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INTRODUCTION
Asthma, in common with many other
disease processes, shows a pronounced
circadian variation in the majority of
patients who demonstrate a striking decline in lung function overnight termed
nocturnal asthma (NA). Nocturnal
asthma is a marker for more severe
disease and carries significant morbidity1 and mortality.2 The nocturnal
worsening of asthma is well recognized by patients, but not always appreciated by practitioners. A classic
survey conducted by Turner-Warwick3
included more than 7,600 asthma patients and revealed that 74% of those
surveyed awakened from sleep at least
once per week with symptoms of
wheezing, chest tightness, or cough requiring inhaled b2 agonist use. Almost
40% awakened nightly due to asthma
From the Department of Medicine, The National Jewish Medical and Research Center,
Denver Colorado.
Received for publication September 14,
1998.
Accepted for publication September 29,
1998.
378
strictly refer to the day and night periods, respectively, and are part of the
circadian cycle as a whole. A mammalian circadian pacemaker located in the
suprachiasmal nucleus of the brain
controls many physiologic functions
such as core temperature which itself is
used to monitor the phase of the circadian rhythm. In man, the circadian cycle is about 24.1 hours in length and
continues to cycle in the absence of
external stimuli such as ambient light.
The sleep-wake cycle, controlled by
a sleep homeostat, also influences
physiologic and pathologic processes
and subserves a homeostatic function.
Normally, the circadian rhythm entrains the sleep-wake cycle to facilitate
daytime activity for humans and nighttime activity for nocturnal species. The
circadian and sleep-wake cycles, however, can become desynchronized, eg,
in international travel, a condition popularly known as jet lag. Similar to
circadian rhythms, the sleep-wake cycle continues in the absence of external
stimuli. The intentional desynchronization of the circadian and sleep cycles
can allow study of their separate physiologic effects (forced desynchrony).
Both circadian and the sleep-wake
rhythms control the propensity to sleep
and wakefulness on a continuous basis.
The balance between these two cycles
determines the sleep-wake pattern and
also quality of sleep.
The investigation of circadian physiologic and pathologic changes are relevant to the elucidation of the pathogenesis of asthma and may help design
more effective therapy. The variation
in asthmatic lung function may be under the control of both circadian and
sleep-wake cycles. In addition, the
state of sleep itself has additional phys-
Lung volumes
Functional residual capacity (FRC) is
increased in asthmatics as compared
with normal subjects, a condition
termed hyperinflation. An increased
FRC is associated with a greater airway caliber and thus is beneficial. Ballard et al,11 using a horizontal body
plethysmograph, measured FRC in
non-asthmatic and asthmatic subjects
during sleep. Functional residual capacity which was higher in the asthmatics before the onset of sleep, fell in
both groups and equalized in the two
groups especially during rapid eye
movement phase sleep. The observed
fall in FRC could account in part for
the increase in airway resistance which
occurs in NA. In a subsequent study,
however, application of a negative
pressure device around the chest to
reduce this decline in FRC did not alter
the overnight changes in FEV1 or bronchial reactivity.12 Thus, the change in
Figure 1. Airway resistance (Ria, cm H2O/L/s) in 6 asthmatic subjects progressively increases from
midnight to 6 AM (0600 h) independent of sleep (- -) but sleep itself has a profound effect on the increase
in airway resistance (--). Reprinted with permission from reference 7.
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Other Hormones
Other circulating hormones may also
have a pathogenic role in asthma. An
example is melatonin,2325 the cyclic
variation of which has been used to
characterize the periodicity of the circadian rhythm. Treatment with melatonin has been used by some to counteract jet lag.
Section Summary
Circulating hormone levels appear
to be unaltered in asthma. There is,
however, evidence for altered hormone binding with possible reduction of tissue responsiveness.
CIRCADIAN CHANGES IN
AIRWAY INFLAMMATION IN
NOCTURNAL ASTHMA
The current concept of airway inflammation as the primary process in asthma4 has led to studies that examine
airway cells and mediators at different
time points in the circadian cycle. The
Bronchoscopic Assessment of
Airway Inflammation
Direct sampling of lung cells and mediators have generally shown that in-
Figure 2. The number per volume (Nv) of eosinophils in the nocturnal asthma (NA) and non-nocturnal
asthma (NNA) groups are shown in the endobronchial (airway tissue-EBBX) and transbronchial (alveolar
tissue TBBX) biopsies at 4:00 AM and 4:00 PM. More eosinophils are present in TBBX at both time points
in both NNA and NA. At 4:00 PM, there is no significant difference between the NA and NNA groups.
At 4 AM however, the number of eosinophils in TBBX has dramatically increased in the NA group alone.
Reprinted with permission from reference 28.
Section Summary
Bronchoscopic studies have shown
that airway inflammation increases
at night in NA in BAL and even
extends into the gas exchange regions of the lung.
Gastroesophageal Reflux
Although gastroesophageal reflux disease (GERD) is often discussed as a
possible trigger for nocturnal bronchospasm, Tan and colleagues31 studied
subjects with NA and GERD using pH
probes in the esophagus to detect reflux and found no correlation between
increased overnight acid secretion and
nocturnal bronchospasm. During a trial
of an H2 antagonist that reduces stomach acidity, inpatients with both symptomatic reflux and nocturnal bronchospasm showed a small but significant
improvement in asthma symptoms but
with no change in morning PEFR.
Asthmatics with GERD should certainly be treated for their symptoms,
but GERD does not appear to be a
significant trigger of nocturnal bronchospasm.
Sleep Apnea
Chan et al32 reported that asthmatics
with sleep apnea had a significant improvement in asthma control and a reduction in the severity of NA following the application of nasal CPAP.
Nasal CPAP in non-apneic asthmatics,
however, did not appear to convey any
benefit.33 The association between
sleep apnea and asthma may involve
stimulation of pharyngeal afferents
causing reflex bronchoconstriction, or
other mechanisms such as hypoxia-induced bronchospasm or negative intrathoracic pressure increasing lung
blood volume.
THE TREATMENT OF
NOCTURNAL ASTHMA
Chronopharmacology
Chronopharmacology or chronotherapy
is a branch of pharmacology that aims to
optimize therapy by taking into account
cyclical variation in a disease process
and cyclical pharmacokinetics (drug absorption and delivery) and pharmacodynamics (drug effects). The pharmacokinetics and pharmacodynamics of certain
drugs may vary on a circadian basis and
this requires investigation so as to optimize therapy. The previous discussion
has outlined some of the pathogenic features that may underlie nocturnal
asthma. There are, however, several
well-established approaches to the treatment of NA which take into account
chronopharmacologic findings. The nocturnal augmentation of inflammation in
NA has led to the design of therapy
aimed at preventing airway inflammation and bronchospasm to maximize
drug effects overnight.
Corticosteroids
Corticosteroids are the cornerstone of
antiinflammatory therapy in asthma
and physicians attempt to maximize
the therapeutic effect while minimizing systemic toxicity. On the toxicity
side, one popular approach to therapy
in Europe takes into account the circadian rhythm-dependent susceptibility
and tolerance of the body to the adverse effects of synthetic corticosteroids. Inhibition of the brain hypothalamic-pituitary axis may result in a
lack of endogenous steroid hormone if
the therapy is stopped abruptly with
symptoms such as weakness, apathy,
and decreased circulatory volume. The
susceptibility of the hypothalamic-pituitary axis to suppression varies on a
circadian basis being more susceptible
at night. In the European approach,
two-thirds of the total daily dose is
taken in the morning upon awakening,
and the remaining one third is taken
about 8 hours later (approximately 3
PM for most patients). On the therapeutic side, the therapeutic effect of corticosteroids also demonstrates a circadian fluctuation.
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REFERENCES
1. Fitzpatrick MF, Engleman H, Whyte
KF, et al. Morbidity in nocturnal asthma:
sleep quality and daytime cognitive performance. Thorax 1991;46:569 573.
2. Hetzel MR, Clark TJ, Branthwaite
MA. Asthma: analysis of sudden
deaths and ventilatory arrests in hospital. Br Med J 1977;1:808 811.
3. Turner-Warwick M. Epidemiology of
nocturnal asthma. Am J Med 1988;85:
6 8.
4. Shelhamer JH, Levine SJ, Wu T, et al.
NIH conference. Airway inflammation. [Review] [162 refs]. Ann Intern
Med 1995;123:288 304.
5. Guidelines for the diagnosis and management of asthma. National Institutes
of Health (NHLBI), 1997.
6. Hetzel MR, Clark TJ. Comparison of
normal and asthmatic circadian
rhythms in peak expiratory flow rate.
Thorax 1980;35:732738.
7. Martin RJ, Cicutto LC, Ballard RD.
Factors related to the nocturnal worsening of asthma. Am Rev Respir Dis
1990;141:3338.
8. Ballard RD, Saathoff MC, Patel DK, et
al. Effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol
1989;67(1):243249.
9. Wagner EM, Liu MC, Weinmann GG,
et al. Peripheral lung resistance in normal and asthmatic subjects. Am Rev
Respir Dis 1990;141:584 588.
10. Kraft M, Pak J, Martin RJ, Irvin CJ.
Peripheral airways resistance increases
at night in nocturnal asthma [Abstract].
Am J Respir Crit Care Med 1997;155:
A679.
11. Ballard RD, Irvin CG, Martin RJ, et al.
Influence of sleep on lung volume in
asthmatic patients and normal subjects.
J Appl Physiol 1990;68:2034 2041.
12. Martin RJ, Pak J, Irvin CG. Effect of
lung volume maintenance during sleep
in nocturnal asthma. J Appl Physiol
1993;75:14671470.
13. Desjardin JA, Sutarik JM, Suh BY,
Ballard RD. Influence of sleep on pulmonary capillary volume in normal
and asthmatic subjects. Am J Respir
Crit Care Med 1995;152:193198.
14. Morrison JF, Pearson SB. The effect of
the circadian rhythm of vagal activity
on bronchomotor tone in asthma. Br J
Clin Pharmacol 1989;28:545549.
15. Barnes P, FitzGerald G, Brown M,
Dollery C. Nocturnal asthma and
changes in circulating epinephrine,
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CME Examination
Identification No 008-004
Questions 120, PE Silkoff and RJ Martin. 1998;81:378 387.
CME Test Questions
1. In the classical survey by
Turner-Warwick,
nocturnal
asthma was reported at least
once a week by:
a. Less than 20% of subjects
b. At least 30% of subjects
c. At least 40% of subjects
d. At least 50% of subjects
e. At least 70% of subjects
2. Nocturnal asthma
a. is present in a minority of
asthmatics
b. is a significant cause of
morbidity and mortality
c. is well appreciated by practitioners
d. is not a significant health
problem
e. while causing morbidity is
rarely life-threatening
3. Asthma
a. has shown dramatic increases in recent years in
the North American Continent alone
b. has shown increases in
many different geographical locations
c. while increasing has not resulted in a rising mortality
d. is less common since the
use of corticosteroids
e. is still primarily regarded
as a disorder of smooth
muscle function
4. The recent NIH publication
Guidelines for the diagnosis
and management of asthma
recommended antiinflammatory therapy for:
a. All severities of asthma
b. All severities except the
mild persistent and mild intermittent groups.
c. All severities except the
mild intermittent group
d. The severe persistent group
alone
e. The severe and moderate
persistent groups alone.
384
5. Circadian rhythms:
a. Are entrained by the sleep
wake cycle
b. Are controlled by a frontal
lobe pacemaker
c. Are abolished if external
stimuli such as light are removed
d. Continue to cycle in the absence of external cues
e. Have a cycle of approximately 22 hours in man.
6. The sleep-wake cycle
a. Is entrained by the circadian pacemaker
b. Is primarily under the control of the circadian pacemaker
c. Is always synchronized
with the circadian pacemaker
d. Alone controls the propensity to sleep
e. Is abolished in the absence
of external cues
7. Circadian changes in spirometry:
a. Are found in asthmatics
only
b. Show the maximal values
at 10 AM
c. Show minimal values in
the early morning (2 to 4
AM)
d. Are only found in nocturnal asthma
e. Are not associated with
changes in nonspecific
bronchial reactivity in nocturnal asthma
8. Airway resistance in asthma:
a. increases between 12 PM to
6 AM
b. falls at night in contrast to
spirometric parameters
c. starts to increase at 4 PM
d. remains constant overnight if
the subjects are kept awake.
e. increases as a result of
changes in central airway
caliber alone
9. In nocturnal asthma:
a. FRC increases greatly
overnight reflecting dynamic hyperinflation
b. FRC which is initially high
falls during the night.
c. maintenance of FRC using
external thoracic cage negative pressure attenuates
nocturnal bronchoconstriction
d. intrathoracic blood volume
falls
e. vagal tone is decreased
10. Circulating cortisol levels
a. are maximal at 4 AM in nocturnal asthma
b. show different circadian
patterns in nocturnal as
compared to non-nocturnal
asthma
c. show trough levels in the
late evening in asthmatics
alone
d. show trough levels in the
late evening in asthmatics
and normal subjects
e. show trough levels at 4 PM
in asthmatics
11. Steroid responsiveness
a. may be reduced in nocturnal asthma as evidenced
by glucocorticoid binding
studies
b. can be assumed to be normal as circulating hormone
levels are unaltered in nocturnal asthma
c. can be assumed to be normal as patients respond to
inhaled or oral steroids
d. is irrelevant to nocturnal
asthma as glucocorticoid
binding is unchanged in
asthma
e. is impaired as shown by a
lack of a therapeutic response to corticotrophin releasing factor in nocturnal
asthma
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