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Review article

Supported by an unrestricted grant from Zeneca Pharmaceuticals

Pathophysiology of nocturnal asthma

Philip E Silkoff, MD and Richard J Martin, MD

Learning Objectives: This article will focus on the pathophysiologic changes

underlying the nocturnal worsening of asthma and the therapeutic approach to this
Data Sources: Selected articles appearing since 1985 dealing specifically with
the underlying pathologic features and therapy of nocturnal asthma.
Study Selection: Studies that aimed to elucidate the pathologic features, mechanisms, and therapeutic strategies for the treatment of nocturnal asthma are summarized.
Results: Nocturnal asthma is associated with significant decline in pulmonary
function and increase of airway inflammation at night. The administration of
medications must be designed to achieve the maximal effect during the night in
nocturnal asthma.
Conclusions: The further elucidation of the reasons underlying nocturnal asthma
should lead to more specific therapeutic interventions with maximal effect at night.
Ann Allergy Asthma Immunol 1998;81:378387.

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,
Accepted for publication September 29,


and 64% reported awakening at least

three times per week.
Asthma incidence, with resultant increased morbidity and mortality, is rising in western societies despite modern
therapy. Airway inflammation is regarded as the primary abnormality underlying the manifestations of asthma
such as airway obstruction and this has
been the focus of recent research and
therapy.4 A recent document Guidelines for the Diagnosis and Management of Asthma by the National
Asthma Education and Prevention Program of the National Institutes of
Health5 recommended anti-inflammatory medication, eg, inhaled corticosteroids in all severities of asthma except
the mildest category termed the mild
intermittent group.
Biologic Rhythms
Chronobiology is the study of the biologic rhythms of physiologic and
pathologic processes. Circadian cycles
have approximately a 24-hour period.
The terms diurnal and nocturnal

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-


iologic effects such as change in posture, fluid distribution, and muscle

tone. The relative contribution of the
circadian and sleep-wake cycle and
sleep itself to nocturnal asthma are not
completely understood.
Airflows and Bronchial Reactivity
Normal and asthmatic subjects show
circadian variation in pulmonary function as assessed by spirometric parameters such as FEV1 and peak expiratory
flow rate (PEFR) which are maximal
around 4 PM and lowest around 4 AM.6
The magnitude of change in non-asthmatic subjects and non-nocturnal asthmatic subjects (NNA) is about 8%
while in NA the changes are much
larger. The change in airway caliber is
associated with a change in non-specific airway reactivity. In one study,
bronchial reactivity assessed by methacholine challenge worsened overnight
by factor of 8 in NA compared with a
factor of 2 in NNA.7
Airway Resistance
There are dynamic changes in airway
resistance overnight. In one study,
lower airway resistance to airflow rose
progressively from 12 midnight to 6

in asleep asthmatic subjects (Fig 1).

This pattern of change was also seen,
albeit to a milder degree, during a subsequent night when sleep was withheld.8 In an ongoing study here, peripheral airway resistance measured
with a bronchoscope according to the
method of Wagner et al9 increased at 4
AM in NA compared to 4 PM.10

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

airway caliber is not solely due to the

reduction in FRC.
Intrathoracic blood volume
In contrast to the FRC decline, Desjardin et al13 reported that intrathoracic
blood volume increased in NA subjects
(but not in NNA or normal subjects)
due to a shift of blood from peripheral
venous to central compartments. The
increased lung blood volume could
cause engorgement of airways with reduction in airway caliber, and also displace gas from the thoracic cavity leading to an decrease in lung compliance
and increased work of breathing.
Autonomic tone
Stimulation of the vagus nerve results
in bronchoconstriction in normal and
asthmatic subjects. Vagal tone is increased at night and this may worsen
airway function. Morrison and colleagues14 demonstrated that atropine, a
muscarinic antagonist, resulted in an
improvement in the 4 AM PEFR in NA
as compared with placebo.
Section Summary
The net effects of the changes in
pulmonary function in NA will be
to narrow airway caliber (decreased FRC, increased vagal tone
and increased lung blood content)
and to increase reactivity to nonspecific and specific stimuli, eg,
nocturnal environmental allergens.
Circulating hormones vary in a circadian
fashion in everyone and may contribute
to overnight fall in lung function.

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.


Adrenal Cortical Hormones

Peak levels of circulating cortisol occur upon awakening with trough levels
noted between 10 PM and midnight.15
The circadian change in cortisol is similar in both asthmatic and non-asthmatic individuals.16 The occurrence of
trough cortisol levels in the late
evening could set the scene for NA as
cortisol exerts an anti-inflammatory effect upon the chronically inflamed air-


ways of asthmatics. Additionally, the

absence of higher cortisol levels in the
NA group could represent a deficiency
in cortisol production inappropriate to
the stress of bronchoconstriction. Certainly, the administration of corticosteroids attenuates nocturnal asthma17 as
does the infusion of corticotrophin releasing factor (CRF).18 Finally, there
may be defects in the binding affinity
of cortisol to glucocorticoid receptors
in asthma19 with decreased steroid-responsiveness. Recently, a nocturnal reduction in glucocorticoid binding and
steroid responsiveness has been demonstrated in peripheral blood monocytes in NA.20
Adrenal Medullary Hormones
The adrenal hormone epinephrine is a
bronchodilator due to stimulation of
airway b2 receptors and inhibits leakage of histamine and other mediators
from sensitized mast cells. Epinephrine reaches peak levels during the afternoon hours with trough levels during the early morning hours.15 This
circadian pattern could promote NA by
reducing bronchodilatation and by allowing the release of spasmogenic mediators from mast cells. In one study,
however, infusion of physiologic doses
of epinephrine lessened but did not
abolish the overnight decline in airway
caliber.15 This suggests that the circadian change in epinephrine is just one
component of many factors that influence airway caliber at night.
Similar to the changes in glucocorticoid binding described above, nocturnal bronchoconstriction could be due
in part to a reduction in the number of
and/or physiologic response of b2 receptors located in the smooth muscle
and inflammatory cells in the airways.
Indeed a reduced density of b-adrenergic receptors has been noted on circulating leukocytes of asthmatic subjects with NA as compared with those
with NNA and normal controls.21
While this reduction in receptors may
be a down regulation mechanism as a
result of previous b2 agonist therapy, a
reduced density of receptors has also
been reported on untreated asthmatics.
This phenotypic down regulation may


be related to a genetic abnormality of

the b2 receptor22 and thus lead to a
genetic predisposition to NA.

reason for airway inflammation in

asthma and the exacerbation of this
inflammation at night are not yet clear.

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.

IgE/Mast Cell Interaction

IgE-mediated allergy is one important
mechanism underlying asthma with
binding of relevant allergens to IgE on
airway mast cells resulting in degranulation and release of mediators, eg,
histamine which causes bronchospasm. Serum IgE is fivefold greater in
asthma compared with nonallergic
controls. In asthmatics, IgE levels peak
around midday and fall at night.26 This
pattern is opposite to that seen in inflammatory parameters and may reflect temporal differences in the binding of IgE to tissue or cells rather than
a fall in production. Serum histamine,
a mast cell product, also varies in a
circadian fashion with the peak levels
coinciding in time with the greatest
bronchoconstriction, ie, 4 AM.15 This
suggests that mast cell activation is
enhanced at night in NA.

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.
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.


dices of inflammation increase from 4

PM to 4 AM in asthmatics with NA. In
one recent study at our institution, (Fig
2), bronchoalveolar lavage (BAL)
fluid contained significantly more inflammatory cells, eg, eosinophils and
neutrophils in NA at 4 AM compared
with NNA, whereas at 4 PM there was
no difference between the groups.27 In
a recent study, bronchial and transbronchial biopsies (sampling of alveolar tissue) were taken in subjects with
and without NA.28 First, alveolar tissue
in the NA group contained significantly increased inflammatory cells
such as eosinophils and macrophages
when compared with the NNA group.
Second, the degree of alveolar inflammation was worse at 4 AM compared
with 4 PM in the NA group only. In the
same subjects, bronchial biopsies,
which sample proximal large and medium sized airways, did not show the
same differences between the NA and
NNA groups. The degree of eosinophilic alveolar infiltration correlated
with the overnight decline in airway
caliber. This study demonstrated the
importance of inflammation in the gas
exchange area of the lung in the NA
group associated with or even preceding nocturnal bronchospasm.

bed throughout an entire 24-hour period still display day-night variation in

airway tone.30
Section Summary
The sleep state itself may play a role
in the pathogenesis of NA. The circadian pattern in lung function persists in nocturnal asthmatics kept
awake and in subjects who maintain
the supine posture throughout a 24hour period.

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.


The relationship between sleep itself
and asthma is not clear. The state of
sleep involves postural and neurophysiologic changes. Bronchoconstriction
and the increase in airway resistance
still occur in NA during the night when
patients are kept awake but the
changes observed are greater when the
subjects sleep.29 The state of sleep itself does not seem essential for the
development of NA. Finally, NA does
not seem to be related to postural
change from an upright to supine position. Patients who are confined to

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.


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 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.


In a placebo-controlled study, Beam

et al17 examined nocturnal FEV1 fall,
blood eosinophils and 4 AM BAL cytology after 50 mg predisone given at 8
AM, 3 PM, and 8 PM (six visits) in 7
subjects. The study showed that the
3-PM dose of oral prednisone alone resulted in a significant attenuation of
the overnight fall in mean FEV1 from
228.2% (placebo) to 210.4% accompanied by a significant FEV1 response
to bronchodilator. The mean FEV1 at 4
AM was almost a liter better than that
seen on placebo. The 3 PM dose resulted in a significant pancellular reduction in BAL cytology not seen with
the 8 AM or 8 PM dosing; thus, 3 PM may
prove to be an effective and safe time
to administer oral corticosteroids for
treatment of reactive airway disease
with nocturnal exacerbation. Inhaled
steroids, a first-line therapy for asthma,
have also been evaluated chronotherapeutically. Pincus et al34 showed that 3
PM dosing of inhaled steroid was
equally efficacious for improvement of
AM and PM PEFR and FEV1 as taking
the medication four times a day. Neither regime was associated with evidence of pituitary axis suppression
which reflects systemic absorption of
the medication.
Theophylline is a bronchodilator used
in COPD and asthma but may also
possess anti-inflammatory effects.
Many different preparations exist with
distinct pharmacokinetic properties.
Twice-daily theophylline preparations
designed to produce consistent serum
theophylline concentrations give rise
to varying serum levels over 24 hours.
Other preparations produce higher
nighttime levels to meet increased nocturnal demands without compromising
daytime asthma control. Chronotherapeutic dosing of theophylline, oncedaily in the evening around 6 to 7 PM,
attenuates nocturnal symptoms and
early morning bronchoconstriction
without deterioration in asthma control
at other times of the day. This regimen
has been found to be clinically superior
to conventional twice daily dosing.3537
Lung function is improved by higher


serum theophylline levels during sleep

with preservation of sleep quality and
architecture and less nocturnal oxygen
Long-Acting Bronchodilators
Slow release b-agonist tablets, which
are used to maintain a longer period of
bronchodilation (10 to 12 hours), can
significantly moderate the morning dip
in airways patency in asthmatic patients. Recently, the long-acting inhaled b2-agonist salmeterol has shown
promise in improving the overnight
decrement in lung function, but further
evaluation is needed.38
Section Summary
Asthma varies in a circadian fashion, making it ideally suited for
chronotherapy. The three classes of
medications most efficacious for the
chronotherapy of reactive airway
disease are corticosteroids, slow-release theophylline and slow-release
b2 agonists. The benefits are most
pronounced in the asthma population, but these medications also benefit the COPD population, especially
the long-acting theophylline preparations.
It is important to specifically inquire
about nocturnal asthma and to monitor
the frequency and severity as this may
be life-threatening. The home monitoring of asthma should record nocturnal
awakenings and rescue medication use
and include objective measures of pulmonary function such as PEFR. Patient
education should include specific instructions about the course of action to
be taken if nocturnal asthma occurs
including early telephone consultation
with medical personnel in the event of
a change in the frequency and severity
of the nocturnal events. Relatives
should also be instructed about the
course of action to be taken. Nocturnal
asthma is a sign of more severe disease
reflecting more airway inflammation.
Correspondingly, effective therapy
with antiinflammatory medications is
recommended and at present this

usually entails inhaled or even oral

corticosteroids. The role of newer
medications such as salmeterol and
leukotriene inhibitors in asthma in general and nocturnal asthma in particular
remains to be defined. Chronopharmacologic considerations may help design therapeutic regimens that may
include nocturnal theophylline or longacting oral or inhaled b2 agonists. The
afternoon administration of oral corticosteroids may also be indicated as
discussed previously. General measures that may require attention include the identification and treatment
of nocturnal gastroesophageal reflux,
reduction of allergen load in the home
and particularly in the bedroom, the
exclusion of other non-asthmatic conditions such as sleep apnea, and heart failure that may be concurrent with asthma.
Section Summary
Nocturnal asthma is a marker of
more severe disease. The physician-patient partnership is important in educating the patient and his
family how to manage nocturnal episodes of asthma. Home monitoring
with recording nocturnal symptoms
will allow an objective assessment of
NA and the response to management.
The chronotherapeutic approach will
usually include inhaled or even oral
corticosteroids with the addition of
theophylline, long-acting oral or inhaled b2 agonists with timing of therapy to give adequate effect during the
night as discussed above.
Nocturnal asthma results in considerable morbidity and mortality.2 This requires a concerted effort to elucidate
the mechanisms of the nocturnal
asthma exacerbations and to design
therapy towards a maximal effect during the critical hours of the night. The
further elucidation of the relative contributions of the circadian and sleepwake cycles to the pathogenesis of NA
may allow more specific therapeutic
measures to be taken.


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
8. Ballard RD, Saathoff MC, Patel DK, et
al. Effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol
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:
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
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,















histamine, and cortisol. N Engl J Med

Kraft M, Pak J, Martin RJ. Serum cortisol in asthma: marker of nocturnal
worsening of symptoms and lung function? Chronobiol Int 1998;15:8592.
Beam WR, Weiner DE, Martin RJ.
Timing of prednisone and alterations
of airways inflammation in nocturnal
asthma. Am Rev Respir Dis 1992;146:
1524 1530.
Georges G, Kraft M, Vianna EO, Martin RJ. Human corticotrophin-releasing
hormone improves overnight FEV1 in
nocturnal asthma. J Asthma 1998;
Spahn JD, Leung DY, Surs W, et al.
Reduced glucocorticoid binding affinity in asthma is related to ongoing allergic inflammation. Am J Respir Crit
Care Med 1995;151:1709 1714.
Kraft M, Vianna E, Martin RJ, Leung
DYM. Nocturnal asthma is associated
with reduced glucocorticoid receptor
binding affinity and decreased steroid
responsiveness at night. J Allergy Clin
Immunol 1998; (In Press)
Szefler SJ, Ando R, Cicutto LC, et al.
Plasma histamine, epinephrine, cortisol, and leukocyte beta-adrenergic receptors in nocturnal asthma. Clin Pharmacol Ther 1991;49:59 68.
Turki J, Pak J, Green SA, et al. Genetic
polymorphisms of the beta 2-adrenergic
receptor in nocturnal and nonnocturnal
asthma. Evidence that Gly16 correlates
with the nocturnal phenotype. J Clin Invest 1995;95:16351641.
Weekley LB. Influence of melatonin
on bovine pulmonary vascular and
bronchial airway smooth muscle tone.
Clin Auton Res 1995;5:5356.
Weekley LB. Effects of melatonin on
pulmonary and coronary vessels are
exerted through perivascular nerves.
Clin Auton Res 1993;3:45 47.
Lopes C, deLyra JL, Markus RP, Mariano M. Circadian rhythm in experimental granulomatous inflammation is
modulated by melatonin. J Pineal Res
Gaultier C, De Montis G, Reinberg A,
Motohashi Y. Circadian rhythm of serum total immunoglobin E (IgE) in
asthmatic children. Biomed Pharmacother 1987;41:186 188.
Martin RJ, Cicutto LC, Smith HR, et
al. Airways inflammation in nocturnal
asthma. Am Rev Respir Dis 1991;143:
Kraft M, Djukanovic R, Wilson S, et










al. Alveolar tissue inflammation in

asthma. Am J Respir Crit Care Med
Ballard RD, Saathoff MC, Patel DK, et
al. Effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol
Ballard RD, Pak J, White DP. Influence of posture and sustained loss of
lung volume on pulmonary function in
awake asthmatic subjects. Am Rev Respir Dis 1991;144:499 503.
Tan WC, Martin RJ, Pandey R, Ballard
RD. Effects of spontaneous and simulated gastroesophageal reflux on sleeping asthmatics [see comments]. Am
Rev Respir Dis 1990;141:1394 1399.
Chan CS, Woolcock AJ, Sullivan CE.
Nocturnal asthma: role of snoring and
obstructive sleep apnea. Am Rev Respir Dis 1988;137:15021504.
Martin RJ, Pak J. Nasal CPAP in nonapneic nocturnal asthma. Chest 1991;
100:1024 1027.
Pincus DJ, Humeston TR, Martin RJ.
Further studies on the chronotherapy
of asthma with inhaled steroids: the
effect of dosage timing on drug efficacy. J Allergy Clin Immunol 1997;
Martin RJ, Cicutto LC, Ballard RD, et
al. Circadian variations in theophylline
concentrations and the treatment of
nocturnal asthma [published erratum
appears in Am Rev Respir Dis 1989
Apr;139(4):1065]. Am Rev Respir Dis
1989;139:475 478.
Grossman J. Multicenter comparison
of once-daily Uniphyl tablets administered in the morning or evening with
baseline twice-daily theophylline therapy in patients with nocturnal asthma.
Am J Med 1988;85:1113.
Welsh PW, Reed CE, Conrad E. Timing of once-a-day theophylline dose to
match peak blood level with diurnal
variation in severity of asthma. Am J
Med 1986;80:1098 1102.
Kraft M, Wenzel SE, Bettinger CM,
Martin RJ. The effect of salmeterol on
nocturnal symptoms, airway function,
and inflammation in asthma. Chest
1997;111:1249 1254.

Request for reprints should be addressed to:

Philip E Silkoff, MD
National Jewish Medical and Research Center
1400 Jackson St
Denver, CO 80206


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
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
b. is a significant cause of
morbidity and mortality
c. is well appreciated by practitioners
d. is not a significant health
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
e. The severe and moderate
persistent groups alone.


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
b. Show the maximal values
at 10 AM
c. Show minimal values in
the early morning (2 to 4
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
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
c. show trough levels in the
late evening in asthmatics
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
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
e. is impaired as shown by a
lack of a therapeutic response to corticotrophin releasing factor in nocturnal


12. Circulating catecholamines:

a. show an abnormal circadian pattern in nocturnal
b. show maximal levels at the
time of nocturnal bronchoconstriction due to stress
c. show trough levels in the
early morning in asthmatics alone
d. show trough levels in the
early morning in asthmatics and non-asthmatics
e. show trough levels at 4 PM
in nocturnal asthmatics as
this is the time of best lung
13. IgE levels
a. are normal in asthma
b. are maximal during the
night in nocturnal asthma
c. paradoxically fall at night
in nocturnal asthma possible due to increased tissue
d. show maximal levels at the
same time as circulating
e. peak at 8 PM in asthmatic
14. Airway inflammation
a. increases from 4 PM to 4 AM
in subjects with nocturnal
b. is present even in non-asthmatics at 4 AM compared to
4 PM
c. is increased at 4 PM compared to 4 AM as it takes 12
hours for this inflammation
to result in bronchospasm
d. is present in central airways only in nocturnal
e. has resolved by the time
nocturnal bronchoconstriction develops


15. Concerning the sleep state:

a. sleep is essential for nocturnal bronchoconstriction
to occur
b. sleep results in a decrease
in intrathoracic blood volume
c. sleep if associated with
sleep apnea can worsen
nocturnal asthma
d. nasal CPAP improves sleep
apnea but not nocturnal
e. nasal CPAP helps subjects
with nocturnal asthma even
without sleep apnea
16. Gastroesophageal reflux
a. shows a clear relationship
to nocturnal asthma
b. occurs in all subjects with
nocturnal asthma due to
mechanical effects on the
lower esophageal sphincter
c. may play a role in the individual patient as evidenced
by a lessening of nocturnal
symptoms after anti-reflux
d. should be investigated in
all subjects with nocturnal
e. could cause asthma by
stimulating esophageal b2
17. Chronopharmacology studies
a. are concerned with the side
effects of chronic administration of drugs
b. suggest that the timing of
oral steroid administration
at 3 PM is optimal in nocturnal asthma
c. suggest that the timing of
inhaled corticosteroid administration at 8 AM is optimal in nocturnal asthma

d. suggest that pituitary axis

suppression after steroids is
not affected by time of administration
e. have shown that theophylline given only at night
alone has a reduced clinical
effect as compared to bid
18. Long-acting bronchodilators
a. are well-established firstline therapies in nocturnal
b. should not be used in nocturnal asthma for fear of
worsening asthma
c. are important therapeutic
options in nocturnal asthma
d. given at bedtime do not attenuate nocturnal bronchospasm due to hyporesponsive b2 receptors
e. can be safely substituted
for anti-inflammatory drugs
19. The overall approach to nocturnal asthma requires
a. patient and family education
b. home monitoring of PEFR
and symptoms
c. recognition that nocturnal
asthma is a sign of disease
d. treatment with antiinflammatory therapy, e.g. inhaled
corticosteroids in the majority of cases
e. all of the above
20. Nocturnal asthma
a. is a significant health problem
b. is a good example of a circadian disease
c. is associated with circadian
changes in the severity of
airway inflammation
d. is best managed with a
chronopharmacological approach
e. all of the above