PEDIATRICS
Autonomic Dysfunction in Children with Sleep-Disordered Breathing
Louise M. O’Brien, PhD; David Gozal, MD
Kosair Children’s Hospital Research Institute, and Division of Pediatric Sleep Medicine, Department of Pediatrics, University of Louisville, Louisville, KY
continuously monitored during immersion and 20-minute recovery periods. Signal amplitude changes were expressed as percentage change
from corresponding baseline.
Results: The magnitude of sympathetic discharge-induced attenuation
of pulse arterial tonometry signal was significantly increased in children
with sleep-disordered breathing during sigh maneuvers (74.1%±10.7%
change compared with 59.2%±13.2% change in controls; P<.0001) and
the cold pressor test (83.5%±7.3% change compared with 74.1%±11.4%
change in controls; P=.039). Further, recovery kinetics in control children
were faster than those of children with sleep-disordered breathing.
Conclusion: Children with sleep-disordered breathing have altered autonomic nervous system regulation as evidenced by increased sympathetic
vascular reactivity during wakefulness.
Keywords: Sleep-disordered breathing, autonomic nervous system, peripheral arterial tonometry.
Citation: O’Brien LM; Gozal D. Autonomic dysfunction in children with
sleep-disordered breathing. SLEEP 2005;28(6):747-752.
Study Objectives: To measure sympathetic responses in children with
and without sleep-disordered breathing.
Design: Prospective, observational study.
Setting: Kosair Children’s Hospital Sleep Medicine and Apnea Center.
Participants: Subjects were prospectively recruited from children undergoing overnight polysomnographic assessments and were retrospectively
grouped according to the results of the polysomnogram. Sleep-disordered
breathing was defined as an apnea-hypopnea index >5 and children were
assigned to the control group if their apnea-hypopnea index was < 1.
Intervention: N/A.
Measurements and Results: During quiet wakefulness, pulse arterial
tonometry was used to assess changes in sympathetic activity following
vital capacity sighs in 28 children with sleep-disordered breathing and 29
controls. Each child underwent a series of 3 sighs, and the average maximal pulse arterial tonometry signal attenuation was calculated. Further, a
cold pressor test was conducted in a subset of 14 children with sleep-disordered breathing and 14 controls. The left hand was immersed in ice cold
water for 30 seconds while right-hand pulse arterial tonometry signal was
effect of SDB on the autonomic nervous system in childhood has
not been systematically investigated, it is likely that autonomic
nervous system dysfunction is also present in some children, albeit to a lesser degree than in adults.10,11
A recently developed technique allowing for noninvasive moment-to-moment measurement of sympathetic tone is peripheral
arterial tonometry, (PAT, Itamar Medical, Caesarea, Israel).12 PAT
has been previously well described and employs a finger plethysmographic approach that eliminates venous pulsations and
continuously measures the arterial pulse waveform of the digit.
PAT continuously measures the pulsatile volume change using a
pneumo-optic probe, which reflects the relative change of blood
volume in the finger. Changes in sympathetic nervous system activity, which are mediated by alpha adrenoreceptor activation, result in episodic vasoconstriction of the digital vascular beds with
corresponding attenuation of PAT signal.13,14 Thus, increases in
sympathetic activity will elicit robust changes in peripheral vascular cutaneous perfusion and can be readily detected on a beatto-beat basis. In adults, PAT is exquisitely sensitive to changes
in sympathetic autonomic nervous system activity.12 The purpose
of this study was, therefore, to investigate dynamic responses of
the sympathetic autonomic nervous system in children with and
without SDB.
INTRODUCTION
SLEEP-DISORDERED BREATHING (SDB) IN ADULTS IS
ASSOCIATED WITH INCREASED CARDIOVASCULAR
MORBIDITY AND MORTALITY, PARTICULARLY SYSTEMIC hypertension and ischemic heart disease.1-6 Although the mechanisms that mediate cardiovascular morbidity in adults with SDB
are poorly understood, autonomic nervous system dysfunction is
believed to play a key role.7 It is likely that both intermittent hypoxia and increased arousals mediate the elevation in sympathetic
nerve activity that results in altered vasomotor tone regulation.
Indeed, recurrent hypoxemia, associated with mild hypercapnia,
and increased chemoreceptor firing all lead to increased muscle
sympathetic nerve activity and increased blood pressure.8 In addition, arousals during sleep will directly activate the sympathetic
nervous system with a resultant pressor response.9 Although the
Disclosure Statement
This was an industry supported study supported by Itamar Ltd. Itamar
Ltd. provided an unrestricted grant and the PAT instrumentation required
for the measurements. No involvement by Itamar occurred in regards
to the original idea for the research project or project design. Dr. Gozal
serves on the national speakers’ bureau for Merck Inc. Dr. O’Brien has
indicated no financial conflict of interest. The data were analyzed and
the paper was written by the authors.
METHODS
Subjects were prospectively recruited from children being
evaluated for potential SDB at Kosair Children’s Hospital Sleep
Medicine Center. In addition, healthy children with no reports of
sleep disturbance were also recruited from a community-based
survey to act as controls. The study was approved by the University of Louisville Human Research Committee. Parental in-
Submitted for publication September 2004
Accepted for publication February 2005
Address correspondence to: David Gozal, MD, Kosair Children’s Hospital Research Institute, University of Louisville School of Medicine, 570 S.
Preston Street Suite 204, Louisville, KY 40202; Tel: (502) 852 2323; Fax:
(502) 852 2215; E-mail: [email protected]
SLEEP, Vol. 28, No. 6, 2005
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Autonomic Dysfunction in Apneic Children—O’Brien and Gozal
formed consent and child assent, in the presence of a parent, were
obtained. Children were excluded if they had any chronic medical
condition, received medications known to alter autonomic nervous system function, or had any psychiatric diagnoses or any genetic or craniofacial syndromes. All children underwent a standard
overnight multichannel polysomnographic evaluation in the sleep
laboratory to confirm the presence or absence of SDB rather than
rely on parental report. No drugs were used to induce sleep. The
following parameters were measured: chest and abdominal wall
movement by respiratory impedance or inductance plethysmography; heart rate by electrocardiogram; air flow was monitored with
a sidestream end-tidal capnograph, which also provided breathby-breath assessment of end-tidal carbon-dioxide levels (BCI SC300, Menomonee Falls, Wisc); and a thermistor. The SpO2 was assessed by pulse oximetry (Nellcor N 100; Nellcor Inc., Hayward,
Calif), with simultaneous recording of the pulse waveform. The
bilateral electrooculogram, 8 channels of electroencephalogram,
chin and anterior tibial electromyograms, and analog output from
a body position sensor (Braebon Medical Corporation, NY) were
also monitored. All measures were digitized using a commercially
available polysomnography system (Rembrandt, MedCare Diagnostics, Amsterdam, The Netherlands). Tracheal sound was monitored with a microphone sensor (Sleepmate, Virg), and a digital
time-synchronized video recording was performed.
Sleep architecture was assessed by standard techniques.15 Obstructive apnea was defined as the absence of airflow with continued chest-wall and abdominal movement for duration of at
least 2 breaths.16,17 Hypopneas were defined as a decrease in nasal
flow of at least 50% with a corresponding decrease in SpO2 of at
least 4%, an arousal, or both a decrease in SpO2 and an arousal.17
The obstructive apnea-hypopnea index (AHI) was defined as the
number of apneas and hypopneas per hour of total sleep time.
Children with an AHI of 5 or more per hour of total sleep time
were considered to have SDB, whereas children without a history
of snoring and an AHI less than 1 were considered to be controls.
The mean SpO2, as measured by pulse oximetry, in the presence
of a pulse waveform signal void of motion artifact and the SpO2
nadir were recorded. Since criteria for arousals have not yet been
developed for children, arousals were defined as recommended
by the American Sleep Disorders Association Task Force report18
using the 3-second rule, the presence of movement arousal, or
both.19 Arousals were divided into 2 main subtypes: spontaneous
arousals and respiratory arousals.
Immediately prior to initiation of the polysomnographic recordings, PAT was used to assess changes in sympathetic activity
during quiet wakefulness. The PAT probe was placed on the right
hand of each child, and both raw and filtered PAT signals were
digitally acquired and incorporated into the polysomnographic
montage. Each child sat up on the bed with both hands resting on
a table in front of him or her. Baseline PAT measurements were
obtained when the child was sitting quietly and the PAT signal
was steady for at least 2 minutes. Baseline values were obtained
by taking the mean measurement across a 10-second period of
steady, good-quality signal. Following baseline measures, each
child underwent a series of 3 vital capacity sighs, each separated
by at least 60 seconds of normal breathing wherein the PAT signal remained steady and artifact free. The maximal attenuation
of PAT signal was measured over 10 seconds and calculated as a
percentage change from baseline. Measurements were averaged
over the series of sighs. Figure 1 illustrates a PAT attenuation associated with a sigh.
A subgroup of children also underwent a cold pressor test 5
minutes after the series of sighs. This subgroup comprised all
SLEEP, Vol. 28, No. 6, 2005
Figure 1—Peripheral arterial tonometry attenuation associated with a
vital capacity sigh.
children recruited to the study following the addition of the pressor test to the challenge protocol. The left hand was immersed
in ice-cold water for 30 seconds while the right hand remained
still. PAT signal was continuously monitored throughout the immersion and recovery periods. Changes in signal amplitude were
calculated by averaging the mean amplitude over a 10-second
period before the pressor test (baseline), during the pressor test
(challenge), immediately following the removal of the hand from
the water (post challenge), and then at 1-minute intervals during
the 20-minute recovery phase. All measures were obtained from
a steady and regular artifact-free PAT signal. Amplitudes were
expressed as percentage change from corresponding baseline.
All maneuvers were performed at least 3 hours following ingestion of food or caffeine, since these variables may confound
the results. In addition, ambient temperature remained constant
throughout the assessments.
Data Analysis
All data were coded and analyzed blind to the subject group
upon completion of recruitment. Data are presented as means ±
SD and 95% confidence intervals (CI) unless otherwise indicated.
Independent t tests were employed for comparisons of measures
between the study groups, with the Fischer Exact Test used for
dichotomous outcomes. For the cold pressor test, an analysis of
variance with repeated measures was employed. All P values reported are 2 sided with statistical significance set at <.05.
RESULTS
Children were retrospectively grouped according to the results
of the overnight polysomnogram. A total of 28 children (14 boys)
were found to have SDB, whereas 29 children (19 boys) were
designated as controls. Of these, 14 children in each group participated in the cold pressor test. Table 1 illustrates the demographic
information for the 2 groups.
748
Autonomic Dysfunction in Apneic Children—O’Brien and Gozal
Table 1—Demographic Characteristics of Children with Sleep-Disordered Breathing and Controls
90
*
Characteristic
Subjects
Sleep-disordered breathing
Control
n=28
n=29
Age, y (range)
10.2 ± 3.1 (6.2-15.8)
9.8 ± 3.0 (5.9-17.0)
Boys, %
58
67
Apnea-hypopnea index,
no./h
12.8 ± 8.1
0.4 ± 0.2 **
Spontaneous arousal
index, no./h
5.9 ± 3.2
8.2 ± 4.1
Respiratory arousal
index, no./h
7.8 ± 6.1**
0.6 ± 0.8
SpO2 nadir, %
85.8 ± 10.1
91.5 ± 3.9*
Body mass index,
kg/m2
26.5 ± 13.7
24.4 ± 8.7
Blood pressure,
mm Hg
Systolic
112.2 ± 15.4
103.5 ± 10.0
Diastolic
59.2 ± 4.5
57.1 ± 8.0
80
% PAT
Change
60
50
SDB
Control
*P<.0001
Figure 2—A box and whiskers plot illustrating the mean and 95%
confidence intervals of peripheral arterial tonometry (PAT) signal during the vital capacity sighs.
strength of the present study is that all children underwent polysomnographic evaluation, and only children with confirmed SDB
(ie, AHI>5) were included in the SDB group. Furthermore, control children were recruited from a community sample of healthy
children. All children identified as controls also underwent polysomnographic assessment to confirm the absence of SDB. Furthermore, SDB and control groups were similar with respect to
age, sex distribution, and body mass index. Nonetheless, children
with mild SDB (ie, AHI 1-5) were not included in this cohort,
and, therefore, further studies will be required in order to determine whether PAT technology has clinical application in the full
spectrum of SDB. In the current study, we used 2 simple noninvasive strategies, namely vital capacity sighs and the cold pressor
test, to perturb sympathetic activity and elicit a stereotypic response. The sympathetic nervous system regulates the peripheral
vasculature in the limbs,20 and a deep breath causes vasoconstriction in the extremities that is sympathetically mediated21 and is
blocked by the α-receptor antagonist phentolamine. Furthermore,
the cold pressor test is a classic vasconstrictive stimulus that also
induces an α-adrenoreceptor-mediated vasoconstriction in the
peripheral vasculature22 and a rise in total peripheral resistance.
Increased sympathetic tone can be identified with PAT technology as a corresponding attenuation of the PAT signal, with greater
sympathetic activity resulting in greater signal attenuation.12,23-25
Thus, the implementation of PAT technology in the assessment
of moment-to-moment changes in sympathetic vasomotor tone
is novel and permitted accurate noninvasive determination of the
sympathetic responses in children.
Although the mechanisms that link cardiovascular disease and
SDB in adults are not fully understood, sustained and aberrant
autonomic activation, endothelial dysfunction, and inflammation
have all been implicated in the increased prevalence and severity of cardiovascular morbidity associated with SDB.5,6,8,9,26 Such
studies are clearly lacking in the pediatric arena. Nevertheless,
few studies exist in children with SDB. In 1997 Aljadeff and colleagues10 examined heart-rate variability (a noninvasive probe of
autonomic nervous system tone) in a small group of children with
moderate to severe SDB compared with that of matched controls.
Inspection of moment-to-moment changes in RR intervals re-
Data are presented as mean ± SD unless otherwise indicated.
*P<.05 vs controls.
**P<.001 vs controls.
Sigh Maneuvers
The mean magnitude of sympathetic-induced attenuation of
the PAT signal following a sigh is illustrated in Figure 2. Children with SDB showed significantly greater attenuation as
compared with control children; mean attenuation from baseline was 74.1%±10.7% (95% CI 70.1%-78.1%) compared with
59.2%±13.2% in controls (95% CI 54.4%-64.0%; P<.0001). No
differences were observed between boys and girls.
Cold Pressor Test
The magnitude of sympathetic-induced attenuation of the PAT
signal during the cold pressor test showed that children with
SDB had greater attenuation than controls; 83.5%±7.3% (95%
CI 79.7%-87.3%) compared with 74.1%±11.4% (95% CI 68.1%80.1%) respectively; P=.039. Furthermore, the recovery dynamics of the control children were faster than those of children with
SDB (Figure 3), with the control children demonstrating a return
to baseline within 4 minutes, compared with 10 minutes for children with SDB (P=.018).
The degree of PAT attenuation in either of the 2 challenges
above was not correlated with the severity of SDB.
DISCUSSION
The major finding of this study is that children with SDB
demonstrate altered autonomic function compared with children
without SDB, as evidenced by alterations in vascular reactivity.
While substantial evidence has accumulated over the last decades
to show that adults with SDB have increased sympathetic nervous
system activity compared with that of controls, information on
this issue is markedly scant in children. The present study, utilizing PAT as a marker of sympathetic activation, extends the observation on increased sympathetic activity in SDB to the pediatric
age range.
Several aspects of this study merit consideration. A major
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Autonomic Dysfunction in Apneic Children—O’Brien and Gozal
% change
is also likely that the persistent enhancements in sympathetic activity associated with SDB will facilitate elevation of pulmonary
artery pressures,32,33 as well as left ventricular hypertrophy and
abnormal ventricular geometry resulting from persistent increases
in systemic vascular resistance.34 Indeed, enhanced sympathoadrenal discharge, altered homeostasis of the renin-angiotensin and
of the renal kallikrein-kallistatin pathways, and heightened sympathetic autonomic nervous system tone occur with SDB along
with increases in small arteriolar vasomotor contractility suggestive of endothelial dysfunction.35-45 The increased sympathetic
activation associated with SDB in children could be also mediated from initiation and propagation of inflammatory responses
within the microvasculature. C-reactive protein, an important
serum marker of inflammation, has emerged as one of the most
powerful independent predictors of risk for future cardiovascular
morbidity.46-48 In adults with SDB, elevated levels of C-reactive
protein have been found and correlate with the severity of SDB.26
Elevated C-reactive protein levels decrease following treatment
with CPAP,49 suggesting that SDB leads to inflammatory responses that ultimately may promote cardiovascular complications. In a
recent study, we reported on our preliminary evidence indicating
that C-reactive protein levels are also elevated in children with
SDB and are correlated with disease severity.50
The long-term implications of persistently elevated sympathetic tone on cardiovascular morbidity during later stages of
childhood or even adulthood have yet to be explored. It also
remains unclear whether untreated or long-lasting SDB will be
associated with vascular remodeling of the pulmonary circulation in these children. Evidence from animal models exposed to
hypoxia for a short period of time during early postnatal life reveals that pulmonary hypertension is increased when exposed to
hypoxia later in infancy.51 These authors speculated that disrupted
alveolarization and vascular growth following the brief hypoxic
insult during a critical period of development may increase the
risk for severe pulmonary hypertension later in life. Moreover, in
preliminary animal experiments, when rodents were exposed to a
model of obstructive sleep apnea52 at an age corresponding to the
peak prevalence of pediatric SDB in childhood, marked attenuation of their baroreceptor function lasting into late adulthood was
found.53 Thus, early childhood perturbations may lead to lifelong
consequences, or, in other words, certain types of adult cardiovascular disease may represent, at least in part, sequelae from a
priori “unrelated events” during childhood. Therefore, identification of children with alterations of baroreceptor and autonomic
nervous system function in the context of pediatric SDB may lead
to detection of a population potentially at risk for development
of hypertension and of other cardiovascular-associated morbidities. While the reversibility and overall long-term implications of
the increased sympathetic responses in children with SDB remain
unknown, our findings provide, for the first time, conclusive evidence that persistent waking-associated autonomic nervous system dysfunction is present among children with SDB and further
support the notion supporting early diagnosis and treatment in
such children.
Control
Baseline
SDB
Recovery time (min)
Figure 3—Recovery trajectory of peripheral arterial tonometry signal
following the cold pressor test for both controls and children with
sleep-disordered breathing (SDB). Figure shows means and 95%
confidence intervals of peripheral arterial tonometry signal during
the recovery period. Controls returned to baseline values faster than
children with SDB (P=.018).
vealed increases in sympathetic activity throughout, as well as
increased vagal discharge during, respiratory events. Similarly,
Baharav et al11 found evidence for increased sympathetic tone
as derived from spectral analysis of cardiac periodicities in children with SDB. Moreover, an index of overall autonomic balance
was computed for each subject and was found to correlate well
with the respiratory disturbance index. Our study provides further evidence for the occurrence of increased sympathetic tone
during wakefulness in pediatric SDB, as evidenced by more-pronounced PAT signal attenuations during both the vital-capacity
sighs and the cold pressor tests. Furthermore, children with SDB
took significantly more time to return to baseline following the
cold pressor test, suggesting the presence of either altered vascular reactivity or the inability to down regulate obstructive sleep
apnea-associated sympathetic hyperactivation following a challenge in this group.
Modifications in autonomic function may alter the diurnal control and variability of blood pressure. Indeed, in adult patients as
well as in animal studies, repetitive apneic events not only induce
elevation of systemic blood pressure with each apnea, but also
induce a more prolonged elevation of blood pressure that extends
beyond the apneic period.27 The magnitude and severity of blood
pressure elevation in pediatric patients with SDB are not as prominent as those described for older patients, presumably as a result
of the increased vascular compliance in the pediatric age range.
Nevertheless, elevations of blood pressure do occur, as shown by
elevations in systolic, diastolic, or systolic and diastolic blood
pressure compared with that of control populations.28-30 In a more
recent study by Amin and colleagues,31 pediatric SDB patients
exhibited altered state-dependent circadian blood pressure regulation during both sleep and wakefulness, suggesting that alterations in autonomic nervous system control of blood pressure will
manifest as increased variability in blood pressure values rather
than emerge as a sustained elevation in blood pressure values.
The exact pathophysiology of autonomic nervous system dysfunction in the context of SDB is still not completely elucidated.
However, autonomic alterations are likely mediated by both the
episodic hypoxia that may accompany SDB, as well as by the repeated arousals and carbon dioxide elevations of this condition. It
SLEEP, Vol. 28, No. 6, 2005
ACKNOWLEDGEMENTS
This research was supported by NIH grant HL-65270 and an
unrestricted educational grant from Itamar Medical, Caesarea, Israel. We thank the parents and children for their cooperation.
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Autonomic Dysfunction in Apneic Children—O’Brien and Gozal
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