Nocturnal Events Related to "Morning
Dipping" in Bronchial Asthma*
Jeremy M. Kallenbach, M.B., F.C.C.P.; Vanessa R. Panz;
Barry I. Joffe, MB., D.Sc.; David Jankelow, M.B.;
Ronald Anderson, P h . D . , t Byron Haitas, M.Sc, M.B.; and
HaroldC.
Seftel, B.Sc,
M.B.
The m e c h a n i s m o f e a r l y m o r n i n g b r o n c h o s p a s m i n a s t h m a
and w i t h o u t (n = 7) " m o r n i n g dipping" and normal subjects.
was i n v e s t i g a t e d b y a n a l y z i n g c i r c a d i a n v a r i a t i o n s i n t h e
Findings suggested that an e x a g g e r a t e d n o c t u r n a l n a d i r in
p l a s m a levels o f Cortisol, A C T H , e p i n e p h r i n e , a n d n o r e p i -
plasma Cortisol levels may p r e c i p i t a t e " m o r n i n g d i p p i n g "
n e p h r i n e , as w e l l as i n the s e r u m n e u t r o p h i l c h e m o t a c t i c
i n some p a t i e n t s w i t h a s t h m a .
a c t i v i t y a n d h e a r t r a t e i n a s t h m a t i c p a t i e n t s w i t h (n = 6)
An
i n c r e a s e in t h e s e v e r i t y
during the
early
o f airway
obstruction
m o r n i n g hours is a
common
o c c u r r e n c e in b r o n c h i a l asthma. A i r w a y c a l i b e r e x h i b its a circadian r h y t h m w i t h t h e t r o u g h o c c u r r i n g in
the early m o r n i n g hours, and t h e a m p l i t u d e o f variation
b e i n g c o n s i d e r a b l y g r e a t e r in asthmatic, than n o r m a l ,
individuals.
1
I t is p r o b a b l e that " m o r n i n g d i p p i n g " in
asthma is associated w i t h this e x a g g e r a t e d
circadian
variation in p u l m o n a r y function, t h e p r e c i s e cause o f
which remains, however, undefined.
T h e b e n e f i c i a l effects o f e p i n e p h r i n e and Cortisol in
asthma l e n d c r e d e n c e t o t h e postulate that " m o r n i n g
d i p p i n g " m a y b e r e l a t e d t o n o c t u r n a l t r o u g h s in t h e
subjects with the nadir occurring in the early morning.
This may be related to a degree of sympathetic
withdrawal, with a shift to dominant vagal tone. The
possibility that "morning dipping" may be related to
vagal mechanisms is suggested by the finding that it
can be markedly attenuated by ipratropium bromide.
Barnes has postulated that "morning dipping" may
be due to the coincidence of a number of these
variables in the early morning as a result of biologic
rhythms originating in the hypothalamus. The object
of the present study was to assess their relative
importance by studying the diurnal changes in them
in relation to fluctuations in airway caliber.
9
10
11
plasma l e v e l s o f t h e s e h o r m o n e s . A t e m p o r a l association has b e e n
shown
t o exist b e t w e e n
nadirs in p l a s m a C o r t i s o l ,
2
the
diurnal
plasma e p i n e p h r i n e ,
3
and
u r i n a r y c a t e c h o l a m i n e l e v e l s , and e a r l y m o r n i n g b r o n 4
c h o s p a s m in asthmatic patients. A n u n e q u i v o c a l causeeffect r e l a t i o n s h i p b e t w e e n t h e s e v a r i a b l e s and a i r w a y
function has not, h o w e v e r , b e e n e a s y t o c o n f i r m , and
n e i t h e r Cortisol infusions
salbutamol
6
5
nor therapeutic levels
of
result in c o m p l e t e a b o l i t i o n o f " m o r n i n g
d i p p i n g " in asthmatic patients.
B o t h a n t i g e n and e x e r c i s e - i n d u c e d
7
8
bronchospasm
are associated w i t h i n c r e a s e d s e r u m n e u t r o p h i l c h e m o tactic a c t i v i t y A similar p h e n o m e n o n c o u l d b e o c c u r ring in relation t o " m o r n i n g d i p p i n g " as a result o f
i n c r e a s e d mast c e l l m e d i a t o r r e l e a s e p r e c i p i t a t e d b y
the
nocturnal
nadirs in p l a s m a c a t e c h o l a m i n e
and
c o r t i c o s t e r o i d l e v e l s . D o c u m e n t a t i o n o f this has not,
h o w e v e r , b e e n available.
T h e r e is a circadian v a r i a t i o n in h e a r t rate in n o r m a l
*From the Departments of Medicine and Cardiology; University of
the VVitwatersrand, Johannesburg, South Africa,
f Institute of Pathology, University of Pretoria, South Africa.
Manuscript received June 18; revision accepted September 23.
Reprint requests: Prof Kallenbach, University of Witwatersrand
Medical School, Parktown 2193, Johannesburg, South Africa
SUBJECTS A N D M E T H O D S
We studied 13 asthmatic patients and 11 normal subjects. Informed consent was obtained in each case, and the study was
approved by the Ethics Committee of the University of the
Witwatersrand. Each asthmatic patient was a nonsmoker with a
long history of the disease, the diagnosis being confirmed by the
finding of at least one of the following: (1) a FEV, level less than 70
percent of the predicted value with significant reversibility following
inhalation of a bronchodilator; (2) a fall in peak expiratory flow rate
(PEF) of at least 20 percent on exercise.
The asthmatic patients were divided into two subgroups, namely:
"dippers" and "nondippers," depending on whether or not they
demonstrated significant morning dipping during the study. This
was arbitrarily defined as a fall of 20 percent or greater in the PEF
at 4:00 AM compared with the basal value the previous afternoon,
based on data suggesting that PEF may exhibit a circadian variation
of up to almost 20 percent even in normal individuals (mean
amplitude of variation 8.3 percent, standard deviation 5.2 percent).
1
Each patient was using a beta-adrenergic bronchodilator aerosol
regularly This was discontinued a week prior to the study None
was using another bronchodilator preparation. No patient had
received systemic corticosteroid therapy for at least two years prior
to the study. Ten patients were using beclomethasone dipropionate
aerosol which was discontinued on the morning of the study Full
details of corticosteroid therapy in the asthmatic patients are given
in Table 1.
The normal subjects were nonsmokers with no history of bronchial
asthma or any atopic condition. Each had normal pulmonary function
CHEST / 93 / 4 / APRIL, 1988
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751
Table 1—Details of Corticosteroid Therapy in Asthmatic Patients Ranked in Ascending Order of
Midnight Plasma Cortisol Levels
Midnight
Cortisol Level
(ng/ml)
Patient
No.
Fall in
PEF During
Study (%)
1
9
55
2
11
20
3
12
27
4
16
25
5
17
20
Use of
Bedomethasone*
Use of Systemic
Steroids
Regular short-term
(500 M,g)
Regular long-term
(400 u,g)
Nil
Nil
Short course 3
years previously
Short course ± 10
years previously
Nil
Dippers
Regular long-term
(300 u.g) '
Regular long-term
6
7
18
18
21
13
8
9
10
22
23
23
11
11
28
5
(300 M-g) '
Nil
Regular long-term
(300 u.g)
Irregular short-term
Nil
Regular long-term
(400 p,g)
Irregular short-term
12
13
108
138
10
15
Irregular short-term
Irregular short-term
7
7
Nondippers
Nil
Nil
Two month course 2
years previously
Nil
Nil
Nil
Used for 2 years
± 14 years previous
Nil
Short course 3
years previously
•Short-term is less than one month; long-term, more than 2 years; doses given in parentheses are maximum daily doses.
and none had a significant fall in PEF on exercise.
The subjects were studied individually in the recumbent position
in a quiet room. A 19-gauge or larger cannula was inserted into an
arm vein at midday and kept patent with a saline infusion.
Subsequently; each subject was attached to a 24-hour ambulatory
electrocardiograph (ECG) recorder. A standardized light meal was
given at 6:00 PM. Water was the only beverage permitted. Blood
was sampled through the cannula at 4:00 PM, 4:30 PM, midnight,
4:00 AM, and 8:00 AM. Aliquots of the blood taken at each time were
kept for measurement of the plasma levels of epinephrine, norepinephrine, Cortisol and adrenocorticotropic hormone (ACTII), and
for assessment of the serum neutrophil chemotactic activity. However, as the number of investigations was limited by cost, measurements of plasma catecholamines and studies of serum neutrophil
chemotactic activity were omitted at midnight, and plasma ACTH
levels measured only in the midnight and 8:00 AM specimens.
For plasma specimens, aliquots of blood were placed into iced
tubes, immediately centrifuged, and the separated plasma then
stored at — 20°C until assayed. For serum specimens, blood was
allowed to clot at room temperature for 20 to 30 minutes and then
centrifuged, and the separated serum stored at - 20°C until analysis.
Measurements of PEF were made subsequent to the sampling of
blood at 4:00 PM, 4:30 PM, 4:00 AM, and 8:00 AM using a Wrights
peak flow meter. The best of three readings was recorded at each
time. The basal PEF was the arithmetic mean of the values obtained
at 4:00 PM and 4:30 PM.
Analytical Methods
Hormones. Plasma Cortisol and ACTH levels were measured using
radioimmunoassay kits (lower limits of sensitivity 4 ng/ml for CORTISOL;
10 pg/ml for ACTH).
Plasma epinephrine and norepinephrine levels were measured
by a radioenzymatic method (lower limits of sensitivity 2 to
5 pg/ml).
The intraassay coefficient of variation for each of these assays was
less than 5 percent. Each sample was assayed in duplicate, the
mean of the two radioactivity counts being used to calculate the
final value.
For basal hormone levels, equal aliquots of the 4:00 PM and 4:30
PM specimens were mixed and integrated basal levels obtained.
Serum Neutrophil Chemotactic Activity. Polymorphonuclear leukocytes (PMNLs) were prepared from heparinized venous blood
obtained from adult human donors.
(1) P M N L migration assay: The leukotactic potential of the
7
Table 2—Demographic and Pulmonary Function Data
Normal subjects
(n = l l )
Dippers
(n=6)
Nondippers
(n = 7)
Airway
Resistance
(cmlljO/L's)
Fall in PEF
on Exercise (%)
1.5 (0.5)
1.7 (2.8)
Age (yrs)
Sex
FEV,
(% Predicted)
21.2 (3.2)
6M.5F
107.2 (11.2)
20.3 (2.9)
3M.3F
67.0 (22.5)*
6.9 (4.9)*
32.8 (14.3)
21.1 (5.5)
4M.3F
88.6 (16.9)*
3.2 (1.9)*
31.1 (8.7)
*Dippers vs nondippers significantly different (p = <0.025).
752
Morning Dipping in Bronchial Asthma (Kallenbach
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et al)
Table 3—Peak Expiratory Flow Rates*
Normal subjects
(n = l l )
Dippers
(n = 6)
Nondippers
study, the asthmatic patients were subdivided into six
Basal
4:00 AM
8:00 AM
490 (73)
477 (69)
490 (72)
323 (94)
238 (102)
284 (111)
443 (107)
402 (106)
416 (112)
dippers and seven nondippers.
Demographic and pulmonary function data are
shown in Table 2. The F E V , was lower and the airway
resistance higher in the dippers than in the nondippers
(p<0.025), There was no difference between these
subgroups, however, in the P E F response to exercise.
Fluctuations in P E F during the study are shown in
(n = 7)
•Values are mean (SD) liters/minute. (Percent fall in PEF at 4:00
AM compared with basal value —dippers = 28.0± 14.0%; nondippers = 9.8 ± 3.7%—p = <0.0001.)
specimens was measured using modified Boyden chambers with
5 urn pore-size millipore filters. The sera were diluted to a final
concentration of 20 percent. The filters were processed after
incubation for 60 minutes at 37°C and the results expressed as
PMNL per microscope high-powered field. Corresponding control
specimens for random migration in the absence of serum were
included and subtracted from each test.
(2) Activation of P M N L membrane-associated oxidative metabolism: The effects of the serum specimens on P M N L membrane-associated oxidative metabolism were measured by a myeloperoxidase-mediated iodination assay as an alternative method of
detection of serum-associated leukoattractants. Sera were tested
at a final concentration of 20 percent and the results expressed in
fmoles I after 30 minutes incubation at 37°C.
7
12
13
125
Each individual specimen was coded prior to storage, the code
only being broken once the results were available.
The basal value in the tests of neutrophil chemotactic activity was
the arithmetic mean of the 4:00 PM and 4:30 PM values.
ECG Analysis. For ECG analysis, strips of 20 beats taken five,
ten, and 15 minutes prior to each sampling of blood were studied.
From these 60 beats, the maximum, minimum, and mean heart
rates and the magnitude of respiratory sinus arrhythmia (RSA) were
obtained for each time in the study.
The basal value for each ECG variable was the arithmetic mean
of the values obtained at 4:00 PM and 4:30 PM.
Statistical Analysis. For each variable, comparisons were made
between the following: (1) asthmatic dippers and asthmatic nondippers, (2) dippers and normal subjects; and (3) nondippers and normal
subjects. Pairwise comparisons were made using the two-tailed
Mann-Whitney U test conducted at a simultaneous 5 percent
Bonferroni level. The degree of variation in each variable during
the study was assessed within each group using Friedman's two-way
analysis of variance.' Correlations between variables were done
using Spearman's rank correlation coefficient.
14
4
14
Table 3. The mean fall in PEF" from the basal value to
that at 4:00 A M was 2 8 . 0 ± 14.0 percent in the dippers
and 9.8 ± 3 . 7 percent in the nondippers (p<0.0001).
The P E F exhibited a significant degree of variation in
both dippers and nondippers (p<0.01), but not normal
subjects (p = >0.1),
Hormones
Plasma Cortisol levels are shown in Table 4. The
plasma
Cortisol
exhibited a significant degree of vari-
ation in each group of subjects during the study
(dippers and nondippers, p<0.0001; normal subjects,
p<0.001). Midnight plasma Cortisol levels were significantly lower in the asthmatic dippers than in either
the nondippers (p<0.005) or the normal
subjects
(p<0.001). There was no difference, however, between
nondippers and normal subjects in the midnight
plasma Cortisol level (p>0.38). The dippers exhibited
greater fluctuations in the plasma
CORTISOL
level during
the study, the ratio between the basal and midnight
levels being higher than in nondippers (p<0.025) or
normal subjects (p<0.001). There was no difference,
however, between nondippers and normal subjects in
this ratio (p>0.16).
Plasma A C T H levels are shown in Table 5. The
mean values in each group were consistent with the
normal diurnal levels for our laboratory. There was no
significant difference between the groups at either
time.
Plasma catecholamine levels are shown in Table 6.
The plasma norepinephrine level exhibited a significant degree of variation in the normal subjects during
the study (p<0.02). There was no significant variation
RESULTS
in norepinephrine levels, however, in either the asth-
On the basis of the fluctuations in P E F during the
matic dippers or the nondippers. Although plasma
Table 4—Plasma Cortisol Levels*
Normal subjects
(n = l l )
Dippers
(n = 6)
Nondippers
Basal
Midnight
4:00 AM
8:00 AM
Ratio
BasahMidnight
74.6(26.1)
50.5 (32.3)t
97.5 (48.8)
151.8 (32.5)
1.8 (0.7)t
57.3 (16.9)
13.8 (3.7)
63.8 (29.2)
119.2 (35.8)
4.3 (1.7)
87.1 (50.3)
50.4 (48.5)*
81.3 (44.1)
173.7 (48.6)
2.5 (1.1)§
(n~7)
*Values are mean (SD) ng/ml; conversion to nmol/Lx2.76.
tNormal subjects vs dippers significantly different (p = <0.001).
JNondippers vs dippers significantly different (p = <0.005).
INondippers vs dippers (p = <0.025).
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753
Table 5—Plasma ACTH Levels*
Normal subjects
(n = l l )
Dippers
(n = 6)
Nondippers
(n = 7)
Table 7—Serum Neutrophil Chemotactic Activity
Midnight
8:00 AM
76.9 (24.6)
100.8 (40.9)
71.3 (8.8)
110.0 (24.6)
98.0 (34.6)
113.6 (21.7)
•Values are mean (SD) pg/ml; conversion to pmol/LX 0.22.
epinephrine levels appeared to exhibit minor degrees
of variation, this was not statistically significant in any
group. There was no significant difference between
the groups in either the epinephrine or norepinephrine
levels at any time.
Serum Neutrophil
Chemotactic
Activity
The results of measurements of the serum neutrophil chemotactic activity are shown in Table 7. Serum
neutrophil chemotactic activity did not vary significantly in any group during the study There was no
significant difference between the groups at any time.
ECG
Basal
Polymorphonuclear
Normal subjects
(n = l l )
Dippers
(n = 6)
Nondippers
(n = 7)
Polymorphonuclear
metabolismt
Normal subjects
(n = l l )
Dippers
(n = 6)
Nondippers
(n = 7)
4:00 AM
leukocyte migration assay*
53 (28)
53 (29)
8:00 AM
53 (24)
54 (25)
63 (25)
58 (23)
57 (30)
58 (19)
60 (25)
leukocyte membrane-associated oxidative
6160 (4115)
5890 (3977)
5856 (4028)
6211 (3718)
6132 (3879)
5725 (4011)
4980 (1322)
5119 (1665)
4395 (1290)
*Values are mean (SD) polymorphonuclear leukocytes/high-powered field.
tValues are mean (SD) fmoles I .
185
patients (dippers plus nondippers n = 13) were combined, there was a strong inverse correlation between
the midnight plasma Cortisol levels and the magnitude
of the fall in P E F from the basal value to that at 4:00 A M
Analysis
(r = - 0.79, p<0.0002) (Table 1). There was no correla-
The E C G data are shown in Table 8. There was no
tion between the 4:00 A M plasma Cortisol level and the
significant variation in the heart rates or the RSA in
fall in P E F (r = - 0.15, p < 0 . 6 ) . No correlation could be
either normal subjects or nondippers during the study.
demonstrated between either the 4:00 A M plasma
In the dippers, on the other hand, all heart rates and
epinephrine or norepinephrine levels and the magni-
the RSA varied significantly during the study (maxi-
Table 8--ECG Data*
mum heart rate p < 0 . 0 0 5 , m i n i m u m heart rate
p<0.05, mean heart rate p < 0 . 0 5 , RSA p<0.005). The
maximum heart rate tended to diminish to a greater
degree in the dippers than in either the nondippers
or the normal subjects at midnight and 4:00 A M , with
corresponding decreases in the RSA at these times.
There was no significant difference, however, between
the groups in any of the E C G variables at any time.
Correlations
When the data from the two subgroups of asthmatic
Table 6—Plasma Catecholamine Levels*
Basal
Epinephrine
Normal subjects
(n = l l )
Dippers
(n = 6)
Nondippers
(n = 7)
Norepinephrine
Normal subjects
(n = l l )
Dippers
(n = 6)
Nondippers
4:00 AM
8:00
AM
37.1 (17.4)
27.1 (12.6)
39.1 (17.4)
23.5 (12.1)
19.2 (1.5)
30.2 (7.5)
33.9 (18.4)
25.6 (11.6)
29.4 (11.0)
Midnight
4:00 AM
8:00
51 (9)
50 (8)
57 (11)
50 (10)
48 (7)
56 (10)
55 (8)
55 (7)
59 (12)
67 (10)
70 (12)
76 (13)
72 (9)
64 (11)
64 (11)
80 (11)
79 (9)
74 (5)
75 (4)
82 (9)
62 (9)
59 (8)
59 (10)
65 (11)
60 (9)
56 (11)
56 (11)
66 (11)
67 (11)
65 (6)
65 (5)
72 (9)
21 (6)
19 (9)
17 (6)
26 (6)
20 (6)
22 (9)
Minimum heart rates
54 (8)
Normal subjects
AM
(n=ll)
Dippers
52 (7)
(n = 6)
Nondippers
56 (12)
(n = 7)
Maximum heart rates
Normal subjects
72 (9)
(n = l l )
Dippers
(n = 6)
Nondippers
In — 7\
in — i)
Mean heart rates
Normal subjects
(n = l l )
Dippers
(n = 6)
Nondippers
In
—7)
t
'1
Magnitude of respiratory sinus arrhythmia
Normal subjects
18 (6)
16 (4)
(n=ll)
Dippers
21 (6)
14 (5)
(n = 6)
Nondippers
23 (7)
18 (5)
(n = 7)
n
223.5 (103.5)
153.9 (43.0)
135.5 (65.4)
137.0 (34.5)
106.2 (59.3)
242.5 (230.7)
218.4 (169.6)
144.9 (51.2)
137.8 (57.4)
* Values are mean (SD) pg/ml; conversion to nmol/L X 0.0055 for
epinephrine, x 0.0059 for norepinephrine.
754
Basal
*Values are mean (SD) beats per minute.
Morning Dipping in Bronchial Asthma (Kallenbach
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et al)
tude of the fall in P E F ( r = - 0 . 4 9 , p > 0 . 0 9 and
r = —0.23, p > 0 . 4 , respectively). There was no correlation between any of the E C G variables at 4:00 A M and
the magnitude of the fall in P E F (minimum heart rate,
r = - 0 . 2 2 , p > 0 . 4 ; mean heart rate, r = - 0 . 2 8 , p > 0 . 3 ;
maximum heart rate, r- — 0.33, p > 0 . 2 ; R S A ,
r = - 0 . 3 1 , p>0.2).
Details of corticosteroid therapy in the asthmatic
patients are given in Table 1. There was no difference
between the midnight Cortisol levels of the five longterm users of bedomethasone dipropionate and those
of the remainder of the asthmatic patients ( p > 0 . 2 ,
Mann-Whitney U test).
DISCUSSION
The occurrence of extremely low midnight plasma
Cortisol levels in the asthmatic patients with morning
dipping clearly requires careful analysis in the light of
their use of corticosteroid medications. As only two
dippers had received short courses of systemic corticosteroids some years prior to the study, it is primarily
the effect of inhaled bedomethasone dipropionate on
hypothalamic-pituitary-adrenal (HPA) function that is
of direct relevance in the interpretation of our results.
Law et al recently suggested that children using
relatively large doses of bedomethasone dipropionate
(300 to 1300 (xg/day) may have nocturnal suppression of
corticosteroid secretion. Neither clinical data with
special reference to dipping nor plasma A C T H levels
were reported, and the possibility cannot be excluded
that these findings reflect the occurrence of a similar
phenomenon to that documented in the present study,
this being, however, directly related to the disease,
rather than to the drug therapy. W h i l e other authors
have reported the occurrence in children of some
depression of plasma Cortisol levels by bedomethasone
dipropionate used in doses ranging from 300 to 800
|ig/day,
the majority of the studies performed in
children, using it in similar doses,
including those
related to nocturnal adrenal function, have provided
no support for the occurrence of H P A suppression.
Studies in adults using the drug have demonstrated the
occurrence of H P A suppression with 1,600 to 2,000 |xg/
day.
The dippers were adults, only two-thirds of
whom were using relatively small doses of beclomethasone dipropionate (200 to 500 u,g/day, mean
300 jag/day). There is no convincing evidence of H P A
suppression in adults in association with doses of this
magnitude
nor any effect on nocturnal Cortisol
levels.
is
16-18
192 2
23
2426
25-27
26
Another important finding militating against a HPAdepressant effect of bedomethasone dipropionate in
the dippers is the finding in them of normal plasma
A C T H levels. T h e A C T H is secreted in a pulsatile
fashion with a delay between the occurrence of a pulse
and the subsequent Cortisol response. It is difficult,
28
therefore, to clearly interpret the relationship between
the levels of these two hormones when obtained from
one blood sample. Although the response of the
plasma Cortisol level to insulin and the metyrapone test
are more sensitive tests of H P A function, the finding of
plasma A C T H levels in the normal range makes it
considerably less likely that suppression by beclomethasone dipropionate was the underlying cause
for the low midnight CORTISOL levels in the asthmatic
dippers.
That beta-adrenergic receptor "subsensitivity" may
be an underlying pathogenetic mechanism in bronchial asthma remains a popular postulate, and it has
long been thought likely that corticosteroid deprivation may be associated with a degree of adrenergic
blockade. Glucocorticoids potentiate the relaxant
response of respiratory tract smooth muscle to catecholamines, and reverse the tachyphylaxis to the
bronchodilator response of beta-adrenergic-agonists
after three to five hours. These properties may be
related to an "upregulation" in number of beta-receptors,
as well as to an increase in their affinity for
agonists, occurring after as little as four hours. An
exaggerated midnight plasma CORTISOL trough could
theoretically, therefore, precipitate airway narrowing
within a few hours by the induction of a relative state of
beta-adrenergic "subsensitivity."
29
30
31
32
3334
35
34
If morning dipping is directly related to excessively
low midnight plasma Cortisol levels, it should be
preventable by Cortisol therapy, and Soutar et al have
suggested that an infusion of corticosteroids has no
protective effect against morning dipping. However,
the fluorometric method of plasma corticosteroid
determination used to assess the adequacy of their
doses is insensitive and subject to spurious elevation
related to various medications. Clearly, a similar
study should be undertaken using a radioimmunoassay
to measure plasma Cortisol levels.
In contrast to Barnes et al, we were unable to
demonstrate a statistically significant diurnal variation
in the plasma epinephrine levels in any group of
subjects. Although the asthmatic dippers appeared to
demonstrate the greatest degree of variation in this
variable, it is unlikely that the small changes which
occurred were closely related to the large fluctuations
in simultaneously recorded P E F in this group.
It has been suggested that the nocturnal nadirs in
plasma Cortisol and epinephrine levels may have a
direct effect on the airway smooth muscle of asthmatic
patients and also predispose to the release of mast cell
mediators. Although an increase in mast cell-associated neutrophil chemotactic activity has been shown to
occur in association with both exercise and allergeninduced bronchospasm, the present data provide no
support for the occurrence of a similar phenomenon in
relation to morning dipping.
3
36
37
3
11
7,8
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7 55
The relationship between vagal tone and the fluctuations in airway caliber which occurred in the asthmatic
dippers is less easy to assess. Only the dippers exhibited significant variations in heart rate during the
study. The most marked was that in maximum heart
rate which produced corresponding changes in the
RSA. As heart rate is, at any time, the net result of both
sympathetic and parasympathetic factors, it is clearly
difficult to attribute the diminution in maximum heart
rate which occurred at midnight and 4:00 A M in the
dippers purely to an increase in vagal tone, particularly
as vagal neural output has been clearly shown to be
directly related to the R S A
38
which actually diminished
at these times. However, the possibility cannot be
excluded that a nocturnal increase in vagal tone was
related to the early morning diminution
in airway
caliber in the asthmatic dippers.
Of the different variables investigated, the plasma
Cortisol level demonstrated the most significant degree
of variation in all groups during the study period, the
fluctuations
being
most pronounced,
moreover,
in
those subjects with the greatest changes in airway
caliber, namely the asthmatic dippers. The nondippers, on the other hand,
exhibited patterns
more
closely resembling those of normal subjects in the
magnitudes of the changes which occurred in both
plasma Cortisol levels and airway caliber. The midnight
plasma Cortisol level was the only variable in our study
which
differed
significantly
between
the
different
groups of subjects, being extremely low in the dippers
and showing, in addition, a strong negative correlation
with the magnitude of the fall in P E F in the asthmatic
patients. W e suggest, therefore, that an exaggerated
nocturnal nadir in Cortisol levels may directly precipitate morning dipping in some patients with asthma. It
must be emphasized, however, that the dippers had a
greater impairment of pulmonary function than the
nondippers, resulting in the use by a greater number of
them of regular beclomethasone dipropionate therapy.
The possibility cannot completely be excluded, therefore, that the lower midnight plasma Cortisol levels of
the dippers were the result of this therapy, and clearly,
the effect of low doses of the drug on the H P A function
of adults requires elucidation.
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Coronary Angiography 1988
The Department of Radiology, Brigham and Women's Hospital and Harvard Medical School,
in cooperation with the Council on Cardiovascular Radiology of the American Heart Association,
will sponsor this annual course June 6-9 at the Hyatt Regency Hotel, Cambridge, Massachusetts. For information, contact Ms. RosaBondar, Coordinator of Continuing Education, Brigham
and Women's H o s p i t a l , D e p a r t m e n t of Radiology, 75 Francis S t r e e t , Boston 02115
(617:732-6265).
New Perspectives in Pulmonary Rehabilitation and
Smoking Cessation
This three-day meeting, sponsored by St. Helena Hospital and Health Center, co-sponsored
by the California Chapter of the A C C P and endorsed by the American Association for
Cardiovascular and Pulmonary Rehabilitation, will be held at the Clarion Inn, Napa, California,
May 4-6. For information, contact John E. Hodgkin, M . D . , FCCP, St. Helena Hospital and
Health Center, D e e r Park, California 94576 (707:963-3611).
CHEST / 93 / 4 / APRIL. 1988
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757