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Central nervous system maturation in the stressed premature.

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Central Nervous System
Maturation in the Stressed Premature
Gregory L. Holmes, MD, William J. Logan, MD, Barry V. Kirkpatrick, MD, and Edwin C. Meyer, MD
The developmental sequence of sleep cycles has been found to be a useful index of central nervous system maturation in premature infants. To determine the effects of severe reversible stress on the maturation of sleep cycles, 6- to
8-hour sleep studies were done on 10 premature infants with severe hyaline membrane disease (HMD) and 10
healthy premature babies. The studies were done in the neonatal intensive care unit and included patients from 30
weeks’ gestation to term and in all stages of the disease.
Prior studies were confirmed showing that percentage of quiet sleep increases, transitional sleep changes little,
and active sleep decreases from 30 weeks’ gestation to term. In infants with severe HMD, the percentage of quiet
sleep was less and active sleep higher than in unstressed infants of similar age who acted as controls. Once the
infants recovered from HMD, sleep patterns became similar to those found in the control group. These data suggest
that when respiratory distress occurs in the premature infant, there is a transient delay in central nervous system
maturation as measured by sleep cycle analysis.
Holmes GL, Logan WJ, Kirkpatrick BV, et al: Central nervous system maturation in the stressed premature.
Ann Neurol 6:518-522, 1979
Physicians working with premature infapts have endeavored for many years to develop a means of assessing neurological maturation. Recent studies suggest that sleep state evolution correlates well with the
neurophysiological changes in maturing brain. Since
premature and full-term infants spend most of their
time asleep, it is an excellent aspect of behavior to
Aserinsky and Kleitman in 1955 [ l , 21 observed
that sleeping infants alternate between quiet periods
and periods of body movements associated with eye
movements. Shortly thereafter, Dement and Kleitman [4] described a state of sleep in adults characterized clinically by rapid eye movements (REM) and
body movements concomitant with a low-voltage,
rapid-rhythm electroencephalogram (EEG), and observed that most dreaming occurs in this sleep
state. Roffwarg et a1 [16], Dreyfus-Brisac [5], and
Dreyfus-Brisac and Monod [7] have described similar
sleep states in neonates. Roffwarg e t al [16] noted
that REM sleep constitutes about 50% of total sleep
time in the full-term infant, in contrast to 20% in the
adult. Parmelee et a1 [13, 141 further delineated the
clinical and electroencephalographic features of sleep
in neonates: quiet sleep is characterized by few body
movements, regular heart and respiration rates, no
eye movements, and an active chin electromyogram
(EMG), while active sleep is marked by frequent
small movements of the limbs and face, REM, irregular respirations and heart rate, and minimal chin
EMG activity. The EEG in active sleep consists of a
low-amplitude continuous tracing, while quiet sleep
is characterized by a discontinuous or track alternant
pattern. Parmelee et a1 [ 141, studying infants at various gestational ages, found that as an infant approaches term, the percentage of sleep time spent in
active sleep decreases and quiet sleep increases.
In view of these findings one can concur with Stern
e t a1 [20] and Watanabe et a1 [221 that sleep state
maturation is a useful index of brain maturation.
Maturation of sleep state with increasing gestational
age has also been demonstrated in other mammalian
species [ 11, 19, 2 13. Members of mammalian species
with primarily postnatal brain development (i.e., cat,
rat, and rabbit) exhibit only active sleep immediately
postpartum; quiet sleep appears later, when maturation of the cortical network is achieved. By contrast,
both quiet and active sleep are present immediately
postpartum in mammalian species born with a welldeveloped central nervous system (i.e., guinea pig
and lamb).
Little work has been done t o date on the effects of
reversible stress on the maturation of sleep cycles in
premature infants. This study monitored the effects
From the Department of Neurology, University of Virginia School
of Medicine, Charlottesville, VA, the Division Of
Hospital for Sick Children, Toronto, Ont, Canada, and the Departments of Pediatrics and Neurology, Medical College of Virginia, Richmond, VA.
Accepted for publication Apr 22, 1979.
Address reprint requests to D~Holmes, Department of Pediatrics
and ~
~university ~of connecticut
~ center, Fl ~ ~ - ~
mington, CT 06032,
518 0364-5134/79/120518-05$01.25 @ 1979 by Gregory L. Holmes
of hyaline membrane disease ( H M D ) o n brain maturation using sleep cycle development as an index of
brain maturation.
Forty-eight 6- to 8-hour sleep studies were done on 10
normal growing premature infants and 10 premature infants with severe HMD. Five infants from each group had
at least three serial studies, with monitoring begun during
the first week of life and continued for every two weeks
until discharge.
Gestational age was determined for all infants by the
method outlined by Dubowitz et al [8]. Severe H M D was
defined as: (1) ground-glass appearance on chest roentgenoqams, with air bronchograms; (2) arterial oxygen pressure
below 50 mm Hg at an inspired oxygen concentration
above 80%; and (3) need for continuous positive airway
pressure or ventilatory assistance for at least 24 hours. N o
infants with a one-, five-, or ten-minute Apgar score below
6 were used in the study. Infants with proved sepsis, prolonged periods of hypoxia, or other major medical problems were not studied. Data from infants who died were
not used. All infants had normal neurological examinations
at the time of discharge from the newborn unit.
All testing was done in the newborn intensive care unit
and included infants of gestational age 30 weeks to term in
all stages of respiratory distress. Infants requiring mechanical ventilation were included in the study. After permission
was obtained from the parents, the patient had a minimum
of 8 scalp and 2 mastoid electrodes applied in a modification of the 10-20 system [23]. Silver cup electrodes filled
with saline jelly were fixed to the scalp with collodion.
Small cup electrodes were applied to the outer canthi of the
eyes for recording the electrooculogram (EOG). Heart and
respiration rate were recorded from needle electrodes
applied to the chest. Respiration was also recorded from a
thermistor placed across the nostrils except in infants with
nasal tracheal tubes. Movement was detected by 2 electrodes placed on the infant’s leg. Recordings were done on
a Grass EEG/polygraph and included a four-channel EEG,
two-channel EOG, one or two channels for respiration, and
one channel each for heart rate and movement (technical
information is available from the authors on request).
Paper speed varied from 3.6 to 30 mm per second. All
visually observed changes of behavior were noted on the
recording paper.
Each 25 seconds of recording was analyzed using a
method similar to that of Parmelee et a1 [14]. Sleep was
coded as active if any four of the five following criteria
made up more than 50% of the 25-second epoch: (1) an
EEG with either a mixed pattern (both high-voltage slow
and low-voltage polyrhythmic components with little periodicity) or a low-voltage (14 to 35 pv), irregular pattern
dominated by theta and delta activity; (2) rapid eye movements; (3) trunk or body movements; (4) irregular respirations; and (5) irregular heart rate. The epoch was
classified as quiet sleep if any four of the five following
criteria made up the majority of the 25-second epoch: (1)
in infants below 34 weeks’ gestational age, an EEG showing
a discontinuous pattern; in infants older than 34 weeks’
gestational age, a trace alternant pattern with bursts of
high-voltage slow waves (0.5 to 3 Hz) with superimposed
low-voltage rapid waves and sharp waves lasting 3 to 8
seconds or a high-voltage slow, moderately rhythmic
(0.5 to 4 Hz), high-amplitude (50 to 150 pv) pattern; (2) no
eye movements; (3) no trunk or body movements; (4) regular respirations; and (5) regular heart rate. Epochs that did
not fit either category of active or quiet sleep were considered transitional. The infants were coded as awake if their
eyes were open. The percentage of total time spent in each
sleep state during the recording period was calculated for
each infant.
The average gestational ages in the two groups at the
time of the sleep study w e r e similar: 35.3 weeks for
t h e normal infants, 34.0 weeks for those with H M D .
The mean percentages of sleep spent in the differe n t sleep states were compared between the HMD
group and t h e normal growing premature infants.
The infants with HMD had significantly m o r e ( p S
0.05) active sleep and significantly less ( p < 0.02)
quiet sleep than t h e normal growing premature
babies (Table 1). There was n o significant difference
between amounts of transitional sleep. W h e n the
sleep studies are subdivided according t o the infants’
gestational ages at the time the study was done,
changes of sleep state with maturation become evident. Figure 1A shows that in the normal growing
premature babies, the percentage of time spent in
active sleep declines with increasing gestational age.
In the group with severe HMD a t the time of the
recording, active sleep also decreases with increasing
gestational age except in infants older than 38 weeks.
Figure 1B shows increasing quiet sleep with greater
gestational age in the normal group. The HMD
Table 1. Comparison of Sleep State Percentages in Normal Premature
Infants and Premature lnfants with Hyaline Membrane Diseasea
Sleep State
Normal Premature Infants
Infants with H M D
55.7 ? 3.60
24.4 2 3.16
19.8 2 2.68
66.3 ? 3.32
13.6 2 2.67
20.0 ? 1.46
p S 0.05
p s 0.02
aValues are means f standard error.
HMD = hyaline membrane disease; NS = not significant.
Holmes et al: CNS Maturation in Stressed Premature
“Norrnol” Growing Remature
H M D-Smwre Dimaim
pIS .01
Percentage 6o
Time in
Active Sleep 5o
ps ,0025
Time in
Quiet Sleep
group did not have a similar steplike rise in quiet
sleep at increasing gestational age. Transitional sleep
changed little with gestational age, and no differences
were found between the H M D group and normal
premature babies. At all ages studied, infants with
H M D had more active sleep and less quiet sleep than
the controls, though this result was not always statistically significant.
It was unusual for an infant to have H M D persist
until 38 weeks’ gestational age. In Figure 1, the high
amount of active sleep and low amount of quiet sleep
in the H M D group older than 38 weeks is based on
only one infant. The infant did fit the protocol, however, and he recovered at age 4 2 weeks and was subsequently discharged with a normal neurological examination.
Infants with H M D who had recovered at the time
of the study were then compared with the normal
group (Table 2). Recovery was defined as requiring
no supplemental oxygen or ventilatory assistance. No
infants at 3 0 to 32 weeks’ gestational age had recov-
520 Annals of Neurology
Gestational Age (weeks) at Time of Study
F i g 1 . Percentage of sleep spent i n (A)active sleep and (B)
quiet sleep at gestational ages 30 weeks to term among normal
premature babies and infants with hyaline membrane disease
(HMD). (The number ofpatients is given in parentheses;
standard error is indicated.)
ered from H M D at the time of the study. Although
the sleep cycles continued to be slightly immature
after recovery, in only one comparison were the differences between groups of statistical significance.
The number of patients is small, but it appears that
once the infant recovers from HMD , the sleep cycles
begin to mature and approach those of the normal
premature baby.
Two examples of serial sleep studies are given in
Figures 2 and 3. Figure 2 shows four studies from a
normal growing premature baby, Figure 3 , five studies from an infant who had severe H M D until age 36
weeks. Once the infant came off the ventilator, there
Vol 6 No 6 December 1979
Table 2. Comparison of Percentage of Active and
Quiet Sleep in Normal Premature Infants and
Premature Injants Who Had Recovered from H M D a
63.3 ? 11.00
60.5 ? 6.44
59.8 5 2.53
49.2 t 5.61
44.8 f 3.05
(3) . . .
( 4 ) 62.5 t 19.0 ( 2 )
(4) 56.4 2 0.40 ( 2 )
( 6 ) 56.1 2 3.80 ( 2 )
( 5 ) 57.4 f 1.20 ( 2 )
of Sleep
t 1.05
"Values are means
17.4 t 17.35
28.7 t 4.53
29.0 t 3.62
Age (weeks) at Time of Study
Fig 2. Sleep state changes with age i n a normal premature infant.
* standard error. Number of studies is given in
Active Slsspb
Ouiet Sleep 0
HMD = hyaline membrane disease. NS = not significant.
was fairly rapid progression to a more mature sleep
During the last trimester of pregnancy the brain
changes rapidly, with marked glial proliferation and
neuronal maturation, organization, and myelination
[3]. However, current methods used to assess nervous system function in premature infants is limited
[lo]. The evolution of sleep cycles appears to be dependent only on brain maturation; for example, birth
weight has been shown to have little effect on EEG
and sleep cycle development [6]. This relationship
appears to be time-locked to gestational age, as Parmelee et a1 [ 131 could accurately estimate gestational
age from a subject's EEG tracing. The maturation of
the EEG and sleep cycles is similar in both preterm
infants who reach term after a long period of extrauterine existence and those born near term [9, 131.
Our studies of sleep cycle maturation in normal
growing premature babies support those studies,
demonstrating that as the infant approaches term,
there is increasing quiet sleep and decreasing active
or REM sleep [141.
Although some work has been done on sleep cycle
maturation in hypoxic infants [ 12, 221, infants of diabetic mothers [ 181, infants with hyperbilirubinemia
[ 151, infants born to heroin-addicted mothers [ 171,
and high-risk infants [ 171, few studies have been
performed on neonates with transient, reversible ill-
Percentage 50
of Sleep
Intuboted, on ventilator
Age (weeks) at Time of Study
F i g 3. Sleep state changes with age i n an infant with severe
hyaline membrane disease.
ness. In this study, premature infants with the severe
stress of H M D exhibited altered sleep cycle patterns
during the acute phase of their illness when compared with unstressed matched controls. During the
severe phase of the disease the sleep cycles of the
stressed infants had a more immature pattern than
those of their normal counterparts matched for gestational age. Sleep cycles in these stressed prematures became similar to those of the control group
when the patient recovered from HMD. This work
emphasizes the value of sleep cycle development as a
means of following cerebral maturation in preterm
in fan ts .
Holmes et al: CNS Maturation in Stressed Premature 521
Presented in part at the Seventh Annual Meeting of the Child
Neurology Society, Keystone, CO, September 1978.
The authors are indebted to Dr John Slevin for suggestions and to
the nursing staff of the Neonatal Intensive Care Unit at the Medical College of Virginia.
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Vol 6 No 6 December 1979
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central, stresses, nervous, maturation, system, prematurely
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