Cardiorespiratory Functioning of
Preterm Infants: Stability and Risk
Associations for Measures of
Heart Rate Variability and
Oxygen Saturation
JANET A. DIPIETRO
MARGARET O’BRIEN CAUGHY
Department of Maternal & Child Health
Johns Hopkins University
Baltimore, Maryland
REGINA CUSSON
Sclzool of Nursing
University of Maryland at Baltimore
Baltimore, Maryland
NATHAN A. FOX
Institute f o r Child Study
University of Maryland
College Park, Maryland
Cardiorespiratory measures are used with increasing frequency to assess individual differences in development in full-term and preterm infants, yet little information exists concerning the stability of these measures
or their relations to each other. This study assessed three common cardiac measures (heart period, heart
period variability, and vagal tone) and two measures of arterial oxygenation based on pulse oximetry (mean
pulse oxygen saturation and variability) in a sample of 35 preterm infants. Data were collected on five
occasions: on 3 consecutive days in the early neonatal period, at 34 weeks postconceptional age, and at
discharge. Results indicate both short-term and longer term stability for all cardiac measures. Oxygen
saturation demonstrated only short-term stability prior to 34 weeks. Mean heart period was positively
associated with both measures of heart period variability at each assessment point, while mean oxygen
saturation level was inversely related to oxygen saturation variability. In addition, significant associations
between cardiorespiratory patterns and perinatal risk measures were found. It is concluded that these measures
reflect stable characteristics of neuroregulatory function in preterm infants. 0 1994 John Wiley & Sons, Inc.
Reprint requests should be sent to Janet A. DiPietro, Department of Maternal and Child Health, Johns
Hopkins University, 624 N . Broadway, Baltimore, MD 21205, U.S.A.
Received for publication 14 July 1993
Revised for publication 15 September 1993
Accepted for publication 20 September 1993
Developmental Psychobiology 27(3):137-152 (1994)
0 1994 by John Wiley & Sons, Inc.
CCC 00 12-1630/94/030137-16
138
DIPIETRO ET AL.
Research into psychophysiologic correlates of infant development is an established
and productive field of inquiry. In particular, the relation between infant cardiorespiratory functioning and development has been an active area of investigation. The first,
most traditional use of cardiorespiratory measures is to quantify relatively small, evoked
responses to stimuli (see Von Bargen, 1983, for a review). A second, related application
is to use cardiorespiratory measures to quantify responses to stressful or novel procedures over more prolonged time periods (e.g., DiPietro & Porges, 1991; Porter, Miller,
Cole, & Marshall, 1991; Porter, Porges, & Marshall, 1988). In a third application,
individual differences in baseline or tonic physiologic levels have been related to other
aspects of infant functioning, such as neonatal behavior (DiPietro, Larson, & Porges,
1987; Stifter & Fox, 1990), temperament and behavioral style (DeGangi, DiPietro,
Greenspan, & Porges, 1991; Kagan, Reznick, & Snidman, 1987),cognitive development
(Fox & Porges, 1985; Richards &Cameron, 1989), reactivity (DiPietro, Porges, & Uhly,
1992; Fox, 1989) and attachment (Izard et al., 1991). This approach assumes a trait
orientation to baseline cardiorespiratory functioning, implying that individual differences in these measures are stable over time and that they reflect core attributes of
centrally mediated infant neurologic function.
There are several ways to quantify baseline or reactive cardiorespiratory function.
These include measures involving either cardiac or respiratory activity only, or their
interrelation. Within each domain, several different methods have been reported. The
most common cardiac variables used are heart rate (number of beats per minute) or
heart period (interbeat interval), and variability in heart rate. Variability in heart rate
reflects the competing influences of the sympathetic and parasympathetic branches of
the autonomic nervous system, a5 well as more transient oscillations of direct neural
control (Cabal, 1987). Thus it is often considered an index of t h e functional integrity
of the nervous sytem. Variability in heart rate can be quantified as either short term
(i.e., beat-to-beat) or long term (i.e., range over time) and both are used. Because
variability in heart rate is a function of both neural and extraneural influences, some
investigators have developed measures which attempt to quantify only the variability
in heart rate that is neurologically mediated. Vagal efferents modulate the transient
acceleration of heart rate that occurs with inspiration and deceleration upon expiration
(i.e., respiratory sinus arrhythmia). Quantification of variation in heart period within
the frequency band associated with breathing has been developed and termed vagal
tone (V) by Porges (1983, 1985). Other techniques to quantify respiratory sinus arrhythmia have also been implemented (Richards, 1987), as have other methods of spectrally
analyzed variability (Zeskind, Goff, & Marshall, 1992).
Components of heart rate regulation develop postnatally. Although heart period
increases later in infancy, a decrease in heart period has been noted in the first weeks
of life in both full-term (Harper, Hoppenbrouwers, Sterman, McGinty & Hodgman,
1976) and preterm (Cabal, Siassi, Zanini, Hodgman, & Hon, 1980) neonates. Similarly,
heart period variability also increases during the first days or week postpartum (Cabal
et al., 1980; van Ravenswaaij-Arts et al., 1991a), a trend which is generally attributed
to stabilization or maturation of the autonomic nervous system. The development of
the vagus in humans has not been well documented, although postnatal neuronal maturation in the first 3 months has been established (Pereyra, Zhang, Schmidt, & Becker,
1 992).
Although measures of cardiac function have become commonly applied to developmental issues involving individual differences, there is little documentation of their
stability over time. Kagan et al. (1989) report correlations for heart period variance
ranging between .21 and .40 at three points between 14 and 32 months. One of the most
CARDIORESPIRATORY FUNCTIONING OF PRETERM INFANTS
139
comprehensive reports of this issue measured stability in vagal tone, heart period, and
short- and long-term heart period variability at four points under 1 year of age, beginning
at 3 months (Izard et al., 1991). Correlations ranged from .OO-.33 for HP, .OO-.34 for
long-term variability (heart period range), .06-.42 for short-term variability (heart period
variance), and from .13-.49 for vagal tone. In general, vagal tone demonstrated the
greatest stability as compared to the other measures, although it was not stable across
all intervals.
Findings concerning stability of psychophysiologic measures in older infants may
not apply to younger infants, given differences in maturity and developmental rates.
Neonatal physiologic functioning has been investigated in full-term neonates (e.g.,
Baldzer et al., 1989; DiPietro et al., 1987; Porter et al., 1988; Stifter & Fox, 1990). A
single published study on stability in these measures failed to document day-to-day
stability in heart period variability or vagal tone (Arendt, Halpern, Maclean, & Youngquist, 1991), although this conclusion may be limited by methodologic issues which
will be discussed subsequently.
Measurement of cardiac function as an index of neural status has particular relevance to populations of infants who are either medically compromised at birth andlor
who may be at-risk for developmental sequelae. Full-term infants who display anthropometric characteristics indicative of atypical patterns of fetal growth also demonstrate
less optimal patterns of heart rate variability (Zeskind, Goff, & Marshall, 1991). Preterm
neonates in general, and those with specific medical complications such as respiratory
distress in particular, have been reported to have reduced heart rate variability (Cabal
et al., 1980; Fox, 1983; van Ravenswaaij-Arts et al., 1991b) and V (Porges, 1983, 1992).
There are currently no published data on baseline stability in cardiac measures in
preterm infants. The transitional nature of the neonatal period, coupled with the unstable
medical course of preterm infants, limits generalizability from findings on older infants
to this population.
Physiologic studies of respiratory function in infants have often relied on quantifying
ventilatory activity (e.g., abdominal wall movements, tidal volume, and respiratory
rate). However, advances in technology have permitted more direct measurement of
respiratory function based on blood gas levels. Noninvasive methods of quantifying
blood oxygen levels include monitoring of transcutaneous oxygen tension (TcPO,) and
oxygen saturation (SpOJ. The former method quantifies the partial amount of pressure
exerted by oxygen on capillaries; the latter quantifies the proportion of hemoglobinbound oxygen in pulsatile arterial blood using photodetection techniques. This value
reflects the amount of oxygen available for tissue perfusion at any given time. Although
the measures are not clinically interchangeable, SpO, values are highly correlated with
TcPO, and with both oxygen saturation and partial pressure values collected directly
from arterial sampling (Hay, Thilo, & Curlander, 1991; Hay, Brockway, & Eyzaguirre,
1989). Pulse oximetry is a recent technology which has fewer undesirable characteristics
than TcPO, monitoring, in that it lacks the potential for cutaneous trauma, does not
require prolonged calibration, and is more responsive to rapid changes in saturation
values, and has quickly become standard care in most neonatal intensive units.
Much research on blood oxygen levels has been directed at evaluating infant condition during neonatal intensive care, including responsiveness to therapeutic interventions (e.g., Morrow et al., 1991). There is a relatively small, but growing literature
examining the development of blood gas regulation in early infancy. Mean levels of
TcPO, and SpO, increase as preterm infants near term (Mok et al., 1988), and they
continue to increase for full-term and preterm infants from birth through 6 weeks to 3
months of life (Hoppenbrouwers, Hodgman, Arakawa, Durand, Lk Cabal, 1991; Mok
140
DlPlETRO ET AL.
et al., 1986; Poets, Stebbens, & Southall, 1991). Both values are also state-dependent, with higher mean levels and greater variability in waking, as opposed to sleep,
states (Mok et al., 1988; Hoppenbrouwers et al., 1991). Episodic decrements in oxygen
saturation levels have been observed in preterm infants and their incidence decreases with advancing gestational and postnatal age (Poets, Stebbens, Alexander, et
al., 1991;Poets et al., 1992).Desaturations have also been observed but are less common
in healthy full-term infants, with little change noted over time (Stebbens, Poets, Alexander, Arrowsmith, & Southall, 1991). Although many of these studies have used a
longitudinal design, data concerning individual stability in blood oxygen levels or variability have not been presented.
Maintenance of homeostatic levels of oxygen and avoidance of chronic or episodic
hypoxemia is the primary goal in the development of respiratory regulation; thus these
measures may provide insight into individual differences in autonomic functioning in
the same way that cardiac measures have been applied. Little data exist concerning the
relation between cardiac measures and blood oxygen levels and reports are conflicting:
although one study reports a negative relation between heart rate variability and TcPO?
(Aarimaa, Kero, & Valimaki, 1985), another failed to detect any relation (van Ravenswaaij-Arts et al., 1991a). We propose that higher tonic levels of oxygen saturation
and fewer fluctuations in this level during undisturbed conditions are associated with
more optimal autonomic regulation in preterm infants. However, before oxygen saturation can be considered characteristic of individual functioning, documentation of stability over time is prerequisite.
This study was undertaken to document the stability and development of cardiorespiratory measures during the course of neonatal hospitalization in preterm infants. In
order to minimize the impact of both medical complications and procedures on examination of this issue, we selected relatively healthy preterm infants from a restricted
gestational age, and began assessing psychophysiologic function once their conditions
were stabilized. Stability was assessed over both the short-term (on 3 consecutive days)
and longer-term (through discharge from the hospital). In addition, an intermediary
assessment point standardized by postconceptional age (i.e., 34 weeks) was added
to ascertain whether postnatal or postconceptional maturation impacted stability of
physiological function.
From the range of methods for quantifying cardiac and respiratory function, we
selected three cardiac measures derived from electrocardiograph data that are common
in the literature and two measures of respiratory regulation based on pulse oximetry .
Cardiac measures included mean heart period, heart period variability, and Porges’
vagal tone (1985). Respiratory regulation was quantified in terms of oxygen saturation.
As with the cardiac measures, we calculated both mean SpO, levels and a measure of
SpO, variability.
This study was designed to explore the relations among different measures of
cardiorespiratory function and to investigate the following hypotheses:
1. Cardiorespiratory functioning will demonstrate short-term and longer-term stability in preterm infants;
2. Cardiorespiratory functioning will mature over the course of hospitalization; and
3. Cardiorespiratory function will vary based on risk status on the infant. Specifically, more compromised infants will display faster heart rate, reduced variability
in heart period, lower vagal tone, lower oxygen saturation, and increased variability in oxygen saturation.
CARDIORESPIRATORY FUNCTIONING OF PRETERM INFANTS
Table 1
Characteristics of Preterm Sample ( n
Perinatal measures
Gestational age (weeks)
Birth weight (9)
Ponderal index"
Days oxygen supplementation
Days mechanical ventilation
Hobel Scale at entry
Hobel Scale at discharage
Days neonatal intensive care
Maternal measures
Education (year)
Age
96 Public assistance
% Married
=
141
35)
Mean
SD
31.4
1487.4
2.2
2.4
2.6
39.7
48.5
18.6
1.3
230.0
.3
3.1
3.4
11.3
15.5
14.4
12.2
25.2
2.7
5.9
49%
26%
Range
39-33
1000- 1900
1.33-2.93
0-13
0-13
20-65
25-8 1
4-63
8-19
14-39
a The ponderal index, a weight-supine length ratio, is useful in ascertaining patterns of fetal growth. Ponderal index = birthweight (gm) x loo/
birth length ( ~ r n ) ~ .
Subjects
Subjects were 35 preterm infants recruited from a Level I11 NICU in a Universityaffiliated urban hospital. The research protocol was approved by the institutional review
board and parental consent was obtained for research participation. Subject selection
criteria included all infants born < 34 weeks gestational age, weighing between
1000-2000 g without any of the following conditions: major congenital anomalies, maternal intravenous drug use, surgery, medications with central effects, seizures, or persistent mechanical ventilation. Medical data were collected by chart review. In addition,
the Hobel Neonatal Scale (Hobel, Hyvarinen, Okada, & Oh, 1973), a cumulative risk
index, was scored upon entry into the study and again at discharge. Perinatal and
maternal characteristics of the sample are presented in Table 1 . Given the difficulties
in assigning gestational age to very preterm infants (DiPietro & Allen, 1991),gestational
age was based on a method of best estimate, which considered both obstetric and
postnatal data sources. This procedure relies on criteria for ascertaining gestational age
based on the following hierarchy: (a) maternal interview to ascertain recall of last
menstrual period date, (b) early sonogram (<I8 weeks), and (c) postnatal Ballard exam
administered within 24 hr postpartum by an experienced nurse or physician. For comparison purposes, the final gestational ages used were within t 2 weeks of the postnatal
exam date for 30 of the cases (no postnatal exam was performed in three additional
cases). Fifty-four percent ( n = 19) of the subjects were male. In addition to the medical
information presented in Table 1, the following conditions were present
in the sample: intraventricular hemorrhage [Grade 1 ( n = 611; respiratory distress
syndrome ( n = 8); patent ductus arteriosus ( n = 1); intrauterine growth retardation
( n = 1).
142
DIPIETRO ET AL.
Procedure
Infants entered the protocol when they were medically stable (determined by initiation of enteral feeding and discontinuation of all respiratory support) but still receiving
neonatal intensive care. Short-term stability data collection occurred at the same time
on 3 consecutive days, commencing approximately 20 min before a scheduled feeding.
Longer-term stability data were collected at 34 weeks postconceptional age, and again
on the day of discharge. Due to variability in infant schedules, it was not possible to
standardize the time of data collection on these 2 days in relation to the earlier data
points. All data collection began with the infants in a sleep state and continued for 15
min of undisturbed time.
Because both cardiac (Harper et al., 1976) and oxygen saturation (Mok et al., 1986)
values vary across behavioral states, state data were collected to ensure comparability
across recordings. State was coded every 30 s using Anderson’s 12-level Behavioral
State Scale (Gill, Behnke, Conlon, McNeely, & Anderson, 1988). This scale was designed for preterm infants and includes the following states: regular and irregular quiet
sleep; active and very active sleep; drowsy; alert inactive; quiet awake; active and very
active awake; fussing; crying and hard crying. Interrater training on state scoring took
place before the study began and was maintained during periodic reliability checks. A
total of thirty 15-min reliability trials yielded a reliability coefficient of .94, based on
exact matching of state score. Most physiological recordings were conducted when the
infants were in a period of predominantly active (REM) sleep. Based on the state data
collected, the percentage of time in active sleep for each recording period was: baseline
X = 97%; Day 2 X = 87%; Day 3 X = 89%; 34 weeks X = 94%; and at discharge
X = 85%. Most of the remaining time was in either quiet sleep or a drowsy state.
Because the episodes of states other than active sleep were brief and sporadic in nature,
it was not possible to separate the physiological data collected during these intervals.
However, given the small amount of time spent in these states relative to the proportion
of active sleep, the arithmetic influence of these other states on the overall physiologic
means calculated for the whole recording was relatively minor.
Physiologic Data Collection and Quant$cation
Continuous heart rate data were recorded on an FM tape recorder (Vetter model
C-4, Rebersberg, PA) from the infant’s existing ECG monitor. The data were digitized
off-line on software which detected the peak of the R wave for each heart beat and
quantified sequential R-R intervals in msec (i.e., heart periods). Heart period data were
edited to remove movement artifact. Heart period data were quantified as: (a) mean
heart period (HP);(b) heart period variability (HPV), quantified as the standard deviation
of the heart period divided by N - 1, where N is the number of sampled beats; and
(c) vagal tone (V). Vagal tone, or the amplitude of the respiratory sinus arrhythmia,
was computed using methods developed by Porges (1985) in patented MXedit software.
These steps include: (a) conversion of heart period into time-based data by sampling
in 200-msec intervals; (b) detrending of periodicities in heart rate slower than RSA with
a 21-point moving polynomial; (c) band-pass filtering to extract the variance of heart
period within the frequency band of spontaneous breathing in the neonate; and (d)
calculation of the natural logarithm of the band-passed variance, which served as the
estimate of vagal tone (V). Means of all cardiac values were computed in 15-s epochs
and the overall means derived from these values.
CARDIORESPIRATORY FUNCTIONING OF PRETERM INFANTS
143
Table 2
Short- Term Stability of Physiologic Measures
Days 1-2
Cardiac Measures ( n = 28)
HP
HPV
V
Oxygen Saturation ( n = 26)
SpOz level
SpOz variability
Episodic desaturations
Assessment Interval
Days 2-3
Days 1-3
.75***
.s7***
.71***
.73***
.37*
.51**
.70***
.49**
.70***
.62***
.48**
.14
.3 1 *
.47**
.12
.04
- .2s
.58***
Pulse oxygen saturation (SpO,) data were generated by a pulse oximeter monitor
(Nellcor model N-200, Hayward, CA) through placement of an oximeter probe on the
infant’s foot. The output of this monitor was magnified by a high impedance amplifier
and data were continuously recorded on a second channel of the tape recorder. These
data were subsequently digitized and the voltage output converted to calibrated units
ranging from 0-100% saturation. Oxygen saturation data were edited to remove movement artifact, and were quantified as (a) mean oxygen saturation level (SpO,) and (b)
oxygen saturation variability (SpO, var). Short-term oxygen saturation variability was
calculated by computing the standard deviation in SpO, per 15-s epoch. In addition,
the number of oxygen desaturations were counted from the continuous data. An episode
of desaturation was defined as a transient decline in SpO, to less than 80%.
Results
Short-Term Associations
Of the original 35 subjects, 4 could not be tested at the same time on the 3 consecutive
days due to intervening medical procedures. Technological problems resulted in either
poor quality heart rate ( n = 3) or SpO, ( n = 5 ) data on one of the test days. On the
first day of testing, infant mean conceptional age = 31.8 weeks (SD = 1.1 ; range 29-33
weeks); mean postpartum day = 7.3 (SD = 5.4; range 2-29 days). Pearson correlation
coefficients, computed for each of the remaining 3-day pair combinations, are presented
in Table 2. With the exception of SpO, variability, all measures demonstrated significant
short-term associations.
Long-Term Associations
Repeated measures and correlational analyses were conducted on data collected
on the first day of the protocol, at 34 weeks postconceptional age, and at discharge.
At 34 weeks, data collection for 8 subjects was unavailable due to transfer to another
hospital. At discharge, an additional subject had been transferred, and data were unavailable for 4 other subjects due to unanticipated discharge. Thus longer-term analyses
were based on 22 of the original 35 infants.
144
DIPIETRO ET AL.
Table 3
Physiologic Measirres Over Time: Baseline, 34 weeks, and Discharge
Baseline
Assessment age
Postpartum day
SD
range
Conceptional age (wks)
SD
range
Cardiac meawres (n = 22)
HP
SD
range
HPV
SD
range
V
SD
range
Oxygen saturation ( n = 20)
SpOz level (96)
sD
range
SpOz variability
SD
range
Episodic desaturations
SD
range
*p
Assessment period
34 weeks
Discharge
5.9
(3.5)
2-13
32.0
(0.8)
31-33
17.7
(6.7)
7-3 1
34.0
(0.0)
422.2
(40.2)
360.4-524.3
4.7
( I .O)
3.4-6.6
I .8
(.9)
.5-3.3
383.4
(24.3)
336.6-425.4
4.6
(1 .O)
2.3-6.4
2.0
(1.3)
- .2-5.3
378.9
(22.4)
342.8-432.6
5.1
(.6)
3.9-6.4
I .9
(.9)
95.1
(3.9)
84.6-99.4
2.5
(1.4)
.7-5.2
1.1
(2.3)
0-9
95.0
(3.4)
88.9-99.6
2.7
(1.0)
.9-4.3
9.5.5
(2.6)
91.4-99.2
3.4
-
.5
(.9)
0-3
F
(time)
32.4
(13.5)
17-63
35.8
(1.5)
34-40
18.31***
.78
1 .00
.1-4.1
.07
3.36*
(1.1)
.8-5.9
1.6
( I ,5)
0-5
1.42
< .05; ***p < ,001
Repeated measures analysis of covariance were conducted on the mean values of
the EKG and SpO, data at each point to document development in these physiological
measures over time. Because there was intersubject variability in the time intervals
between these points, the interval (days) between each pair of time points was covaried.
Means, SDs, and ranges for each measures, and the results of this analysis are presented
in Table 3 . Heart period decreased significantly over time (i.e., heart rate increased).
There was no main effect for either HPV or V. Because the pattern of means for these
measures was not linear over time, separate repeated measures of covariance were
conducted between the last 34 week and discharge recordings. HPV significantly increased from 34 weeks to discharge, F(1,22) = 6.89; p < .05, while V did not. There
was n o change in mean SpO, or desaturations during the study, but SpO, variability
significantly increased. Because the pattern of SpO, desaturations was not linear, separate analyses were conducted between 34 weeks and discharge and indicated a significant
increase between these periods, F(1,19) = 7.91; p < .01. However, mean data for
episodic desaturations do not adequately reflect the nature of the distribution for this
measure: 52%, 52%, and 22% of subjects did not display any desaturations at each of
the three test times.
Pearson correlation coefficients were computed between each pair of the three
time points with the interval (days) between each pair partialled out. These first order
CARDIORESPIRATORY FUNCTIONING OF PRETERM INFANTS
145
Table 4
Long-Term Stability: Partial Correlations Controlling for
Interval Between Each Assessment Period
Baseline34 weeks
Cardiac measures (n = 22)
HP
HPV
V
Oxygen saturation (n = 20)
SpO? mean
SpOz variability
Episodic desaturations
Assessment Intervala
34 weeksBaselinedischarge
discharge
.43*
.s5**
.42*
.43*
.53**
.14
.46*
.38*
.61**
.11***
.I0
.26
.02
.42*
.55**
.I0
.Ol
.05
N o f e . * p < .OS; * * p < .01; * * * p < ,001.
a Days between assessments: baseline-34 weeks, X = 13, SD = 6; 34
weeks-discharge, x = 15, SD = 10; baseline-discharge. X = 26; SD = 12.
correlations are presented in Table 4. Both HPV and V show significant long-term
associations. HP was significantly associated only within adjacent intervals. Significant
correlations for SpO, mean, variability, and episodic desaturations do not appear until
34 weeks postconceptional age.
Interrelations Among Cardiorespiratory Measures
In order to explore the interrelations within and between each of the physiologic
system measures, Pearson correlations were computed for each cardiorespiratory measure with all others for the baseline, 34-week, and discharge assessment points and are
presented in Table 5. Mean HP is significantly related to both measures of cardiac
variability at each time; greater HP is associated with greater variability. Conversely,
mean SpO, is inversely related to SpO, variability; higher oxygen levels are associated
with lower variability. Both measures of variability in heart period (HPV and V) are
Table 5
Correlation Matrix for All Physiologic Measures at Three Assessment Points
HP-Baseline
34 weeks
Discharge
HPV-Baseline
34 weeks
Discharge
V-Baseline
34 weeks
Discharge
Sp0,-Baseline
34 weeks
Discharge
HP
HPV
V
SpOz
SpOz var
\
\
\
.65***
.47**
.25
.60**#
.52**
\
\
\
\
.86***
.36*
.13***
\
\
\
\
\
\
\
\
\
\
\
\
.03
.24
32
-.08
- .05
.06
-.23
.26
.a2
-.30*
-.57**
- .24
-.I6
.09
.30
-.I1
-.I4
.14
- .43**
- .so**
- .60***
\
\
\
\
\
\
\
\
.50**
\
\
\
Desaturations
- .20
- .I1
- .49**
- .09
.I1
.IS
- .22
-.I1
.05
- .70***
- .51**
- .65***
146
DIPIETRO E T AL.
strongly correlated. Finally, there were no significant relations between measures of
variability in heart rate and either S p 0 2 measure.
Relation Between Risk Factors and Physiologic Measures
The relation between the initial cardiac and oxygen-saturation measures with medical risk factors was examined next. Baseline data from all 35 subjects were available
for this analysis. Because the results of the preceding correlational analyses demonstrate
that mean level and variability for each physiological measure are not independent, the
following strategy was adopted to maximize economy of analysis and interpretation.
Based on the initial hypothesis concerning risk and on examination of the correlation
scatterplots, subjects were categorized according to mean level and degree of variability.
For each measure, t h e cutoff value was the group mean. The scatterplots and mean
values for each measure are presented in Figure I . For example, H P was positively
correlated with HPV; thus, subjects with both low H P and low HPV (i.e., below the
mean for each) were grouped together and compared to all others, because lower values
were hypothesized to be associated with risk. This low HP/low HPV group appears in
the highlighted quadrant in Figure la. The same analysis strategy was used to identify
the quadrant of low HP/low V subjects (Figure lb). For SpO,, the coefficient relating
level to variability was negative, thus subjects were categorized based on low SpO,
level/high variability. This group consists of the individuals outside the highlighted
quadrant in Figure lc.
The eight risk variables listed in Table 1 were then analyzed by t tests for each of
the three physiological parameters (i.e., low HP/low HPV ( n = 15) versus others
( n = 19); low HPllow V ( n = 12) versus others ( n = 22); and SpO,/high variability
( n = 18) versus others ( n = 13).
Results of this analysis indicate that low HP/low HPV subjects had required more
respiratory support, r(32) = 2.39; p < .05 for oxygen supplementation; r(29) = 2.54;
p < .05 for mechanical ventilation; were more ill based on Hobel Scales at study entry,
r(32) = 2.60; p < .01, and discharge, f ( 2 6 ) = 3.17; p < .01; and there was a trend
relation to require longer neonatal intensive care, t(26) = 1.99; p < .06. For subjects
with low HP/low V, the only significant relation was for the Hobel Scale at study entry,
r(32) = 2.72; p < .01, with a trend relation at discharge, t(26) = I .99; p = .06. However,
the subjects in the two highlighted quadrants of Figure l a and b are almost identical,
except for the exclusion of 3 subjects from the HP/V quadrant who were slightly above
the mean on V.
Infants who displayed low SpOJhigh variability required greater respiratory support, t(29) = 2.70, p < .O1 for oxygen supplementation; t(29) = 2.40; p < .05 for
mechanical ventilation; longer neonatal intensive care, t(25) = 2.09; p < .05; and
became more ill during the course of hospitalization based on the Hobel risk scale,
t(25) + 2.50; p < .05. Gestational age, birth weight, and the ponderal index were
not significantly associated with either low HP/low HPV or V or with low SpOz/
high variability.
Sex of infant was analyzed in a 2 x 2 chi-square and was highly significant for
both categories based on heart rate measures, but not for SpOz. Twelve of the 15 infants
with low HP/low HPV were male, x2 (1, N = 34) = 7.89; p < .01, as were 10 of the
12 with low HP/low V, x2 ( I , N = 34) = 6.88; p < .01. Post-hoc analyses were
conducted to determine whether perinatal differences accounted for this effect. There
were no significant sex differences for any perinatal risk condition, with the exception
CARDIORESPIRATORY FUNCTIONING OF PRETERM INFANTS
147
a)
520
I
I
I
I
x=4.55
320
2.5
3
3.5
5
4.5
4
6
5.5
6.5
7
Heart Period Variability
8
335
-1
x-i
8
-05
0
05
1
15
50
2
25
35
3
V
Bm
90
m
85
I
80'
05
1
15
2
25
3
35
4
45
5
55
SpOz Variability
Fig. I . Distribution plots of baseline physiological level by Variability. Highlighted quadrants indicate
group classified by means for both variables.
148
DIPlETRO ET AL.
that boys were significantly heavier at birth, t(33) = 2.62; p < .01, even though there
was no difference in gestational age, t(33) = .16. Because of the sex difference in birth
weight, an exploratory analysis was conducted to determine whether this effect might
be associated with subtler indicators of fetal growth. The ponderal index was used to
classify subjects according to normal or atypical patterns of fetal growth. Due to missing
birth length data, this analysis was unavailable for 6 subjects. Based on gestational age
specific ponderal index norms (Lubchenco, Hansman, & Boyd, /966), 7 infants were
identified as having atypically low ponderal indices (i.e., low weight for length); none
had atypically high scores. Five of these infants were female, x2 ( I , N = 29) = 3.43;
p = .06.
Discussion
These results provide a picture of the developmental course of physiologic function
in preterm infants, and suggest that cardiac and oxygen saturation measures are fairly
stable indices of infant function. In general, short-term stability of all the cardiac
measures assessed, as well as oxygen saturation level, was quite high although there was
variability in the magnitude of the correlations from day-to-day and between measures.
Variability in oxygen saturation was not stable at this time, although there was some
stability in the amount of severe but transient episodic decrements in saturation level.
However, data in this study were collected primarily during active sleep, and it cannot
be determined whether similar levels of stability exist within or across other states.
Our findings of neonatal stability in cardiac measures differ from those reported in
another study (Arendt et al., 1991) which was unable to document day-to-day stability
in full-term infants for vagal tone. There are several ways to interpret this discrepancy.
The full-term infants were tested, on average, at an earlier postnatal age than the
preterm infants in this study, and autonomic stability may be attenuated during this
transitional time. Alternatively, individual differences in variability in heart rate may
be more robust in preterm infants. However, because moderate stability has been
documented in older low-risk infants (Izard et al., 1991), and because developmental
instability is particularly characteristic of the period prior to term, this interpretation
seems unlikely. Put simply, if stability of autonomic function is indeed a stable individual
characteristic, it should be much harder to document it in preterm, rather than in fullterm infants. The lack of significant short-term associations for V reported previously
(Arendt et al., 1991) may be due to design limitations, including a small sample size
( n = 1 I ) and lack of sufficient state-based data to adequately assess stability for this
and other measures of cardiac function. A larger, well-controlled study on full-term
infants is needed to adequately assess whether autonomic functioning is stable in the
newborn period.
In the longer term, the cardiac measures continued to show stability from the initial
assessment through discharge, with assessments conducted at approximately 2-week
intervals. With the exception of a lack of a significant relation for HP between baseline
and discharge, all interval pairs demonstrated correlations of similar magnitude. The
size of the correlations, mostly in the .4-.5 range, are large enough for us to conclude
that long-term stability in these measures does exist. It is important to note that the
average coefficient for measures of heart period combined, Y = .49, indicates that only
24% of variance is shared by successive measurements of cardiac activity. Stability of
oxygen saturation was not consistently evident until 34 weeks. However, the occurrence
of episodic desaturations was stable in the initial weeks of the protocol suggesting
CARDIORESPIRATORY FUNCTIONING OF PRETERM INFANTS
149
that these sudden desaturative episodes, unlike more moderate variability, may be
characteristic of the infant’s ability to maintain homeostatic levels of oxygenation during
the course of hospitalization.
Although these subjects were quite premature (<34 weeks with a mean birth weight
< 1500 g), they were relatively healthy and medically stable when assessment began.
These data do not provide information on stability of these measures in very ill, unstable
neonates. However, because illness is confounded with therapeutic medical procedures,
it is difficult, if not impossible, to estimate the true level of cardiorespiratory function
in infants undergoing intensive medical interventions, such as mechanical ventilation.
Within the study’s approximate month-long time period, heart period decreased
(i.e., heart rate increased), and heart period variability increased after 34 weeks. Both
of these findings confirm observations of others made at different ages in the neonatal
period (Cabal et al., 1980; Harper et al., 1976; van Ravenswaaij-Arts, 1991a). Unexpected was the lack of change in vagal tone, because significant increases in myelination
of the vagus have been reported prior to term (Sachis, Armstrong, Becker, & Bryan,
1982). It is possible that the postconceptional age range represented in this study (i.e.,
from 32 through 36 weeks) is too restricted to detect significant vagal maturation. Mean
oxygen saturation level also did not change over time, with an overall mean level of
95%. Although one other report notes a slight increase during this time period (Mok
et al., 1988), this level is well within the range considered normal (Hay et al., 1991;
Mok et al., 1986), and may indicate that once an adequate level of respiratory regulation
has been attained in these infants, significant increases over this level may develop
more slowly over time. Finally, variability in oxygen saturation also increased over
time, suggesting that the development of variability in regulatory systems may be a
maturative process.
There were many interrelations among physiologic measures. Most obvious are the
relations between mean level and physiologic variability. The positive relation between
heart period and both measures of heart period variability (HPV and V) and the negative
relation between oxygen saturation level and variability indicate that these measures
should not be considered independently. The relation between heart period and both
short-term variability and vagal tone confirms that observed by others (Aarimaa et al.,
1985;Cabal et al., 1980;Fox & Porges, 1985).The inverse relation found between oxygen
saturation level and variability provides additional support for the interdependence of
level and variability measures.
Cardiac variability measures and oxygen saturation were unrelated, indicating that
variability in these systems is not an expression of the same autonomic process. Conversely, heart period level tended to be associated with variability in oxygen saturation.
Faster heart rate was associated with greater variability and more frequent episodes of
desaturation, although these relations were not significant at each time. Sympathetic
activation of the cardiorespiratory system may result in oxygen saturation lability which,
for some infants, results in destabilizing episodes of rapid oxygen desaturation.
These conclusions are further strengthened by the associations observed with medical and perinatal risk variables. Infants with short heart periods and low short-term
variability were significantly sicker, required more intensive respiratory support, and
remained in neonatal intensive care longer. Infants with low oxygen saturation and high
variability were more ill, required more respiratory support, and were hospitalized for
longer periods of time. These associations were independent of gestational age or birth
weight. Some investigators have found associations between either of these indices of
birth maturity and measures of variability in heart rate alone (DiPietro & Porges, 1991;
150
DIPIETRO E T AL.
van Ravenswaij-Arts et al., 1991a), however this relation either lessens or disappears
once mean heart rate is controlled (Cabal et al., 1980; van Ravenswaij-Arts et a]., 19914.
Subjects with fast heart rates and low variability or low vagal tone were almost
exclusively boys, even though they were not more ill or less physically mature at
birth. The extensive literature on greater male vulnerability to a variety of medical
and developmental insults is predicated on increased neurological immaturity at birth
(Gualtieri & Hicks, 1985), a premise supported by these data. The fact that girls were
smaller than boys underscores the inutility of birth weight as a measure of risk status
among low birth-weight infants.
Short-term variability and vagal tone were highly correlated at each point, although
the correlation at 34 weeks was lower than at baseline or discharge, and their patterns
of short-term and longer term stability were similar. Although there were more associations with perinatal risk factors for short-term variability than for vagal tone, this was
the result of the exclusion of 3 borderline subjects from the low HPllow V group and
probably does not connote an important difference between measures in distinguishing
risk status. These findings suggest that both heart period variability and V are appropriate and useful measures of individual differences in neurological regulation in preterm
infants. We conclude this based on (a) the consistency of the short- and longer-term
correlation coefficients; (b) documentation of stability from the first postpartum week
in very immature infants; and (c) the lack of association between more accessible
measures of maturation, such as gestational age and birth weight, with cardiac patterns.
The utility of blood oxygenation as a measure of individual differences is less well
established and deserves further investigation. These results represent the first report
on SpOzdevelopment in infants from continuously digitized data. It appears that stability
in oxygen saturation measures may emerge at a later postconceptional age than for
cardiac measures, and that variability in oxygenation is indicative of perinatal compromise, even after the infant has been medically stabilized. Patterns of rapid episodic
desaturations that occur spontaneously also appear to be characteristic. Investigation
into the clinical relevance of these episodes and their relation to autonomic dysfunction
has begun (Poets, Stebbens, Alexander, et al., 1991). Given the importance of maintaining homeostatic function of arterial oxygenation, we suggest that measures of oxygen
saturation variability may index central regulation of ventilation in preterm infants.
Notes
This research was supported by Grant #NR01684 from the National Institutes of Health, Center for
Nursing Research, to Nathan A . Fox. Manuscript preparation was supported, in part, by MCJ-000106 from
the MCH Bureau, Department of Health and Human Services.
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