, FVC and
PEFR in six asthmatic patients. Group mean values zk SEM are plotted against time after prednisolone administration, and are expressed as percentages of the immediate pretreatment values.
* Points significantly different from control (P<0.05).
before drug administration. In order to reduce the effect of individual variation all measurements were expressed as a percentage of the pretreatment value.
Prednisolone produced consistent changes in individuals in FEV1, FVC and PEFR and a
statistically significant increase in these measurements in the group as a whole, which was
evident at 3 h (P<0.05, P<0.05, P<0.025, respectively). In the group as a whole the peak
R.Ehl-Micallef, R. C.Borthwick and G. J. R. McHardy
110
effect observed was at 9 h, after which there was a decline towards the pretreatment values,
as shown in Fig. 2. Individual peaks ranged from 6 to 12 h.
All patients had evidence of hyperinflation, the pretreatment FRC ranging between 115%
and 216% of the predicted values given by Cotes (1968). Static lung volumes (TLC, FRC, RV
c
!
c
$u
t-l
g'
c
C
E
c
g
g
z
r
w
.
5
7 0
12
6
Time ( h )
FIG.3. Effect of a single oral dose of 0.1 I mmol(40 mg) of prednisolone on lung volumes measured
by the closed-circuit helium-dilution technique. Group mean values +SEM are shown for six
patients. * Points significantly different from control (P<0.05).
and RV/TLC%) fell at the time of the first measurement, 6 h after prednisolone administration, as shown in Fig. 3. At this time in the group as a whole the fall in RV and RV/TLC% was
significant (P<O.O25; P<O.O5) but the changes in TLC and FRC were not. In one patient
(no. 4) FRC and TLC did, however, fall by 1100 ml and 1800 ml respectively. When the next
measurements of lung volumes were performed 12 h after the drug had been given there was a
slight increase in all the lung volumes in the group as a whole, which continued over the next
Corticosteroid response in asthma
111
24 h. Two of the patients (nos. 5 and 6 ) , however, showed a further fall in the lung volumes
at 12 h.
Body-plethysmographic measurements showed marked changes at the time of the first
measurement 6 h after prednisolone (Fig. 4), SG,, rising and R,, and V,, falling compared
with their pretreatment values. The most noticeable change was found 12 h after the drug
65
t
75t
0
1“
2
&
I
6
Time (h)
FIG.4. Effect of a single oral dose of 0 1 1 mmol (40 mg) of prednisolone on body-plethysmographic measurements. Group mean values 5 SEM are shown for six patients. * Points significantly
different from control (P<O*OS).
had been given. The changes in R,, and SG,, were significant at 6 h (P<O*OI;P<0.05) but
the change in V,g was not (PcO.1). The latter was, however, significantly decreased by 12 h.
Measurements performed 24 h after the administration of prednisolone showed a return of all
these variables towards pretreatment values.
At 3 h after prednisolone administration both the maximum expiratory flow rate (MEFR)
and the flow rate at 50% VC were significantly greater than before drug administration
220
r
260
/-
V
>
3
8
220-
c
6
r
c
1F
lEO-
8
140-
L
I,
100
/I
I
/i\ 1.:
I
'.'.
I
96 vc
FIG.6. Effect of a single oral dose of 0.11 mmol(40 mg) of prednisolone on maximum expiratory
flow-volume curves in patient no. 4. Expiratory flow is related to volume, expressed as a percentage
and 3 h (W), 9 h (0)and
of vital capacity. Measurements were made 1 h before prednisolone (0)
12 h (A) after prednisolone.
Corticosteroid response in asthma
113
(P<0.05;
P<0=05);
improvement reached a maximum at 9 h, after which a decline occurred.
At 9 h the mean MEFR was 176% of the pretreatment value and the mean flow rate at 50%
VC was 216% (Fig. 5). Individual patients showed similar changes; the maximum expiratory
flow-volume curves for patient no. 4 are representative of the whole group and are shown in
Fig. 6. Only four curves are reproduced on the graph for the sake of clarity. When airway
obstruction was severe the peak flow was reached early in the vital capacity and then the rate
T LC
RV
v, (1)
FIG.7. Effect of a single oral dose of 0.11 mmol(40 mg) of prednisolone on maximum expiratory
flow-volume curves in patient no. 4. Expiratory flow is related to absolute lung volume, measured
by the closed-circuit helium-dilution technique. Measurements were made 1 h before prednisolone
(0)
and 6 h (0)and 12 h (A) after prednisolone.
of flow fell quickly, making the curve convex to the volume axis throughout. After therapy the
curves became less convex to the volume axis and air flow at any given lung volume increased.
Flow has also been plotted against the absolute lung volume obtained from helium dilution
measurements, as shown in Fig. 7. Flow obtained at 20, 40, 50, 60 and 80% of the vital
capacity showed a similar time-course, the maximum change occurring 9 h after prednisolone had been administered, as shown in Fig. 8.
Therefore the six patients, both individually and as a group, showed a similar pattern of
response. A statistically significant improvement was detectable within 3 h of prednisolone
administration, The peak effect was reached within 9-12 h, after which there was a return
114
R. Ellul-Micallef, R. C. Borthwick and G.J. R. McHardy
towards pretreatment values. The mean change in PEFR, FEV,, MEFR and SG,, was still
statistically significant 24 h after the drug had been given (Pt0.05,Pc0.05,P<0*05,Pc0.05
respectively).
However, the mean change in FVC, RV/TLC% and flow at 50% VC was no longer
significant by this time. The mean change in PEFR and FEV, had returned to non-significant
levels by 36 h. SG,, was still markedly improved at this time in four patients (nos. 2,3,4and 5),
however; these patients had values of 161%, 141%, 192% and 176% respectively of their pretreatment measurements. No statistical analysis was attempted on the measurements obtained
at this time as patient no. 6 failed to carry out this test because of the acute onset of breathlessness.
1'
DISCUSSION
The assessment of treatment in patients with reversible airway obstruction is difficult. Patients
with asthma often show changes in the severity of their disease either spontaneously after
admission to hospital, or as a response to placebo preparations. These patients may also
exhibit diurnal variation in airway obstruction, which may make the response to a single dose
of a drug difficult to interpret. The patients studied in this investigation were in a stable state
for at least 48 h before receiving prednisolone. All the patients were screened for respira-
Corticosteroid response in asthma
115
tory tract infection, all having three sputum specimens negative on culture for ordinary pathogens and sputum which was macroscopically mucoid. The chest X-ray and electrocardiogram
were normal in all patients. It has been shown that the clearance of corticosteroids from the
plasma may be abnormal in patients with either renal (Englert, Brown, Willardson, Wallach
& Simons, 1958) or hepatic (Brown, Willardson, Samuels & Tyler, 1954; Petersen, 1960) dysfunction. In all the patients estimations of serum urea and electrolytes, plasma bilirubin, serum
alanine aminotransferase and alkaline phosphatase were all normal. The patients received no
drugs other than prednisolone during the trial period.
All patients who completed the study were found to have a blood eosinophilia but only
two, patients nos. 3 and 5 in Table 1, had sputum eosinophilia. Patients nos. 1, 3 and 4 had
negative skin tests, and patients nos. 2 and 5 reacted to house-dust mite only. Patient 6, the
only one whose asthma began in childhood, reacted to house dust and to grass pollens.
Although the patients studied did not represent a homogeneous group in regard to age of
onset of asthma or to allergic responses elicited, none of the patients showed a response to
prednisolone that was significantly different from the response observed in the group as a
whole.
Although various time-intervals have been suggested as elapsing between the administration
of corticosteroids and the onset of improvement in patients with bronchial asthma, no systematic physiological studies have to our knowledge been carried out. These time-intervals
have been variously reported as 2-3 h (Cope, 1972), 5-9 h (Schwartz, 1951) and 24-48 h and
longer (Herxheimer, 1966). The relief provided by corticosteroids has also been described as
immediate (Saperia, 1966). It is not surprising that conflicting results of this nature have been
reported, because the degree of severity of the condition, the patients studied, drugs given
and the dosage and routes of administration have been widely different. Subjective clinical
observation seems to have been relied on when conclusions were being drawn, instead of
systematic physiological assessment.
We believe that the fact that we have demonstrated consistent changes in the physiological
tests performed after corticosteroid administration is due to careful initial selection, with the
rejection of patients who failed to meet the criteria laid down. No patient was admitted to the
study whose history did not suggest that stable airway obstruction was present during the
period immediately before admission to hospital, and no patient was allowed to complete
the study if the disease showed evidence of significant improvement or deterioration during
the first 2 days of the trial. Collins, Clark, Harris & Townsend (1970) have reported failure to
detect significant improvement in patients with asthma after intravenous hydrocortisone,
assessing response by measurement of PEFR. However, the patients they studied were acutely
ill, whereas in our study such patients were excluded. Although the PEFR is an effort-dependent manoeuvre, our results show it to be as sensitive an index of change as the more complicated tests, provided that the full co-operation of the patient in producing a maximum effort
is ensured on each occasion.
Although the exact location of obstruction in asthma is not known (Macklem, 1971) there
is probably more than one site of airway obstruction. Campbell, Martin & Riley (1957),
basing their work on a mathematical analysis of the factors tending to open and close the
airways during a forced expiration, concluded that critical narrowing occurs in the larger
airways in asthma. Gayrard (1968) has produced some confirmation of their findings. McFadden & Lyons (1969) measured the resistance of airways during forced expiration upstream
116
R. Ellul-Micallef, R. C . Borthwick and G.J. R. McHardy
and downstream from equal pressure points (Mead, Turner, Macklem & Little, 1967), combining the equal pressure point concept with measurements of iso-volume pressure-flow
curves in asthmatics during recovery from acute attacks. They found that both upstream and
downstream resistance were increased, indicating that both large and small airways are involved. However, their data showed that the principal area of obstruction appeared to be in
the upstream pathways, that is, from the alveoli to the equal pressure point. Cade, Woolcock,
Rebuck & Pain (1971), studying lung mechanics during provocation of asthma with methacholine, also showed that the larger as well as the smaller airways were involved, but the
response of the larger airways was faster and of a shorter duration than that of the smaller
airways. In a recent study of MEFV curves measured while air and a helium-oxygen mixture
were respired, Despas, Leroux & Macklem (1972) have shown that the site of airway obstruction lies in the small airways in some asthmatic subjects and in the larger airways in others. Our
results indicate that obstruction was present both in the larger airways, as shown by a marked
diminution in SG,, and MEFR, as well as in the smaller airways, as reflected by a significant
decrease in mid-expiratory flow rate. This improvement in both the larger as well as in the
smaller airways is more evident when the changes of flow rate are plotted against the actual
lung volumes (Fig. 7) rather than the percentage of vital capacity. This is detectable even
though the method of presentation does not allow for compression of intrathoracic gas, which
will lower flow rate measured at the mouth, or air trapping, which may mask part of the
change in lung volumes as measured by helium dilution. These effects would tend to minimize
the changes produced by treatment as measured by our techniques. After corticosteroid
administration, flow occurred at lung volumes at which it had ceased before treatment.
This suggests that some airways previously completely closed were now open.
Full analysis of the flow-volume curves would depend on knowledge of the static recoil
pressure of the lung; this, however, was not measured. Changes in small airways would be
expected to affect pulmonary gas exchange by altering local ventilation/perfusion ratios, thus
altering arterial Po,. The effects of corticosteroids on this aspect of altered pulmonary
function in asthma have been the subject of a separate study (Ellul-Micallef, Borthwick &
McHardy, 1972).
It should be emphasized that the results reported were obtained in patients with chronic
bronchial asthma. It should not be inferred that similar corticosteroid effects would be seen
in patients during acute exacerbations or status asthmaticus.
ACKNOWLEDGMENT
Our thanks are due to Mrs M. M. Jack for typing the manuscript.
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