Relationship Between Rem Density, Duty Cycle, and Obstructive Sleep Apnea in
Children
Laurie Karamessinis, RPFT1; Patricia Galster, RPSGT; Brian Schultz, RPSGT1; Joanne Elliott, RPSGT1; Thornton A. Mason II, MD, MSCE, PhD1; Lee J. Brooks, MD1;
Paul R. Gallagher, MA2; Carole L. Marcus, MBBCh1
The Sleep Center and 2the Division of Biostatistics and Epidemiology, The Children’s Hospital of Philadelphia, University of Pennsylvania School of
Medicine, Philadelphia, PA
1
Study Objectives: The pattern and distribution of rapid eye movement
(REM) sleep changes during development, yet there have been few studies of REM density in children. Although children with obstructive apnea
syndrome (OSAS) obstruct primarily during REM sleep, the relationship
between REM density and obstructive apnea has not been established
for this population. We hypothesized that (i) REM density and REM cycle
duration increases over the course of the night in children, (ii) the duty cycle (inspiratory time divided by respiratory cycle time) increases over the
course of the night in children with suspected OSAS, and (iii) the increase
in REM density over the course of the night is associated with increased
severity of obstructive apnea.
Design: REM density and respiratory parameters were measured during
polysomnography.
Setting: Sleep laboratory
Patients: 76 children with suspected OSAS.
Interventions: NA
Measurements and Results: REM density and the duration of REM
cycles increased over the course of the night until the fifth REM cycle, and
then stabilized. The duty cycle increased across the first 6 REM cycles.
However, the apnea hypopnea index (AHI) did not increase across REM
cycles, and was not affected by the changes in REM density or duty cycle.
We speculate that the increase in the duty cycle is a compensatory response to increased upper airway loads during sleep, and that this may
lead to ventilatory or upper airway muscle fatigue.
Keywords: Duty cycle, REM cycle, progression of apnea
Citation: Karamessinis L; Galster P; Schultz B et al. Relationship between rem density, duty cycle, and obstructive sleep apnea in children.
SLEEP 2007;30(7):837-843.
INTRODUCTION
apnea in children is increased in the last third of the night compared to the first third.5 The mechanisms for this are unclear, but it
was postulated that this could be due to changes in REM density,5
as phasic REM sleep is associated with central inhibition of ventilation.7,8 Theoretically, muscle hypotonia and central inhibition
of breathing may be worse during more intense portions of REM.
Alternatively, the worsening of obstructive apnea over the course
of the night could be due to increasing upper airway fatigue.5
We therefore hypothesized that: (i) REM density as well as
REM cycle duration increases over the course of the night in children; (ii) the duty cycle (inspiratory time [TI] divided by total respiratory cycle time [TT], or TI/TT, a factor that can lead to muscle
fatigue9) increases over the course of the night in children with
suspected OSAS; and (iii) the increase in REM density over the
course of the night is associated with increased severity of obstructive apnea. We therefore measured REM density and cycle
duration and respiratory parameters over the course of the night
in children with suspected OSAS.
THE PATTERN AND DISTRIBUTION OF RAPID EYE MOVEMENT (REM) SLEEP CHANGES WITH AGE AND DEVELOPMENT. THE FUNCTION OF REM SLEEP IS UNKNOWN, but
it has been speculated that REM sleep is important for memory
and learning.1 It is therefore not surprising that infants and young
children have more REM sleep than older subjects, and have a
different distribution of REM sleep.2 The intensity of tonic REM
sleep has been measured using such parameters as the duration
of REM sleep and REM latency, whereas the intensity of phasic
REM sleep is typically measured by assessing the REM density,
i.e., the number of rapid eye movements per unit time.3 Despite
the importance of REM sleep in children, there have been few
studies evaluating the intensity of REM sleep in the pediatric age
group.
Obstructive sleep apnea syndrome (OSAS) is common during
childhood, occurring in approximately 2% of young children.4 In
children, the overwhelming majority of obstructive events occur
during REM.5,6 It has been shown that the severity of obstructive
METHODS
Disclosure Statement
This was not an industry supported study. Dr. Brooks has participated in
research supported by Cephalon. Dr. Marcus has received research support
and use of equipment from Respironics. Ms. Karamessinis, Ms. Galster, Mr.
Schultz, Ms. Elliott, Dr. Mason, and Mr. Gallagher have reported no financial
conflicts of interest.
Studies were performed in children undergoing polysomnography for suspected OSAS. Routine polysomnography was performed, with the addition of extra electrooculogram leads as described below. REM density, TI/TT,and the apnea hypopnea index
(AHI) were calculated for each REM cycle, and the change in
these parameters over the course of the night was measured.
Submitted for publication January, 2007
Accepted for publication March, 2007
Address correspondence to: Carole L. Marcus, MBBCh, Children’s Hospital
of Philadelphia, Pulmonary Division, 5th floor Wood, 34th & Civic Center
Blvd, Philadelphia, PA 19104; Tel: (267) 426-5842; Fax: (215) 590-3500; Email: [email protected]
SLEEP, Vol. 30, No. 7, 2007
Study Group
Children with suspected OSAS, aged 2-12 years, were recruited
from the Sleep Center at Children’s Hospital of Philadelphia. The
younger age limit was chosen to exclude infants and very young
837
REM Density in Children—Karamessinis et al
children, who have more REM than older children. The upper age
limit was used to exclude most children in the later stages of puberty, as sex hormones can affect OSAS.10,11 The suspicion of OSAS
was based on a presenting complaint of habitual snoring associated
with additional symptoms, such as labored breathing during sleep
or excessive daytime sleepiness. Children with significant, chronic
medical conditions other than suspected OSAS secondary to adenotonsillar hypertrophy or obesity were excluded, except for those
with mild asthma requiring only intermittent albuterol therapy.
Thus, children with genetic syndromes, craniofacial anomalies and
neurologic disease were excluded. Children with a history of previous upper airway surgery or previous treatment for OSAS, those on
medications known to affect REM sleep, and those with a history of
blindness or serious injury to one or both eyes, were also excluded.
Subjects were considered obese if their body mass index was greater than the 95th percentile for age, height, and race.12
Written informed consent was obtained from the parents/legal
guardians. In addition, assent was obtained from children ≥7 years
of age. The study was approved by the Institutional Review Board
of Children’s Hospital of Philadelphia, and studies were performed
according to the Declaration of Helsinki.
apneas originating within that epoch were manually calculated,
as described in the literature.13 REM density was defined as the
number of eye movements per each 30-second epoch of REM
sleep. REM cycles of <2 minutes duration were not included in
the analysis. For the purpose of analysis, REM cycles interrupted
by <5 minutes of wakefulness or NREM sleep were considered to
be part of the same REM cycle. Subjects with fewer than 3 REM
cycles during the night were excluded. The obstructive apnea duration was defined as the sum of the duration of all obstructive apneas
and hypopneas during each REM cycle. The inspiratory time and
total respiratory cycle duration were obtained from the respiratory
inductance plethysmographic signal. TI and TT were measured for
each breath during the first and last minute of each REM cycle.
Statistical Analysis
The number of apneas and hypopneas in the first third of the
night compared to the last third of the night was compared using the Wilcoxon signed rank test. The difference in REM density (averaged across all REM cycles) between subjects with an
AHI <1/hr and those with an AHI >1 /hr was performed using
the Mann-Whitney rank sum test. The Spearman correlation coefficient was used for correlational analyses. The effect of REM
cycle on the various outcomes as measured repeatedly across
REM cycles was analyzed based on a longitudinal mixed effects
approach. In order to allow for the possibility that change across
REM cycles has a curvilinear component, terms for quadratic
time and cubic time were included in each model. If these terms
were found to be nonsignificant, they were subsequently dropped
from the final models. In order to explore the study hypotheses,
various models involving time-varying or time-dependent covariates were also examined. For example, the effect of REM density
changing across REM cycle on AHI changing across REM cycle
was examined by including REM density as a time-dependent
covariate and specifying the repeating measures of AHI as the
outcome variable. In this study, using several measurements from
different REM cycles across the night, the compound symmetry
covariance matrix structure was assumed. SAS Proc Mixed models were used.21
Polysomnography
Overnight polysomnography commenced between 20:00-21:00
and ended at 06:00. The following parameters were recorded (using
Rembrandt, Medcare, Buffalo, NY): electroencephalogram (C3/
A2, C4/A1, O1/A2, O2/A1); submental electromyogram (EMG);
tibial EMG; electrocardiogram; chest and abdominal wall motion
by respiratory inductance plethysmography (Respitrace Systems,
Ambulatory Monitoring Inc, Ardsley, NY); airflow by nasal pressure (Pro-Tech Services, Inc, Mukilteo, WA) and 3-pronged thermistor (Pro-Tech Services, Inc, Mukilteo, WA); end-tidal PCO2 by
capnography (Novametrix 7000; Novametrix, Wallingford, CT);
arterial oxygen saturation (Novametrix 7000 or Masimo, Irvine,
CA), oximeter pulse waveform, and digital video.
Four electrooculographic (EOG) gold cup electrodes (Grass,
West Warwick, RI) were placed to detect eye movements. Right
and left EOG leads were placed 1 cm lateral to the outer canthus of each eye, in the horizontal plane. Vertical EOG leads were
placed 1 cm above and below the right eye.13,14 All 4 leads were
used to assess eye movements. EOG changes were scored as eye
movements if they met the following criteria: amplitude >25 µV,
velocity >500/sec, deflection >30, and at least 200 ms between each
eye movement.15
Sleep architecture and arousals from sleep were analyzed using standard techniques.16,17 Respiratory parameters were scored
using standard pediatric criteria,18,19 i.e., obstructive apneas of any
length were scored. Hypopneas were scored if there was a qualitative decrease in oronasal airflow >50% associated with paradoxical respiratory efforts, desaturation >3%,20 and/or arousal. The
obstructive apnea hypopnea index was defined as the number of
obstructive apneas, mixed apneas, and obstructive hypopneas per
unit time. Central apneas were also scored,18 but as very few central apneas occurred, these data are not presented.
RESULTS
Study Group
Seventy-nine subjects were studied. Three subjects were excluded as they had <3 REM cycles during the night. Thus, data
were evaluated for 76 subjects. The mean age was 6 + 3 (SD)
years, range 2-12 years. Fifty-six percent were female, and 29%
were obese. Polysomnography results are shown in Table 1. Subjects had a wide range of severity of OSAS, as shown in Figure 1.
AHI ranged from 0-57/hr, with a median AHI of 1.9/hr.
REM Architecture
With the exception of the 3 subjects excluded from the study
because they had <3 REM cycles, subjects had 3-8 REM cycles
during the night; 5 (7%) subjects had 7 REM cycles, and only 1
(1%) subject had 8 cycles. REM density changed significantly
across the REM cycles, with significant linear and quadratic time
effects (P = 0.0017 and 0.0245, respectively), indicating a lin-
Data Analysis
REM was divided into 1-second mini-epochs. The number of
eye movements in each mini-epoch and the number of obstructive
SLEEP, Vol. 30, No. 7, 2007
838
REM Density in Children—Karamessinis et al
REM density in children, Revision #1
23
Karamessinis
Figure 1
80
Table 1—Sleep Architecture
534 + 33
466 – 615
459 + 41
320 – 530
86 + 9
33 – 98
29 + 28
2 – 191
37 + 24
4 – 121
7+5
1 – 27
46 + 8
29 – 66
26 + 6
10 – 41
20 + 5
11 – 33
118 + 55
35 – 286
5+1
3–8
15 + 9
5 – 64
60
Subjects
Total recording time (min)
Range
Total sleep time (min)
Range
Sleep efficiency (%)
Range
Sleep latency (min)
Range
Wake after sleep onset (min)
Range
Stage 1 (%TST)
Range
Stage 2 (%TST)
Range
Slow wave sleep (%TST)
Range
REM sleep (%TST)
Range
REM latency (min)
Range
REM cycles (N)
Range
Arousal index (N/hr)
Range
Apnea hypopnea index (N/hr)
Median
Range
Mean obstructive apnea duration(s)
Mean hypopnea duration(s)
Arterial oxygen saturation nadir (%)
Range
Peak end-tidal PCO2 (mm Hg)
Range
20
0
0
5
10
15
20 40
60
Apnea Hypopnea Index (N/hr)
Figure 1—The apnea hypopnea index for each of the 76 subjects is
shown.
Apnea Hypopnea Index
The AHI and obstructive apnea duration variables were severely skewed, with a preponderance of values of zero, and could not
be normalized using transformation techniques. Despite the fact
that the number of REM obstructive apneas and hypopneas was
greater during the last third of the night than the first third (first
third, median 0, interquartile range 0-2; last third median 1, interquartile range 0–6.5; P <0.001), there was no significant change
in the AHI across the REM cycles of the night (P = 0.052 for raw
AHI and P = 0.45 for log AHI; Figure 6); nor was there a change
in total obstructive apnea duration across the REM cycles of the
night (P = 0.13 for raw values and P = 0.33 for log transformed
values).
The change in AHI across REM cycles was reevaluated for
those subjects who had any degree of airway obstruction, i.e., afREM
density in children,
Revision
Karamessinis
ter
excluding
those with
an#1AHI =24 0. Under these circumstances,
log transformation helped to normalize the AHI distribution. There
Figure
2 in AHI across the REM
was still no statistically significant
change
1.9
0 – 57
11.7 + 3.2
13.2 + 3.9
88 + 8
66 – 98
51 + 5
37 – 64
Data displayed as mean + SD and range, except for the apnea hypopnea index, which was not normally distributed and is displayed as median and range. TST, total sleep time.
ear increase and an eventual leveling of REM density by the fifth
REM cycle (Figure 2).
There was no correlation between REM density (computed as
the mean REM density per subject) and age (r = 0.11, P = 0.37;
Figure 3). In order to compare this study to previous data in the
literature, the correlation between REM density and age was reevaluated in those children > 6 years of age. There was a slightly
stronger relationship, but this still did not reach significance (r =
0.29, P = 0.11). There was no significant difference in mean REM
density between children with an AHI <1/hr and children with an
AHI >1/hr (P = 0.83).
REM duration changed across the REM cycles, with significant
linear and quadratic time effects (P <0.0001 for both linear and
quadratic time effects), again indicating a linear increase and an
eventual leveling at the fifth cycle (Figure 4).
REM Density (No. REMs/30-second epoch)
3
2
1
0
-1
Duty Cycle
0
1
2
3
4
5
6
7
8
9
REM Cycles
TI/TT increased significantly across the REM cycles of the night
in a linear fashion (P = 0.0033). This is shown in Figure 5. Note
that very few subjects had more than 6 REM cycles; thus, the apparent decrease in TI/TT in cycles 7 and 8 was not significant.
SLEEP, Vol. 30, No. 7, 2007
40
Figure 2—The mean (SD) REM density is shown as a function of
REM cycles across the course of the night. Note that few subjects
had >6 REM cycles.
839
REM Density in Children—Karamessinis et al
Figure 4
Figure 3
40
4
Duration REM (minutes)
REM Density (No. REMs/30-second epoch)
5
3
2
30
20
10
1
0
0
2
4
6
8
10
0
12
Figure 3—The relationship between REM density and age is
shown.
3
4
5
6
7
8
9
ing across REM cycles. There was no relationship between the
changes in either REM density or TI/TT and changes in the AHI
across REM cycles.
Obesity
There were no significant correlations between body mass index z-scores, which serve as an index of obesity, and AHI (P =
0.19), mean REM density (P = 0.60), or mean TI/TT (P = 0.23)
(all parameters computed as the average of the means for each
REM cycle).
DISCUSSION
Relationship Between REM Density, Duty Cycle, and AHI
27
Karamessinis
Although REM density changed across REM cycles, this
change in REM density did not Figure
have an
5 effect on TI/TT chang0.70
This study has shown that REM density and the duration of
REM cycles changed over the course of the night in children,
with an increase until the fifth REM cycle and then a plateau.
The TI/TT increased across REM cycles. However, in contrast to
our initial hypothesis, neither the change in REM density nor the
change in TI/TT affected the AHI.
Changes in REM Sleep with Age
0.65
We have shown that both REM duration and REM density
increase over the course of the night in preschool-aged children
and school-aged children. REM sleep distribution is known to
change with age and development. Newborns have a predominance of active sleep, a state analogous to REM sleep, and frequently enter sleep through this stage.22 The proportion of REM
then decreases during childhood, and continues to decrease further during adulthood and old age.2 Although REM density has
been shown to increase over the course of the night in adults,3,14
REM density has not been well studied in children. Coble et al23
evaluated REM density, for the first 4 cycles of the night only,
in a somewhat older group of children (6-16 years). They found
that REM density tended to increase over the first 4 REM cycles
of the night. Our study confirmed this finding in younger children and showed a highly significant increase in REM density
across all REM cycles. Coble et al also noted a trend towards
0.60
TI/TT
2
Figure 4—The mean (SD) duration of each REM cycle is shown as
a function of REM cycles across the course of the night. Note that
few subjects had >6 REM cycles.
cycles over the course of the night (P = 0.0751 for raw values; P =
0.12 for log values). Similarly, when only children with moderate
OSAS (AHI >5/hr) were evaluated, there was no statistically significant change in AHI across REM cycles (P = 0.17 for raw values;
P = 0.24 for log values). There were 2 subjects who were outliers,
with very severe OSAS. One subject with an AHI of 42/hr had 4
REM cycles; her REM AHI for each cycle, respectively, was 131,
120, 77, and 107/hr. The second outlier, with an AHI of 57/hr, had
3 REM cycles, with a REM AHI of 14, 122, and 32/hr, respectively.
Thus, neither of the most severely affected subjects had a pattern of
worsening during the last REM cycle.
The correlations between AHI and REM density, and AHI and
REM duration, were not significant (r = -0.05, P = -0.69; and r =
-0.03, P = 0.80; respectively).
REM density in children, Revision #1
1
REM Cycles
Age (yr)
0.55
0.50
0.45
0.40
0
1
2
3
4
5
6
7
8
9
REM Cycles
Figure 5—The mean (SD) duty cycle is shown as a function of REM
cycles across the course of the night. Note that few subjects had >6
REM cycles. TI, inspiratory time; TT, total respiratory cycle time.
SLEEP, Vol. 30, No. 7, 2007
840
REM Density in Children—Karamessinis et al
REM density in children, Revision #1
28
Karamessinis
Figure 6
were taken into account, the AHI did not change significantly
across REM cycles. It is most likely that the difference between
the 2 studies is due to the different analytic techniques used.
Alternatively, the difference may be secondary to the inclusion
of subjects with a wide distribution of AHI, as compared with
the previous study, which evaluated subjects with more severe
disease. However, this is less likely, as the results were similar
when only subjects with an AHI >5/hr were studied. In addition,
neither of the 2 subjects with very severe OSAS had their highest REM AHI during the last REM cycle. The variability in their
patterns of AHI illustrates the importance of examining all REM
cycles during the night.
120
Apnea Hypopnea Index
100
80
60
40
20
0
1
2
3
4
5
6
Duty Cycle
7
Rem cycles
The duty cycle (TI/TT) increased significantly across REM cycles. All of the subjects in this study presented with symptoms of
OSAS and a history of habitual nightly snoring. Thus, all of the
subjects had varying degrees of increased inspiratory resistance
loading during sleep, ranging from snoring alone to obstructive
sleep apnea.28 A prolonged TI has been shown to occur as a compensatory response to increased inspiratory resistance loading.
This response has been shown to occur during both REM and
NREM sleep,29,30 although the response during sleep is less than
during wakefulness. Little is known about the relative contributions of upper airway and ventilatory pump muscles to breathing during sleep in children. In adults during wakefulness, it
was recently suggested that the forces generated by these 2 sets
of muscles are linearly related,31 but this may not apply during
sleep. The TI/TT ratio probably represents the combined action
of both upper airway muscles and ventilatory pump muscles. It
is possible that inspiratory muscle (upper airway and pump) tone
decreases as the night progresses, resulting in increased upper airway resistance. This can lead to a compensatory increase in TI/TT.
In support of this theory, we have previously shown that normal
children have a dramatic decrease in tidal volume in response to
inspiratory resistance loading during sleep, accompanied by an
increase in TI/TT.30 In contrast to adults,32 children manifest little
recovery over time.30
An increased TI/TT may lead to ventilatory muscle fatigue.9
This could occur from continued work against an inspiratory
load. Although previous studies (in adults) did not find evidence
of diaphragmatic fatigue during sleep in patients with OSAS,
these studies were all limited to NREM sleep.33,34 Furthermore,
no studies have evaluated the upper airway muscles for fatigue
over time. However, in the current study, the increased TI/TT
across REM cycles was not associated with an increase in AHI,
even in the more severely affected subjects, suggesting that clinically relevant muscle fatigue did not occur. It is possible that the
increase in TI/TT across REM cycles was due to REM-related
changes in upper airway neuromotor control or central regulation of ventilation. The latter appears unlikely. Animal studies using the carbachol model for REM sleep have shown a decrease
in both inspiratory and expiratory time in response to carbachol
injection,35 whereas studies in normal adults without sleep disordered breathing showed a decrease in expiratory time and TT in
relation to REM density, but little change in TI.36 These studies are
in contrast to the present study, which demonstrated an increase
in TI/TTOT.
Figure 6—The apnea hypopnea index for subjects with an AHI >1/hr
is shown as a function of REM cycles across the course of the night.
The boundaries of the boxes indicate the 25th and 75th percentiles,
the line within the boxes marks the medians, the whiskers indicate
the 90th and 10th percentiles, and the points represent the outliers.
increased REM density in younger children, although this was
only significant for the first and third REM cycles. Hoffman et
al24 evaluated REM density in a small sample of females which
included 2 prepubertal and 6 pubertal adolescents, and noted
increased REM density in the prepubertal compared to the pubertal subjects. We found no relationship between age and REM
density when evaluating a younger group of children, although
there was a slight trend towards an increased REM density in
younger children when only school-aged children were evaluated. Thus, in young children, there is no correlation between
REM density and age.
The subjects in the current study had sleep architecture similar
to that of a large, somewhat younger, normal population recently
reported by Montgomery-Downs et al,25 with a similar total sleep
time (459 minutes in the current study compared to 472-475 minutes in the Montgomery-Downs study), a similar percentage of
REM sleep (20% in the current study compared to 20%-21% in
the Montgomery-Downs study), and a similar number of REM
cycles. This is not surprising, as many studies have shown no difference in sleep architecture between children with OSAS and
normal controls,5 or children with OSAS before and after treatment.26,27 The duration of REM cycles across the night increased
in the current study, similar to that reported by MontgomeryDowns. However, the Montgomery-Downs study did not evaluate REM density.
Apnea Hypopnea Index
A previous study showed an increase in the REM AHI in the
last third of the night compared with the first third of the night.5
In that study, the night was arbitrarily divided into thirds, and
only the first and last thirds of the night were evaluated, i.e., there
was no evaluation of the intervening third. In contrast, the current study used sophisticated analytic techniques to evaluate the
entire night. Although the current study found that the number of
REM obstructions was greater during the last third of the night
compared to the first third, when the intervening REM cycles
SLEEP, Vol. 30, No. 7, 2007
841
REM Density in Children—Karamessinis et al
Limitations
9.
It should be noted that polysomnograms were terminated at
06:00, due to laboratory scheduling issues. It is likely that some
children would have had more REM cycles if they had been allowed to sleep until spontaneous awakening. However, total sleep
time, proportion of REM time, and the number of REM cycles
were similar to those previously reported for a large cohort of
normal children,25 so it is unlikely that this had a major impact on
our results.
Children with OSAS may have a pattern of persistent partial
upper airway obstruction associated with hypercapnia, rather then
discrete obstructive events. This has been termed obstructive hypoventilation.18 We did not analyze the relationship between hypercapnia and REM density, as this would have required analyzing the end-tidal PCO2 on a breath-by-breath basis. Future studies
of this relationship would be of interest.
10.
11.
12.
13.
14.
15.
Conclusions
16.
In conclusion, we have shown that REM density and the duty
cycle (TI/TT) increase across REM cycles during the night in
children. Despite this, the degree of obstructive apnea does not
change significantly across REM cycles.
17.
18.
ACKNOWLEDGMENTS
Dr. Marcus was supported by NIH grants #HL58585, MO1RR-000240 and U54 RR023567 and research support from Respironics, Inc. that funded a research technician. Dr. Mason was
supported by K23 RR16566.
We thank all of the Children’s Hospital of Philadelphia sleep
laboratory technologists who helped conduct this study. We are
grateful to the children and their families for their enthusiastic
participation in this study.
19.
20.
21.
22.
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Electroencephalogr Clin Neurophysiol 1996;99:556-61.
Rechtschaffen A, Kales A. A manual of standardized terminology:
Techniques and scoring systems for sleep stages of human subjects.
NINDB Neurological Information network (US), Bethesda, MD
1968.
Sleep disorders atlas task force. Guilleminault C. C. EEG arousals:
scoring rules and examples. Sleep 1992;15:173-84.
American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med
1996;153:866-78.
Marcus CL, Omlin KJ, Basinki DJ, et al.Normal polysomnographic
values for children and adolescents. Am Rev Respir Dis 1992;146(5
Pt 1):1235-9.
Sleep-related breathing disorders in adults: recommendations for
syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine
Task Force. Sleep 1999;22:667-89.
SAS/STAT User’s Guide. Cary, NC: SAS Institute Inc, 1999.
Sadeh A. Maturation of normal sleep patterns from childhood
through adolescence. In: Loughlin GM, Carroll JL, Marcus CL, eds.
Sleep and breathing in children: a developmental approach. New
York: Marcel Dekker, Inc, 2000:63-78.
Coble PA, Reynolds CF III, Kupfer DJ, Houck P. Electroencephalographic sleep of healthy children. Part II: Findings using automated
delta and REM sleep measurement methods. Sleep 1987;10:551-62.
Hoffmann G, Petre-Quadens O. Maturation of REM-patterns from
childhood to maturity. Waking Sleeping 1979;3:255-62.
Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D.
Polysomnographic characteristics in normal preschool and early
school-aged children. Pediatrics 2006;117:741-53.
Frank Y, Kravath RE, Pollak CP, Weitzman ED. Obstructive sleep
apnea and its therapy; clinical and polysomnographic manifestations. Pediatrics 1983;71:737-42.
Marcus CL, Carroll JL, Koerner CB, Hamer A, Lutz J, Loughlin
GM. Determinants of growth in children with the obstructive sleep
apnea syndrome. J Pediatr 1994;125:556-62.
American Academy of Sleep medicine. The International Classification of Sleep Disorders. 2nd ed. Westchester, IL: American Academy of Sleep Medicine, 2005.
Wiegand L, Zwillich CW, White DP. Sleep and the ventilatory response to resistive loading in normal men. J Appl Physiol
1988;64:1186-95.
Marcus CL, Moreira GA, Bamford O, Lutz J. Response to inspiratory resistive loading during sleep in normal children and children
with obstructive apnea. J Appl Physiol 1999;87:1448-54.
REM Density in Children—Karamessinis et al
31. Shepherd KL, Jensen CM, Maddison KJ, Hillman DR, Eastwood
PR. Relationship between upper airway and inspiratory pump muscle force in obstructive sleep apnea. Chest 2006;130:1757-64.
32. Badr MS, Skatrud JB, Dempsey JA, Begle RL. Effect of mechanical
loading on expiratory and inspiratory muscle activity during NREM
sleep. J Appl Physiol 1990; 68:1195-1202.
33. Montserrat JM, Kosmas EN, Cosio MG, Kimoff RJ. Lack of evidence for diaphragmatic fatigue over the course of the night in obstructive sleep apnoea. Eur Respir J 1997;10:133-8.
34. Cibella F, Cuttitta G, Romano S, Bellia V, Bonsignore G. Evaluation
of diaphragmatic fatigue in obstructive sleep apnoeas during nonREM sleep. Thorax 1997;52:731-5.
35. Kimura H, Kubin L, Davies RO, Pack AI. Cholinergic stimulation
of the pons depresses respiration in decerebrate cats. J Appl Physiol
1990;69:2280-9.
36. Neilly JB, Gaipa EA, Maislin G, Pack AI. Ventilation during early
and late rapid-eye-movement sleep in normal humans. J Appl Physiol 1991;71:1201-15.
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REM Density in Children—Karamessinis et al
children, who have more REM than older children. The upper age
limit was used to exclude most children in the later stages of puberty, as sex hormones can affect OSAS.10,11 The suspicion of OSAS
was based on a presenting complaint of habitual snoring associated
with additional symptoms, such as labored breathing during sleep
or excessive daytime sleepiness. Children with significant, chronic
medical conditions other than suspected OSAS secondary to adenotonsillar hypertrophy or obesity were excluded, except for those
with mild asthma requiring only intermittent albuterol therapy.
Thus, children with genetic syndromes, craniofacial anomalies and
neurologic disease were excluded. Children with a history of previous upper airway surgery or previous treatment for OSAS, those on
medications known to affect REM sleep, and those with a history of
blindness or serious injury to one or both eyes, were also excluded.
Subjects were considered obese if their body mass index was greater than the 95th percentile for age, height, and race.12
Written informed consent was obtained from the parents/legal
guardians. In addition, assent was obtained from children ≥7 years
of age. The study was approved by the Institutional Review Board
of Children’s Hospital of Philadelphia, and studies were performed
according to the Declaration of Helsinki.
apneas originating within that epoch were manually calculated,
as described in the literature.13 REM density was defined as the
number of eye movements per each 30-second epoch of REM
sleep. REM cycles of <2 minutes duration were not included in
the analysis. For the purpose of analysis, REM cycles interrupted
by <5 minutes of wakefulness or NREM sleep were considered to
be part of the same REM cycle. Subjects with fewer than 3 REM
cycles during the night were excluded. The obstructive apnea duration was defined as the sum of the duration of all obstructive apneas
and hypopneas during each REM cycle. The inspiratory time and
total respiratory cycle duration were obtained from the respiratory
inductance plethysmographic signal. TI and TT were measured for
each breath during the first and last minute of each REM cycle.
Statistical Analysis
The number of apneas and hypopneas in the first third of the
night compared to the last third of the night was compared using the Wilcoxon signed rank test. The difference in REM density (averaged across all REM cycles) between subjects with an
AHI <1/hr and those with an AHI >1 /hr was performed using
the Mann-Whitney rank sum test. The Spearman correlation coefficient was used for correlational analyses. The effect of REM
cycle on the various outcomes as measured repeatedly across
REM cycles was analyzed based on a longitudinal mixed effects
approach. In order to allow for the possibility that change across
REM cycles has a curvilinear component, terms for quadratic
time and cubic time were included in each model. If these terms
were found to be nonsignificant, they were subsequently dropped
from the final models. In order to explore the study hypotheses,
various models involving time-varying or time-dependent covariates were also examined. For example, the effect of REM density
changing across REM cycle on AHI changing across REM cycle
was examined by including REM density as a time-dependent
covariate and specifying the repeating measures of AHI as the
outcome variable. In this study, using several measurements from
different REM cycles across the night, the compound symmetry
covariance matrix structure was assumed. SAS Proc Mixed models were used.21
Polysomnography
Overnight polysomnography commenced between 20:00-21:00
and ended at 06:00. The following parameters were recorded (using
Rembrandt, Medcare, Buffalo, NY): electroencephalogram (C3/
A2, C4/A1, O1/A2, O2/A1); submental electromyogram (EMG);
tibial EMG; electrocardiogram; chest and abdominal wall motion
by respiratory inductance plethysmography (Respitrace Systems,
Ambulatory Monitoring Inc, Ardsley, NY); airflow by nasal pressure (Pro-Tech Services, Inc, Mukilteo, WA) and 3-pronged thermistor (Pro-Tech Services, Inc, Mukilteo, WA); end-tidal PCO2 by
capnography (Novametrix 7000; Novametrix, Wallingford, CT);
arterial oxygen saturation (Novametrix 7000 or Masimo, Irvine,
CA), oximeter pulse waveform, and digital video.
Four electrooculographic (EOG) gold cup electrodes (Grass,
West Warwick, RI) were placed to detect eye movements. Right
and left EOG leads were placed 1 cm lateral to the outer canthus of each eye, in the horizontal plane. Vertical EOG leads were
placed 1 cm above and below the right eye.13,14 All 4 leads were
used to assess eye movements. EOG changes were scored as eye
movements if they met the following criteria: amplitude >25 µV,
velocity >500/sec, deflection >30, and at least 200 ms between each
eye movement.15
Sleep architecture and arousals from sleep were analyzed using standard techniques.16,17 Respiratory parameters were scored
using standard pediatric criteria,18,19 i.e., obstructive apneas of any
length were scored. Hypopneas were scored if there was a qualitative decrease in oronasal airflow >50% associated with paradoxical respiratory efforts, desaturation >3%,20 and/or arousal. The
obstructive apnea hypopnea index was defined as the number of
obstructive apneas, mixed apneas, and obstructive hypopneas per
unit time. Central apneas were also scored,18 but as very few central apneas occurred, these data are not presented.
RESULTS
Study Group
Seventy-nine subjects were studied. Three subjects were excluded as they had <3 REM cycles during the night. Thus, data
were evaluated for 76 subjects. The mean age was 6 + 3 (SD)
years, range 2-12 years. Fifty-six percent were female, and 29%
were obese. Polysomnography results are shown in Table 1. Subjects had a wide range of severity of OSAS, as shown in Figure 1.
AHI ranged from 0-57/hr, with a median AHI of 1.9/hr.
REM Architecture
With the exception of the 3 subjects excluded from the study
because they had <3 REM cycles, subjects had 3-8 REM cycles
during the night; 5 (7%) subjects had 7 REM cycles, and only 1
(1%) subject had 8 cycles. REM density changed significantly
across the REM cycles, with significant linear and quadratic time
effects (P = 0.0017 and 0.0245, respectively), indicating a lin-
Data Analysis
REM was divided into 1-second mini-epochs. The number of
eye movements in each mini-epoch and the number of obstructive
SLEEP, Vol. 30, No. 7, 2007
838
REM Density in Children—Karamessinis et al
REM density in children, Revision #1
23
Karamessinis
Figure 1
80
Table 1—Sleep Architecture
534 + 33
466 – 615
459 + 41
320 – 530
86 + 9
33 – 98
29 + 28
2 – 191
37 + 24
4 – 121
7+5
1 – 27
46 + 8
29 – 66
26 + 6
10 – 41
20 + 5
11 – 33
118 + 55
35 – 286
5+1
3–8
15 + 9
5 – 64
60
Subjects
Total recording time (min)
Range
Total sleep time (min)
Range
Sleep efficiency (%)
Range
Sleep latency (min)
Range
Wake after sleep onset (min)
Range
Stage 1 (%TST)
Range
Stage 2 (%TST)
Range
Slow wave sleep (%TST)
Range
REM sleep (%TST)
Range
REM latency (min)
Range
REM cycles (N)
Range
Arousal index (N/hr)
Range
Apnea hypopnea index (N/hr)
Median
Range
Mean obstructive apnea duration(s)
Mean hypopnea duration(s)
Arterial oxygen saturation nadir (%)
Range
Peak end-tidal PCO2 (mm Hg)
Range
20
0
0
5
10
15
20 40
60
Apnea Hypopnea Index (N/hr)
Figure 1—The apnea hypopnea index for each of the 76 subjects is
shown.
Apnea Hypopnea Index
The AHI and obstructive apnea duration variables were severely skewed, with a preponderance of values of zero, and could not
be normalized using transformation techniques. Despite the fact
that the number of REM obstructive apneas and hypopneas was
greater during the last third of the night than the first third (first
third, median 0, interquartile range 0-2; last third median 1, interquartile range 0–6.5; P <0.001), there was no significant change
in the AHI across the REM cycles of the night (P = 0.052 for raw
AHI and P = 0.45 for log AHI; Figure 6); nor was there a change
in total obstructive apnea duration across the REM cycles of the
night (P = 0.13 for raw values and P = 0.33 for log transformed
values).
The change in AHI across REM cycles was reevaluated for
those subjects who had any degree of airway obstruction, i.e., afREM
density in children,
Revision
Karamessinis
ter
excluding
those with
an#1AHI =24 0. Under these circumstances,
log transformation helped to normalize the AHI distribution. There
Figure
2 in AHI across the REM
was still no statistically significant
change
1.9
0 – 57
11.7 + 3.2
13.2 + 3.9
88 + 8
66 – 98
51 + 5
37 – 64
Data displayed as mean + SD and range, except for the apnea hypopnea index, which was not normally distributed and is displayed as median and range. TST, total sleep time.
ear increase and an eventual leveling of REM density by the fifth
REM cycle (Figure 2).
There was no correlation between REM density (computed as
the mean REM density per subject) and age (r = 0.11, P = 0.37;
Figure 3). In order to compare this study to previous data in the
literature, the correlation between REM density and age was reevaluated in those children > 6 years of age. There was a slightly
stronger relationship, but this still did not reach significance (r =
0.29, P = 0.11). There was no significant difference in mean REM
density between children with an AHI <1/hr and children with an
AHI >1/hr (P = 0.83).
REM duration changed across the REM cycles, with significant
linear and quadratic time effects (P <0.0001 for both linear and
quadratic time effects), again indicating a linear increase and an
eventual leveling at the fifth cycle (Figure 4).
REM Density (No. REMs/30-second epoch)
3
2
1
0
-1
Duty Cycle
0
1
2
3
4
5
6
7
8
9
REM Cycles
TI/TT increased significantly across the REM cycles of the night
in a linear fashion (P = 0.0033). This is shown in Figure 5. Note
that very few subjects had more than 6 REM cycles; thus, the apparent decrease in TI/TT in cycles 7 and 8 was not significant.
SLEEP, Vol. 30, No. 7, 2007
40
Figure 2—The mean (SD) REM density is shown as a function of
REM cycles across the course of the night. Note that few subjects
had >6 REM cycles.
839
REM Density in Children—Karamessinis et al
Figure 4
Figure 3
40
4
Duration REM (minutes)
REM Density (No. REMs/30-second epoch)
5
3
2
30
20
10
1
0
0
2
4
6
8
10
0
12
Figure 3—The relationship between REM density and age is
shown.
3
4
5
6
7
8
9
ing across REM cycles. There was no relationship between the
changes in either REM density or TI/TT and changes in the AHI
across REM cycles.
Obesity
There were no significant correlations between body mass index z-scores, which serve as an index of obesity, and AHI (P =
0.19), mean REM density (P = 0.60), or mean TI/TT (P = 0.23)
(all parameters computed as the average of the means for each
REM cycle).
DISCUSSION
Relationship Between REM Density, Duty Cycle, and AHI
27
Karamessinis
Although REM density changed across REM cycles, this
change in REM density did not Figure
have an
5 effect on TI/TT chang0.70
This study has shown that REM density and the duration of
REM cycles changed over the course of the night in children,
with an increase until the fifth REM cycle and then a plateau.
The TI/TT increased across REM cycles. However, in contrast to
our initial hypothesis, neither the change in REM density nor the
change in TI/TT affected the AHI.
Changes in REM Sleep with Age
0.65
We have shown that both REM duration and REM density
increase over the course of the night in preschool-aged children
and school-aged children. REM sleep distribution is known to
change with age and development. Newborns have a predominance of active sleep, a state analogous to REM sleep, and frequently enter sleep through this stage.22 The proportion of REM
then decreases during childhood, and continues to decrease further during adulthood and old age.2 Although REM density has
been shown to increase over the course of the night in adults,3,14
REM density has not been well studied in children. Coble et al23
evaluated REM density, for the first 4 cycles of the night only,
in a somewhat older group of children (6-16 years). They found
that REM density tended to increase over the first 4 REM cycles
of the night. Our study confirmed this finding in younger children and showed a highly significant increase in REM density
across all REM cycles. Coble et al also noted a trend towards
0.60
TI/TT
2
Figure 4—The mean (SD) duration of each REM cycle is shown as
a function of REM cycles across the course of the night. Note that
few subjects had >6 REM cycles.
cycles over the course of the night (P = 0.0751 for raw values; P =
0.12 for log values). Similarly, when only children with moderate
OSAS (AHI >5/hr) were evaluated, there was no statistically significant change in AHI across REM cycles (P = 0.17 for raw values;
P = 0.24 for log values). There were 2 subjects who were outliers,
with very severe OSAS. One subject with an AHI of 42/hr had 4
REM cycles; her REM AHI for each cycle, respectively, was 131,
120, 77, and 107/hr. The second outlier, with an AHI of 57/hr, had
3 REM cycles, with a REM AHI of 14, 122, and 32/hr, respectively.
Thus, neither of the most severely affected subjects had a pattern of
worsening during the last REM cycle.
The correlations between AHI and REM density, and AHI and
REM duration, were not significant (r = -0.05, P = -0.69; and r =
-0.03, P = 0.80; respectively).
REM density in children, Revision #1
1
REM Cycles
Age (yr)
0.55
0.50
0.45
0.40
0
1
2
3
4
5
6
7
8
9
REM Cycles
Figure 5—The mean (SD) duty cycle is shown as a function of REM
cycles across the course of the night. Note that few subjects had >6
REM cycles. TI, inspiratory time; TT, total respiratory cycle time.
SLEEP, Vol. 30, No. 7, 2007
840
REM Density in Children—Karamessinis et al
REM density in children, Revision #1
28
Karamessinis
Figure 6
were taken into account, the AHI did not change significantly
across REM cycles. It is most likely that the difference between
the 2 studies is due to the different analytic techniques used.
Alternatively, the difference may be secondary to the inclusion
of subjects with a wide distribution of AHI, as compared with
the previous study, which evaluated subjects with more severe
disease. However, this is less likely, as the results were similar
when only subjects with an AHI >5/hr were studied. In addition,
neither of the 2 subjects with very severe OSAS had their highest REM AHI during the last REM cycle. The variability in their
patterns of AHI illustrates the importance of examining all REM
cycles during the night.
120
Apnea Hypopnea Index
100
80
60
40
20
0
1
2
3
4
5
6
Duty Cycle
7
Rem cycles
The duty cycle (TI/TT) increased significantly across REM cycles. All of the subjects in this study presented with symptoms of
OSAS and a history of habitual nightly snoring. Thus, all of the
subjects had varying degrees of increased inspiratory resistance
loading during sleep, ranging from snoring alone to obstructive
sleep apnea.28 A prolonged TI has been shown to occur as a compensatory response to increased inspiratory resistance loading.
This response has been shown to occur during both REM and
NREM sleep,29,30 although the response during sleep is less than
during wakefulness. Little is known about the relative contributions of upper airway and ventilatory pump muscles to breathing during sleep in children. In adults during wakefulness, it
was recently suggested that the forces generated by these 2 sets
of muscles are linearly related,31 but this may not apply during
sleep. The TI/TT ratio probably represents the combined action
of both upper airway muscles and ventilatory pump muscles. It
is possible that inspiratory muscle (upper airway and pump) tone
decreases as the night progresses, resulting in increased upper airway resistance. This can lead to a compensatory increase in TI/TT.
In support of this theory, we have previously shown that normal
children have a dramatic decrease in tidal volume in response to
inspiratory resistance loading during sleep, accompanied by an
increase in TI/TT.30 In contrast to adults,32 children manifest little
recovery over time.30
An increased TI/TT may lead to ventilatory muscle fatigue.9
This could occur from continued work against an inspiratory
load. Although previous studies (in adults) did not find evidence
of diaphragmatic fatigue during sleep in patients with OSAS,
these studies were all limited to NREM sleep.33,34 Furthermore,
no studies have evaluated the upper airway muscles for fatigue
over time. However, in the current study, the increased TI/TT
across REM cycles was not associated with an increase in AHI,
even in the more severely affected subjects, suggesting that clinically relevant muscle fatigue did not occur. It is possible that the
increase in TI/TT across REM cycles was due to REM-related
changes in upper airway neuromotor control or central regulation of ventilation. The latter appears unlikely. Animal studies using the carbachol model for REM sleep have shown a decrease
in both inspiratory and expiratory time in response to carbachol
injection,35 whereas studies in normal adults without sleep disordered breathing showed a decrease in expiratory time and TT in
relation to REM density, but little change in TI.36 These studies are
in contrast to the present study, which demonstrated an increase
in TI/TTOT.
Figure 6—The apnea hypopnea index for subjects with an AHI >1/hr
is shown as a function of REM cycles across the course of the night.
The boundaries of the boxes indicate the 25th and 75th percentiles,
the line within the boxes marks the medians, the whiskers indicate
the 90th and 10th percentiles, and the points represent the outliers.
increased REM density in younger children, although this was
only significant for the first and third REM cycles. Hoffman et
al24 evaluated REM density in a small sample of females which
included 2 prepubertal and 6 pubertal adolescents, and noted
increased REM density in the prepubertal compared to the pubertal subjects. We found no relationship between age and REM
density when evaluating a younger group of children, although
there was a slight trend towards an increased REM density in
younger children when only school-aged children were evaluated. Thus, in young children, there is no correlation between
REM density and age.
The subjects in the current study had sleep architecture similar
to that of a large, somewhat younger, normal population recently
reported by Montgomery-Downs et al,25 with a similar total sleep
time (459 minutes in the current study compared to 472-475 minutes in the Montgomery-Downs study), a similar percentage of
REM sleep (20% in the current study compared to 20%-21% in
the Montgomery-Downs study), and a similar number of REM
cycles. This is not surprising, as many studies have shown no difference in sleep architecture between children with OSAS and
normal controls,5 or children with OSAS before and after treatment.26,27 The duration of REM cycles across the night increased
in the current study, similar to that reported by MontgomeryDowns. However, the Montgomery-Downs study did not evaluate REM density.
Apnea Hypopnea Index
A previous study showed an increase in the REM AHI in the
last third of the night compared with the first third of the night.5
In that study, the night was arbitrarily divided into thirds, and
only the first and last thirds of the night were evaluated, i.e., there
was no evaluation of the intervening third. In contrast, the current study used sophisticated analytic techniques to evaluate the
entire night. Although the current study found that the number of
REM obstructions was greater during the last third of the night
compared to the first third, when the intervening REM cycles
SLEEP, Vol. 30, No. 7, 2007
841
REM Density in Children—Karamessinis et al
Limitations
9.
It should be noted that polysomnograms were terminated at
06:00, due to laboratory scheduling issues. It is likely that some
children would have had more REM cycles if they had been allowed to sleep until spontaneous awakening. However, total sleep
time, proportion of REM time, and the number of REM cycles
were similar to those previously reported for a large cohort of
normal children,25 so it is unlikely that this had a major impact on
our results.
Children with OSAS may have a pattern of persistent partial
upper airway obstruction associated with hypercapnia, rather then
discrete obstructive events. This has been termed obstructive hypoventilation.18 We did not analyze the relationship between hypercapnia and REM density, as this would have required analyzing the end-tidal PCO2 on a breath-by-breath basis. Future studies
of this relationship would be of interest.
10.
11.
12.
13.
14.
15.
Conclusions
16.
In conclusion, we have shown that REM density and the duty
cycle (TI/TT) increase across REM cycles during the night in
children. Despite this, the degree of obstructive apnea does not
change significantly across REM cycles.
17.
18.
ACKNOWLEDGMENTS
Dr. Marcus was supported by NIH grants #HL58585, MO1RR-000240 and U54 RR023567 and research support from Respironics, Inc. that funded a research technician. Dr. Mason was
supported by K23 RR16566.
We thank all of the Children’s Hospital of Philadelphia sleep
laboratory technologists who helped conduct this study. We are
grateful to the children and their families for their enthusiastic
participation in this study.
19.
20.
21.
22.
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