Apneic
Spells
and Sleep
States
in Preterm
Infants
M. Gabriel, M.D., M. Albani, M.D., and F. J. Schulte, M.D.
From the Department of Pediatrics, University of Gottingen, GOttingeti. West Geniiani,
ABSTRACT. The incidence of apneic spells during different
sleep states, active sleep, quiet sleep, and undifferentiated
sleep was determined in eight preterm infants of 30 to 35
weeks’ conceptional age, by means of a polygraphic
recording technique. They were free of perinatal and
post-natal complications other than apnea. During their active or
rapid eye movement (REM) sleep they showed significantly
more apneic episodes which were also longer lasting and
they were accompanied by bradycardia of a greater severity.
The organization of the immature nervous system with a
preponderance of inhibitory synaptic connections and the
additional inhibition of spinal motoneurons during REM
sleep are likely to be the cause of apneic spells in otherwise
“normal” preterm infants. Pediatrics, 57:142-147, 1976,
NEONATE, APNEA, RESPIRATION, SLEEP.
Bryan and Bryan’ recently described thoracic wall instability in newborn infants during active or rapid eye movement (REM) sleep. In 86% of
preterm infants of less than 37 weeks’
conception-al age Fenner et a!.2 observed periodic breathing
which occurred most frequently while the babies
were in REM sleep. Daily et al.3 found apneic
spells occurring when respiration was periodic,
from which one can assume that the infants were in active sleep.
There is ample evidence from both animal experiments’ and studies in human infants5 that spinal motoneurons are subjected to strong descending inhibitory influences during active sleep. If-as is to be expected-respiratory moto-neurons are included in this inhibition, the main-tenance of regular respiration must be more
difficult during active than during quiet sleep. As
preterm babies spend a much longer time asleep and a much higher percentage of this time in active or HEM sleep than older infants,67 REM
sleep inhibitory mechanisms on respiratory
motoneurons may play an important role in the
preterm baby’s difficulties in breathing.
Thus, in this study the distribution of 493
apneic spells between active or REM and quiet or non-REM sleep was investigated in eight infants
by means of a polygraphic monitoring
tech-nique.
METHODS
Subjects
Eight preterm infants of a gestational age range of 28 to 34 weeks and birthweights between 990 and 2,100 gm were investigated at a conceptional age (gestational age plus age from birth) of 31 to 35 weeks (Fig. 1) with postnatal age varying between 2 and 48 days. The gestational age was calculated from the first day of the mother’s last
menstrual period until birth. Infants were
included in this study only when their mothers were certain about their last menses and when the
Dubowitz et a!.’ score revealed a similar
conceptional age estimate. The infants were care-fully selected on the basis that the pregnancy, birth, and postnatal period were uneventful, except for the premature delivery. Only one infant had a bilirubin level of 14.4 mg/100 ml, probably due to heavy bruising of the lower extremities during delivery; in this instance an exchange transfusion was performed. Neurolog-ical and physical examinations in the postnatal period and at the time of discharge were appro-pnate for conceptional age. On each baby one to four polygraphic recordings were performed with a total of 19 investigations.
Recording Technique
A polygraphic sleep recording of two to four
(Received March 26; revision accepted for publication June
5, 1975.)
Supported by grant SFB 33 from the Deutsche
Forschungs-gemeinschatt.
ADDRESS FOR REPRINTS: (MG.)
weeks
I
asP.28 29 30 31 32 33 34
S I I I
-n
.
..
I-
#{149}
F
.
3969
62
-. 53
101
-. 99
26
F
#{149}
44FIG. 1. Gestational age and age at time of recording (closed circles). a.sp. = total of apneic
spells recorded for each preterm infant.
hours in duration was obtained from each baby lasting for about two interfeeding intervals.
During the recording the infants were kept under
the usual incubator conditions at neutral
temper-ature and breathing room air. Polygraphic
record-ings were done on an eight-channel Schwartzer EEG machine and consisted of (1) respiration,
registered by a thermistor attached to the infant’s
nose and, additionally, by carbon dioxide
estima-tion via a tube in the epipharyngeal space; (2)
heart rate, recorded by conventional
electrocar-diogram; (3) facial and body activity, contin-uously observed during the recording and
mdi-cated by a code on the paper write-out; (4)
observed rapid eye movements, registered by a
push-button device; (5) EEG, recorded with
silver/silver-chloride stick-on electrodes in a
montage of four bipolar leads from bilateral
frontocentral and frontotemporal regions. The
electrode resistance was about 4 to 5 kohms; time
constant, 0.3 second with a high frequency filter
at 70 c/sec.
Visual Analysis of Polygraphic Recordings
All records were visually analyzed
page-by-page (20-second epoch):
Respiration-Respiration was counted and the
ratio of the longest/shortest breath-to-breath
interval was calculated for each 20-second epoch
as an indicator of respiratory regularity. Pauses of
more than ten seconds were coded as apnea. Most
of the apneic spells ceased spontaneously and
some were terminated by manual stimulation;
none of them required artificial ventilation.
Heart Rate-Preceding each apneic episode,
the heart rate was calculated and a decrease of at
least 10% during the apneic episode was indicated as cardiac slowing; a heart rate of below 100 beats per minute was coded as bradycardia.
EEG-The maturational changes in EEC
patterns during sleep in preterm infants were first described by Dreyfus-Brisac.’ According to a
special EEC pattern coding system, introduced
by Parmelee et aL” and extended by Schulte et
steep state mm S 0 /. S 0
AS
Q
SUDS
138 ± 41
37 14
30 ± 7
65 8
18 ± 4
15 8
FIG. 2. Mean and SD (minutes and percentage) for each active or REM sleep (AS), quiet sleep
(QS), and undifferentiated sleep (UDS) calculated from 19 polygraphic recordings of eight
preterm infants.
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x x
. .
x x
x .
x x
x S
80 AS
x
60
40
20
s/S
ioo
80
QS
60
40
20
S/. 100
80
UDS
60
40
S x #{149}
20 ,#{248}x:x:.:.xxe:x: f
record - number
FIG. 3. The distribution of apneic episodes of more than ten seconds in duration during AS, QS,
and UDS. The percentage of total sleep time (X) is compared with the percentage of apneic
episodes (closed circles) occurring during a given sleep state. Individual figures are given for each
of the 19 recordings as well as for the mean and SD calculated from all recordings.
S = significant at the P < .001 level.
0/0 100 . .
.
. .
. o T S.
, x x X
x x
x
xXXXIXI:X
I
.-,---. ...#{149}.
-
_._., . . ..,‘. 1#{149}1 i.i#{149}.a!.,” the EEC pattern predominant within each 20-second epoch was identified. Thus, we were able to recognize special EEC patterns indicative for active or REM sleep and others indicative for quiet or non-REM sleep.
Definition of Sleep States
Three subsequent 20-second epochs were combined for the identification of sleep states, which were defined as follows:
Quiet Sleep-Paroxystic EEG with long-lasting
bioelectric blackouts without any rapid eye movements.
Active Sleep-Non-paroxystic although fre-quently discontinuous EEC with rapid eye move-ments and/or body movements.
Every one-minute sleep-epoch which could not thus be identified as either active or quiet sleep was classified as undifferentiated sleep.
RESULTS
Nineteen polygraphic investigations of eight
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sleep
state
actual
- ratio ofa.sp.
estimated records (n)
AS
Q
S
UDS
129 ± 0.17 S. 0.
0.42
0.22
S. 0.
1.03 0.46 S. 0.
19
11
15
FIG. 4. In 19 recordings of eight preterm infants during AS an excess of 29% apneic spells (asp.)
occurred in respect to what was estimated from the AS proportion of total sleep time. During QS
in eight recordings, no apneic spells were observed. In the remaining 1 1 recordings only 42% of
the apneic spells were encountered from what was estimated on the basis of QS proportion of
total sleep time. During UDS the actual incidence and the estimate of apneic spells was almost
identical.
infants gave a total of 3,971 minutes of recording
time with 209 ± 53 minutes per record.
Sixty-five percent of the time was spent in clearcut
active or REM sleep, 18% in quiet sleep, and 15%
in imdifferentiated sleep (Fig. 2). Regularity of
respiration indicated by the longest/shortest
breath-to-breath interval ratio was significantly
greater in quiet sleep than in active sleep with
ratios of 2.29 ± 2.01 and 4.48 ± 3.09
respective-ly.
A total of 493 apneic spells were recorded, with
a mean of 26 per record and a range between 6
and 76. The duration of the apnea varied from 10
to more than 60 seconds with cardiac slowing in
65%. Only in two recordings of two different infants, both older than four weeks postnatal age, did all the apneic spells last less than 20 seconds. Cardiac slowing occurred in 198 out of the 370 short apneic spells with a duration of 10 to 20 seconds and in 51 of these apneic episodes heart rate fell below 100 beats per minute.
Seventy-nine percent of the 493 apneic spells occurred during active sleep (65% of total sleep time), only 6% during quiet sleep (18% of total sleep time), and 15% during undifferentiated sleep (15% of total sleep time) (Fig. 3). A signifi-cant excess of 29% ± 17% more apneic spells occurred during active sleep than was to be
sleep
state
apnoeic
spe
I Is
(n)
totaL
with
with
cardiac slowing bradycardia
AS
Q S
UDS
390
29
74
252
15
41.
103
(61)
4 (27)
16
FIG. 5. Number of apneic spells with cardiac slowing (decrease in heart rate of more than 10%)
and with bradycardia (heart rate below 100 beats/mm) in respect to different sleep states.
Numbers in parentheses = bradycardia/cardiac slowing X 100.
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Sleep
state
apnoeic
spells(n)
total <2Osec 20-39sec 4Osec
AS
QS
UDS
390
29
74
294
25
51
74
4
13
22
-10
FIG. 6. Number of apneic spells of different durations in respect to different sleep states.
expected from the active/total sleep ratio. Very few apneic spells occurred during quiet sleep. In eight recordings from four infants no apneic spells
were encountered during well-defined quiet sleep
states. In the remaining 1 1 recordings the
mci-dence of apneic episodes during quiet sleep reached only 42% ± 22% of what was expected from the quiet/total sleep ratio. The appearance of apneic spells during undifferentiated sleep showed no significant deviation from the expected value, although four recordings did not
show any episodes in undifferentiated sleep (Fig.
4).
Cardiac slowing was more frequently observed with apneic spells during active sleep (65%) than during quiet sleep (52%). Furthermore, during active sleep in 41% of the apneic spells with cardiac slowing, pronounced bradycardia (heart rate below 100 beats per minute) occurred in comparison with only 27% during quiet sleep (Fig. 5).
Apneic spells of longer than 20 seconds in duration tended to be less frequent in quiet sleep than in other sleep states; the difference, however, was not significant. None of the 32 apneic spells lasting more than 40 seconds occurred during quiet sleep (Fig. 6).
DISCUSSION
Sleep States
The exact definition of sleep states in very immature preterm infants is rather difficult, for, in contrast to older infants and adults, differences in the EEC patterns are less striking, rapid eye movements under closed lids are often easily
missed, small body movements occur in both
sleep states, tonic chin muscle activity cannot
always be encountered during quiet sleep, and
respiration may remain irregular even when all
other parameters are indicative of quiet sleep.’2 We, therefore, defined sleep states according to two parameters which are the most reliable in this age group, i.e., EEC and eye movements.
Regu-larity of respiration, although not used as a
parameter for the definition of sleep in this study, was nevertheless well in agreement with the identification of either well-defined active sleep or quiet sleep. Furthermore, the distribution of sleep states found in this study is similar to that reported in the literature.7
Apneic Spells
The frequency of apneic spells in preterm infants depends on how they are defined. It is noteworthy that apnea of more than 10 seconds in duration occurred in each of our eight infants and many times in each of our 19 polygraphic record-ings. The incidence of such apneic spells has not yet been reported for otherwise “normal” infants of 30 to 35 week’s conceptional age. In Daily et
al.’s study,’ six out of 12 low-birthweight infants without other perinatal or postnatal complica-tions had apneic spells of more than 20 seconds in duration. Our method of long polygraphic
mom-toring appears to reveal more apneic episodes than previously reported, even if we only rely on those longer than 20 seconds.
Since pronounced bradycardia does occur in apneic spells of 10 to 20 seconds in duration, we included all apneic episodes longer than ten seconds. Respiratory pauses of less than ten seconds in duration are usually thought to be of no pathological significance as they are not connected with bradycardia.2- ‘
REM Sleep and Apnea
more often, they are more frequently connected
with cardiac slowing and severe bradycardia, and
they tend to be longer lasting during active than quiet sleep. These findings can be explained by
the well-known inhibitory influences acting on
spinal motoneurons and primary afferents during
active or REM ‘ Whereas during active
sleep small and insignificant muscle twitchings
frequently occur as an expression of the brain
stem noise,’’ all major motor activity is success-fully inhibited. This inhibition, in all groups,
interferes with proprioceptive reflex control of
intercostal muscles and probably with other affer-ents involved in regulating ventilation and,
there-fore, with respiration which becomes irregular
with short pauses.
COMMENT
In the premature baby the inhibition of
respi-ratory motoneurons during REM sleep becomes
particularly effective for two reasons: (1) The
more immature the infant the more time it spends
in active sleep and only few epochs can be
regarded as clearcut quiet sleep. From 32 weeks’
conceptional age to three months after term, the
percentage of quiet sleep increases from about
20% to about 60% of total sleep time.’-
Further-more, during the same maturational period total
sleep time decreases from over 18 to about 14
hours per day. Thus, the time the baby is obliged
to overcome REM sleep inhibition of spinal
respiratory motoneurons becomes much less with
increasing age and maturity. (2) One of the most
important morphological features of central nervous system immaturity is the lack of dendritic arborization and axodendritic synaptic
connec-tions.’5 Thus, we have to assume that synaptic
excitatory drive on respiratory neurons in both brain stem and spinal cord is much weaker in preterni than in term infants. Furthermore,
axoso-matic synaptic connections tend to be more
inhibitory than excitatory and thus exhibit a powerful control of neuronal cell activity.’ In preterm infants, this inhibition is enhanced because of the small overall synaptic connections due to minor arborization.
As a result of these morphological events
during maturation, it is difficult for the preterm infant to maintain a strong excitation of
respira-tory neurons over a long time or with a regular
recurrence rate.
The rhythmic excitation of respiratory neurons, the maintenance of this excitation over a certain period of time to allow a full inspiration, and finally the synchronization of a large motoneuron
pool to guarantee strong muscle power have to
counteract inhibitory mechanisms, which are the
stronger the more immature the infant is. For
reasons based on both structure and function of
the normal but immature brain, it is
understand-able that even without additional risk factors the preterm infant often fails to breath and that it
fails more frequently in active or REM rather
than in quiet sleep.
REFERENCES
1. Bryan AC, Bryan MH: Respiratory control in newborn
infants. Read before the Congress for Perinatal
Medicine, Berlin, 1974.
2. Fenner A, Schalk U, Hoenicke H, ci’ at: Periodic
breathing in prelnattire and neonatal babies:
mci-dence, breathing pattern, respiratory gas tensions,
response to changes in the composition of ambient
air. Pediatr Res 7: 174, 1973.
3. Daily WIR, Klaus M, Meyer HBP: Apnea in premature
infants: Monitoring, incidence, heart rate changes,
and an effect of environmental temperature.
Pediat-rics 43:510, 1969.
4. Pompeiano 0: Muscular afferents and motor control
during sleep. In, Granit R (ed):Muscular Afferents
and Motor Control. Stockholm, Almquist &
\Viksell, 1966, l 415.
5. Prechtl HFR, Viach V, Lenard HG, Kerr-Grant 1):
Exteroceptive and tendon reflex in various
behav-ioral states in the newborn infant. Biol Neonat
11:159, 1967.
6. Roffwarg HP, Mnzio IN, Dement WC: Ontogenetic
development of the human sleep-dream cycle.
Science 152:604, 1966.
7. Parmelee All, Wenner Wil, Akiyama Y, ci’ at: Sleep
states in prelnature infants. Dev Med Child Neurol
9:70, 1967.
8. Dubowitz LMS, Dubowitz V, Goldberg C: Clinical
assessment of gestational age in the newborn infant.
J Pediatr 77:1, 1970.
9. Dreyfus-Brisac C: The electroencephalogram of the
premature infant. World Neurol 3:5, 1962.
10. Parmelee AH, Schulte FJ, Akiyama Y, et at: Maturation
of EEG activity during sleep in premature infants.
Electroencephalogr Clin Neurophysiol 24:319, 1968.
11. Schulte FJ, Michaelis R, Nolte R, et at: Brain and
behavioural maturation in newborn infants of
diabetic mothers: I. Nerve conduction and EEG
patterns. Neuropaediatrie I :24, 1969.
12. Dreyfus-Brisac C: Ontogenesis of sleep in human
prenia-ture after 32 weeks of conceptional age. Dcv
Psychobiol 3:91, 1970.
13. Avery ME: The lung and its disorders in the newl)orn
infant. In, Major Problems in Clinical Pediatrics, ed
3. Philadelphia, WB Saunders Co, 1974, vol 1.
14. Prechtl HFR, Lenard HG: A study of eye movements in
sleeping newborn infants. Brain Res 5:477, 1967.
15. Purpura DP, Schade IP: Growth and maturation of the
brain. In, Progress in Brain Research. Amsterdam,
Elsevier Publishing Go, 1964, vol 4.
16. Eccles IC: The Inhibitory Pathways of the Central
Nervous System. Liverpool, Liverpool University
Press, 1969, pp 101-104.
ACKNOWLEDGMENT
We wish to thank Miss L. Michaelis, Mr. P. Patzig, and
Mr. H. %Vulbrand, without whose skillful technical assistance
this study could not have been completed.
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1976;57;142
Pediatrics
M. Gabriel, M. Albani and F. J. Schulte
Apneic Spells and Sleep States in Preterm Infants
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1976;57;142
Pediatrics
M. Gabriel, M. Albani and F. J. Schulte
Apneic Spells and Sleep States in Preterm Infants
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