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BACKGROUND Modulation of behavior and physiology by dietary perturbations early in life can provide clues to the pathogenesis of adult diseases. We tested the hypothesis that a period of early protein supplementation modulates sympathetic nervous system activity demonstrated indirectly by an increase in active sleep state distribution in very low birth weight (VLBW) infants. METHODS VLBW infants (n = 71) were randomized to a total parenteral nutritional regimen providing 18% of the energy intake as amino acids (AA) or a conventional regimen providing 12.5% to achieve targeted AA intakes of 4 g/kg/day (0.004 kcal/kg/day) and 3 g/kg/day (0.003 kcal/kg/day), respectively. Both groups were weaned to enteral feeding and advanced to provide similar AA intake of 4 g/kg/day (0.004 kcal/kg/day). Six-hour daytime, behavioral sleep studies were performed when the infants reached full enteral intake (165 ml/kg/day). RESULTS Infants in the high protein group spent more time in active sleep (77.2 ± 10.5% vs. 70.7 ± 11.8%), p

Experiments were done to determine if endogenous opiates cause the arousal response decrement that follows repeated exposure to hypoxemia during sleep in lambs. Five lambs were anesthetized and instrumented for sleep staging and measurement of arterial Hb oxygen saturation. No sooner than 3 d after surgery, measurements were made in quiet sleep and active sleep during control periods when the lambs were breathing 21% oxygen and during experimental periods when the lambs were breathing 5% oxygen. The experimental period was terminated during each epoch by changing the inspired gas mixture back to 21% oxygen, once the lamb aroused from sleep. After each lamb had been exposed to 5% oxygen during 100 consecutive epochs of sleep, naloxone—an opiate antagonist—was given i.v. in a dose of 3 mg/kg as a bolus. The animals continued to be exposed to 5% oxygen during six more epochs of sleep after the administration of naloxone. Arousal occurred from both sleep states during rapidly developing hypoxemia but was delayed in active sleep compared to quiet sleep. The arterial Hb oxygen saturation at arousal was significantly lower, and the time to arousal was significantly longer with repeated exposure to hypoxemia during both quiet sleep and active sleep. Naloxone did not alter this arousal response decrement to hypoxemia. Thus, our data provide evidence that endogenous opiates do not play a major role in causing the arousal response decrement that follows repeated exposure to hypoxemia during sleep in lambs.

Different physiologic measures during EEG sleep periods in preterm neonates are postulated to change with maturation and reflect functional brain development. Forty- three healthy preterm neonates received 3-h EEG sleep studies in an environmentally controlled setting. Postconceptional ages of neonates at each recording session ranged from 28 to 35 wk. Minute-by-minute analyses of EEG discontinuity, motility, arousals, and REM were performed. Eight phasic events and continuity measures of sleep were tabulated. Data were analyzed using Spearman rank order correlation coefficients. Increases in arousal numbers (p < 0.001) and durations (p < 0.001) were noted with age only during continuous periods of EEG activity (i.e. active sleep). REM also increased with corrected age during indeterminate or transitional sleep (p < 0.002) and decreased during quiet sleep (p < 0.01). Decreases in small body movements per minute (p = 0.02) and large body movements per minute (p < 0.001) occurred only during discontinuous periods of EEG activity (i.e. quiet sleep). Sleep efficiency (p < 0.001), maintenance (p < 0.001), and latency (p = 0.01) also decreased with increasing postconceptional age. Cycle length between two segments of continuous EEG with an intervening period of EEG discontinuity also lengthened with maturation (p < 0.001). These findings are discussed in the context of previously reported differences in phasic and continuity measures noted between preterm and full-term infants at matched full-term postconceptional ages. Changes in phasic and continuity measures with increasing postconceptional ages reflect maturation of specific neuronal processes of the CNS within a rudimentary sleep cycle of the preterm neonate.

Repetitive polysomnograms were recorded from a total of 33 infants, 19 healthy preterm infants, and 14 term controls between 40 wk postconceptional age and 6 mo of age. These nighttime recordings lasted 2-4 h, except at 52 wk in preterm infants and at 3 mo of age in term infants when an overnight 12-h recording was performed. Minute by minute values of transcutaneous PO2 (PtCO2) and transcutaneous PCO2 (PtcCO2) levels and variability during the awake state, active sleep, and quiet sleep were obtained through computer analyses of the polygraphic data. The results from preterm infants at corrected postconceptional age could not be differentiated from those of control infants. PtCO2 levels rose between 40 wk and 3 mo, and PtcCO2 levels declined. Sleep states modulated only the variability of PtcO2, not the level; in contrast, state modulation was seen in both variability and level of PtcCO2 throughout the age span studied. During sleep the number of transient declines in PtCO2 greater than 2.03 kPa (15 mm Hg) decreased with advancing age. Hypercapnic PtcCO2 values decreased with age as well, but their prevalence in healthy, young infants suggests the need for reevaluation of criteria for hypercapnia based on transcutaneous measurements. The data demonstrate that ventilatory regulation continues to undergo changes between 1 and 3 mo, the age of highest risk for sudden infant death syndrome.

Postural Differences in Cardiac Dynamics during Quiet and Active Sleep in Low Birth Weight Infants † 74

Objectives: To examine the maturational changes in cardiac interbeat interval variability during quiet (QS) and active sleep (AS) in low birth weight (LBW) infants.

Objectives: The objectives of this study were to determine the effects of body position (supine vs prone) on cardiorespiratory activity during quiet and active sleep in growing low birth weight (LBW) infants.

To evaluate the effect of human milk on CNS functional development, we compared HR (RR intervals) an its spontaneous variability (HRV): high-, mid-, low-frequency bands as a function of sleep-wake states in HM and FF premature infants studied at 4 months. All were born AGAs and weighed 1000-1750 g. They were “healthy” and fully fed by 12 days of age, groups were matched by BW and GA. HM fed infants (n=16) showed longer RR intervals in all sleep-wake states, active sleep (AS), quiet sleep (QS), and wakefulness (W) relative to FF (n=20). HM fed presented higher HRV amplitude (milliseconds) relative to FF. Longer RR intervals and higher HRV amplitudes in all sleep states in BF infants, indicates a more mature pattern of CNS functional development. This phenomenon is observed at all frequency suggesting an effect in both sympathetic and parasympathetic autonomic nervous systems. We conclude that human milk favors the progression of CNS functional maturation. (Funded by USA NIH 22380 and Fondecyt 1930820). Table

It was investigated how postnatal development of cardiac control can be described by linear methods and by new application of non-linear methods of time series analysis.

Summary: Continuous measurements of minute ventilation (vI), oxygen consumption (vO2), heart rate (HR), activity, and temperature were made in eleven low birth weight infants during the interval between feedings. Significant increases in vI, vO2, and HR were noted between quiet and active sleep. (vI Active − vI Quiet/vI Quiet) × 100 = 18.4% vO2 Active − vO2 Quiet/vO2 Quiet) × 100 = 10.1% and HRActive − HRQuiet/HRQuiet) × 100 = 6.4%. Significant differences were also noted within epochs of the same state of sleep: mean slope vI versus time in epoch (t) = −156 ml/kg·min/hr, vO2 versus t. = 1.49 ml/kg·min/hr and HR versus t = −15.0 beats/min/hr. Differences between successive epochs of the same state of sleep were also observed: vI, +5.9 to 46.6%; vO2, 4.7 to 24.6%; HR, 1.0 to 9.7%. These differences were related to the length of time after feeding. These data indicate that steady state conditions do not occur in growing low birth weight infants and that the design of studies of respiration and metabolism in these infants should include continuous assessment of the state of sleep or activity and time after feeding to ensure that experimental and control periods are truly comparable. Speculation: The significant variability in minute ventilation, oxygen consumption, and heart rate which occurs spontaneously in low birth weight infants secondary to changes in activity and postprandial interval must be acknowledged in the design of clinical research. It is probable that these factors influence not only mean levels of metabolic and respiratory activity but also the sensitivity to experimental stimuli such as hypoxia, hypercarbia, and drugs.

Summary: Nocturnal sleep organization was compared in normal infants and those “at risk” for sudden infant death syndrome (SIDS) (siblings and near-miss infants). Before 12 weeks of age, sleep modifications were observed in “at risk” infants. During their sleep they had a smaller percentage of intervening wakefulness with a higher amount of active sleep. Quiet and active sleep episodes had longer durations resulting in a longer sleep cycle. After 12 weeks, sleep organization tended to normalize. This fact is discussed as a possible factor for a SIDS event: a higher arousal threshold could play a critical role if homeostasy is disturbed during sleep, mainly at an age when the homeostatic control is not fully established.

Summary: Transcutaneous oxygen tension (tcPO2) was continuously monitored, and behavioral state was evaluated in a group of 10 normal preterm infants and 10 normal term infants. In the preterm infant group, birth weight was 1505 ± 154 g, gestational age was 32.3 ± 2.3 wk, and postnatal age was 8.4 ± 5.1 days (mean ± S.D.). In the term infant group, birth weight was 3245 ± 247 g, gestational age was 39.9 ± 0.3 wk, and postnatal age was 6.3 ± 3.4 days (mean ± S.D.). A mean tcPO2 level for each behavioral state in each infant was calculated, and a paired comparison between all states was made. In the preterm and term infant groups, mean tcPO2 levels were higher in state 1 (“quiet sleep”), state 4 (“active awake state”), and state 5 (“crying”) than during state 2 (“active sleep”). The difference (ΔtcPO2) was significant (P < 0.05). In the preterm infant group, mean tcPO2 level in state 2 was 62.9 ± 17.1 mm Hg (mean ± S.D.). Mean ΔtcPO2 in state 1 was +5.4 mm Hg (range, −0.9 to +9.2 mm Hg), mean ΔtcPO2 in state 4 was +6.8 mm Hg (range, +0.6 to +20.2 mm Hg), and in state 5 was +9.9 mm Hg (range, +5.1 to +17.5 mm Hg). In the term infant group, mean tcPO2 level in state 2 was 64.5 ± 9.6 mm Hg (mean ± S.D.). Mean ΔtcPO2 in state 1 was +5.8 mm Hg (range, −1.2 to +11.0 mm Hg), mean ΔtcPO2 in state 4 was +8.1 mm Hg (range, +2.2 to +32.3 mm Hg), and mean ΔtcPO2 in state 5 was +7.3 mm Hg (range, −1.6 to +26.5 mm Hg). There was insufficient data to evaluate tcPO2 levels during state 3 (“quiet awake state”). In the term infant group, the effect of bottle feeding on tcPO2 was also assessed. Gross alterations in tcPO2 during bottle feeding were not observed, and mean tcPO2 levels during bottle feeding (76.1 ± 8.5 mm Hg; mean ± S.D.) were not significantly different from mean tcPO2 levels found during states 1, 4, and 5. Speculation: In healthy newborn infants, crying (state 5) may be a physiologic mechanism reducing pulmonary atelectasis acquired during state 2 (“active sleep,” “REM sleep”).

Sleep tracings were made of 24 full-term infants on the 2nd or 3rd day of life, using a Beckman Accutrace FEG. There were 9 control infants (Group I) and 15 infants undergoing phototherapy (Group II). FFG tracinos were made 30-60 min. after feeding, for 1 hr. The mean sleep-time recorded for Group I was 24.4 min., and for Group II 24.3 min. Phototherapy lights and eye shields were kept on during EEG tracings of Group II infants. Distinct, and statistically significant (p= 400 sec., in Gp. II infants, whereas REM periods rarely exceeded 120 sec. in Gp. I infants. Active sleep predominated under phototherapy whether or not REM was present, but quiet sleep was present about 30% of the sleep-tine tested in controls. Rather than inhibiting REM sleep and consequent CNS protein synthesis, phototherapy appears to promote it.

NIRS can be used for monitoring cerebral haemodynamics and oxygenation in newborn infants. The AIM of this study was to assess the difference in cerebral Hb volume (Hb-tot = Hb-ox + Hb-red) between quiet and active sleep and to observe Hb during sleep state transitions. METHOD: NIRS (Wyatt. Lancet 1986;2:1063) was performed on 20 healthy term infants (birthweight: 2570 to 4150g, age: 2 to 8 days); TcpCO2, tcpO2, SO2 and heart rate were recorded and sleep states assessed according to Prechtl (Brain Res 76, p 185, 1974). RESULTS (values are median (range) umol/l): After transition from quiet to active sleep Hb-ox decreased: -3.0 (+5 -10) p>0.001 and Hb-tot: -4 (+5 -10) p

Newborns spend a large portion of their time asleep. During the first postnatal month lambs spend about 45% of their time in quiet sleep (QS) and about 10% of their time in active sleep (AS). The extent to which sleep affects the cardiovascular response to perturbation in young lambs is unknown. We, therefore, investigated the effect of sleep on the cardiovascular response to an acute venous hemorrhage in 7 lambs aged 13 to 19 days. Each lamb was anesthetized and instrumented for measurements of electrocorticogram, electro-oculogram, nuchal and diaphragm electromyograms, pulmonary blood flow, aortic and right atrial blood pressures. The lambs were not studied before the third postoperative day. Measurements were made during a 1-min control period and during a 1-min experimental period that followed a 10 ml/kg hemorrhage during quiet wakefulness (QW), QS and AS. Hemorrhage produced similar decreases in right atrial pressure and pulmonary blood flow during the three behavioral states. However, mean aortic pressure decreased more (p

To determine the incidence and "structure" of augmented breaths (AB) in neonates, we studied 13 preterm infants (GA 31± 0.4 wk; BW 1.56±0.09 kg; PNA 25±4 days) and 11 term infants (GA 40±0.3 wk; BW 3.4±0.14 kg; PNA 4±0,8 days). The incidence of AB was higher in periodic than in regular breathing both in preterm (0.914±0.07 vs 0.434±0.09 breaths/min; p=0.0063) and in term infants (0.803±0.09 vs 0.406±0.04 breaths/min; p=0.0009). In term infants the incidence was greater in active than in quiet sleep (0.79±0.12 vs 0.48±0.06 breaths/min; p=0.02). VT of the AB was 18.9±0.71 ml as compared to 7.5±0.71 (p

Altered sleep state patterns have been associated with various clinical entities in the perinatal period, such as infants of diabetic mothers, infants of addicted mothers and premature infants with an abnormal neonatal course. The objective of this study was to provide normative laboratory sleep state values during the first six months of life. Twelve-hour polygraphic measures were obtained in 10 full term infants during the first week of life and at 1, 2, 3, 4 and 6 months of age. Each minute of the recording was coded as Awake (AW), Active Sleep (AS) or REM, Quiet Sleep (QS) and Indeterminate (IN). A computer program calculated sleep variables. The entire study was replicated in another group (N=10). Results were assessed with an analysis of variance. The total percent of time spent in AS decreased with age. This was due to the decrease in the number of AS episodes. Both the duration of AS episodes and intervals between them remained the same. The percent of time in QS increased with age. This was due only to an increase in the duration of QS episodes. The average percent of time spent in AW and IN remained the same. The mean number of awakenings (16) at one and two months was twice as high than at four and six months. Although variability among infants was high, the age effects described were robust. Only relatively large departures from normative values are indicative of abnormal developmental patterns.

This study was undertaken to quantitate the 24 hr. variability in the distribution of states for 5 healthy preterm infants. 12 studies were conducted in which state was coded by independent EEG & behavioral scores for each minute under standard nursing conditions over a continuous 24 hr. period excluding feeding times (x study time = 1225 mins). We calculated the percent time Quiet Sleep (%QS), Active Sleep (%AS), Indeterminate Sleep (%IS), and Wakefulness (%W) for 3 post-conceptional age groups: These data demonstrate increased W and better organization of sleep with maturation. State distribution was also calculated for each interfeed epoch (n=8) to obtain standard deviations (SD) for %QS, %AS, %IS & %W in each study. The average SD (xSD) for each state was used to determine the variability in estimates of 24 hr. state distribution when less than 8 epochs are observed: XSD for %QS when only 1 interfeed epoch is used is 6.45; when 8 epochs are used XSD=2.28. The results demonstrate the importance of long term measurements of state distribution. Short term observations may be misleading.

Sleep and waking were studied in normal term and normal and apneic premature infants at 44 wks post-conceptual age. Percentages of active sleep (AS), quiet sleep (QS) and wakefulness (AW) were determined from polygraphic tracings obtained between 6-10 p.m. Term infants were selected by absence of disease and gestational age between 38-42 wks. Normal prematures were selected by absence of disease between 32 and 36 wks post-conceptual age. Apneic prematures were similar, except they had 2 or more apneic episodes ≥ 20 sec. within an 8 hour period after the first week of life for which no etiology could be found. In normal prematures total sleep time was decreased at the expense of AS, and wakefulness was increased. Apneic prematures were not different from normal term infants. Since QS was similar in all groups, maturation of the forebrain does not appear to be delayed. The data suggest a lower threshold for arousal in the normal premature. Stress produced by apnea in the premature infant appeared to accelerate development toward normal term patterns rather than to cause a delay.

Behavioral observations of state were made for 24 low birthweight healthy premature infants at 32 and 36 weeks gestational age. Each observation lasted for 2-4 hours between feedings and included on a 30-second interval basis an assignment of state (quiet sleep, active sleep, drowse and alert)and a coding of related behaviors. Heart rate and respiratory pattern were also monitored mechanically. After the 32-week observation, 12 of the infants (intervention group) were transferred from the open floor intermediate special care nursery which is busy, bright and noisy, to a small nursery room where day/night cycles are maintained, noise and activity levels are significantly reduced, and nursing care is on a more individualized basis. Twelve infants (control group) remained in the open floor nursery. Developmentally expected improvements in state behavior from 32 to 36 weeks (increase in overall quiet sleep, longer mean interval of REM during active sleep, and less startle/tremor behavior) were greater for the intervention babies compared to the control group. Additionally, we are looking at each subject's change over time for specific improvements in state behavior that comprise our group comparisons and the overall coordination of these specific state behaviors for each subject to arrive at an index of state regulation at each age. This approach to data analysis may more clearly identify individual responses to environmental support or injury.

Non-nutritive sucking (NNS) has been reported to stabilize transcutaneous (tc) PO2 in preterm infants during both gavage feeding and assisted ventilation. To evaluate the effect of NNS in the resting preterm infant, we measured TcPO2, heart rate (HR) and resp. rate in 14 healthy, sleeping infants (G.A. at birth 26-33 wk, B.Wt 710-1450g). Each study was begun in active sleep, and comprised 15 min. of data collection divided into 3 equal periods: preNNS, NNS and postNNS. Sucking was recorded with a pacifier adapted to measure sucking pressure, and respiration was detected with a nasal thermistor. Subjects were studied at two weekly intervals until discharge and divided into 4 groups based on postconceptional age.

Otherwise healthy preterm infants may continue to exhibit prolonged apnea beyond the first week of life, a condition some consider leading to an increased risk for SIDS. To elucidate the significance of these apnea, we studied 17 AGA infants between 32-36 weeks post conceptual age. Eight of these (A) exhibited 2 or more central apnea ≥20 sec. during an 8 hour period after the first week of life. Polygraphic records were obtained between 6-10 pm at 40 weeks, 1 month and 3 months adjusted age, from which Quiet Sleep (QS) and Active Sleep (AS) were derived. Minute by minute values for heart rate (HR), respiratory rate (RR), transcutaneous O2 (PtcO2) and CO2 (PtcCO2) were determined during AS and QS with a computer. Representative results at 40 wks are presented as mean and (sd). Apneic preterms were not different from non-apneic infants (N) at this either of the other follow up ages. While preterm infants are statistically at increased risk for SIDS, these data do not warrant singling out the apneic prcterm as at greater risk for abnormal autonomic sequelae.