Arousal responses to somatosensory and mild hypoxic stimuli are depressed during quiet sleep in healthy term infants

STUDY OBJECTIVES: To compare arousal responses to somatosensory and hypoxic stimuli in sleeping human infants and to determine whether sleep state and postnatal age exerted similar changes in these arousal responses. DESIGN: We delivered somatosensory (nasal air-jet) stimulation and mild hypoxia (15% oxygen) to 10 healthy term infants aged 2 to 4 weeks, 2 to 3 months, and 5 to 6 months during identified sleep states. Hypoxic challenges were terminated at arousal, when the oxygen saturation fell below 85%, or at 5 minutes (failure to arouse). RESULTS: Infants failed to arouse to a greater percentage of hypoxia tests during quiet sleep (QS) than during active sleep (AS) at 2 to 3 months and 5 to 6 months of age (P < 0.01). Infants failed to arouse to a greater percentage of hypoxic challenges during QS at 2 to 3 months and 5 to 6 months than at 2 to 4 weeks of age. Arousal latency to hypoxia was significantly longer in QS than in AS at each study age; however, arousal latency was not affected by postnatal age. Arousal thresholds to somatosensory stimulation were significantly greater in QS than in AS, except at 2 to 4 weeks of age. In AS, arousability to the air-jet was greater at 2 to 3 months compared to 2 to 4 weeks of age (P < 0.05); in QS it was lower at 5 to 6 months compared to 2 to 4 weeks of age (P < 0.05). Arousal latency to hypoxia and arousal thresholds to air-jet stimulation were not correlated within infants. CONCLUSION: We conclude that arousal responses of infants to somatosensory and respiratory stimuli are similarly affected by sleep state and postnatal age. Infants are less arousable to both stimulus modalities in QS than in AS, and less arousable at 5 to 6 months of age than at 2 to 4 weeks in QS.     

Comparison of postnatal development of heart rate responses to trigeminal stimulation in sleeping preterm and term infants

Autonomic dysfunction has been regarded as a possible cause of the sudden infant death syndrome (SIDS) and it has been suggested that preterm infants, who are at a greater risk of SIDS than term infants, may have immature autonomic control. Our aim was to compare the maturation of cardiac autonomic control during sleep in preterm and term infants by examining heart rate responses to arousing and non-arousing trigeminal stimuli. Preterm infants (n = 15) and term infants (n = 24) were studied longitudinally with daytime polysomnography. Air-jet stimulation of the nares was delivered in both active sleep (AS) and quiet sleep (QS), and heart rate (HR) changes recorded for both arousal and non-arousal responses. Changes in HR (DeltaHR%) were calculated as the relative differences between baseline HR (BHR) and either MaxHR (arousal) or MinHR (non-arousal). Comparisons of HR changes between sleep states and postnatal ages were made with two-way anova for repeated measures and between groups with two-way anova. The increase in HR (DeltaHR%) was greater in term than preterm infants (P < 0.05), but only at 2-3 weeks corrected postnatal age (CPA). In preterm infants, there were no differences in BHR between sleep states, whereas in term infants, BHR was higher in AS than in QS at 2-3 weeks and 2-3 months of age. The smaller DeltaHR% to arousing stimuli in preterm infants compared with term infants at 2-3 weeks suggests that cardiac sympathetic activity in preterm infants may be lower than in term infants. This mechanism may account for the increased risk for SIDS of preterm infants.     

Of sleep state and postnatal age on arousal responses induced by mild hypoxia in infants

STUDY OBJECTIVES: It has been suggested that mild hypoxia may not be a potent stimulus for arousal during sleep in infants because infants frequently fail to arouse from quiet sleep (QS). Our aim was to characterize arousal responses of sleeping infants in both active sleep (AS) and QS under normoxic and mildly hypoxic (15% O2) conditions over the first 6 months of life. PARTICIPANTS: Five healthy term and 6 healthy preterm infants were each studied at 2 to 5 weeks, 2 to 3 months, and 5 to 6 months postterm. All infants underwent daytime polysomnography during which nasal airflow was monitored using a purpose-built pneumotachograph. All infants were studied under both normoxic (21% O2) and hypoxic (15% O2, balance N2) conditions (presentation order randomized) in each sleep state at each study age. Tests were terminated at arousal, O2 saturation falling below 85%, or 5 minutes (failure to arouse). MEASUREMENTS: Probability of failure to arouse and mean arousal latency were compared between each experimental condition, with each infant serving as its own control. RESULTS: Infants aroused more frequently under hypoxic conditions than under normoxic conditions. Overall, arousal latencies were shorter during hypoxia compared to normoxia in both sleep states at each age. Arousal latencies were longer in QS compared to AS in both hypoxic and normoxic conditions. CONCLUSION: In sleeping infants, mild hypoxia serves as a stimulus for arousal in both AS and QS. Of particular significance is our finding that arousal from AS is readily elicited by mild hypoxia.     

Maturation of the initial ventilatory response to hypoxia in sleeping infants

In infants most previous studies of the hypoxic ventilatory response (HVR) have been conducted only during quiet sleep (QS) and arousal responses have not been considered. Our aim was to quantify the maturation of the HVR in term infants during both active sleep (AS) and QS over the first 6 months of life. Daytime polysomnography was performed on 15 healthy term infants at 2-5 weeks, 2-3 and 5-6 months after birth and infants were challenged with hypoxia (15% O2, balance N2). Tests in AS always resulted in arousal; in QS tests infants either aroused or did not arouse. A biphasic HVR was observed in non arousing tests at all three ages studied. The fall in SpO2 was more rapid in arousal tests at all three ages. At 2-5 weeks, in non-arousing QS tests, there was a greater fall in respiratory frequency (f) despite a smaller fall in SpO2 compared with 2-3 and 5-6 months. When infants aroused there was no difference in the HVR between sleep states or with postnatal age. However, when infants failed to arouse from QS, arterial desaturation was less in the younger infants despite a poorer HVR. We suggest that arousal in response to hypoxia, particularly in AS, is a vital survival mechanism throughout the first 6 months of life.     

Arousal and ventilatory responses to hypoxia in sleeping infants: effects of maternal smoking

Our aim was to determine whether maternal cigarette smoking affects arousal and ventilatory responses to hypoxia in infants. Infants born to non-smoking (NS, n = 15) and smoking mothers (SM, n= 9) were studied at 2-5 weeks, 2-3 and 5-6 months. Ventilatory responses to 15% O(2) were determined preceding arousal. At each age and in both groups, infants aroused more frequently and earlier to hypoxia in active sleep (AS) than quiet sleep (QS). Arousal latency was longer in SM infants (in QS) at 5-6 months (P < 0.05). Baseline respiratory parameters were not different between groups, except that, at 2-3 months, SM infants had higher SP(O2) during AS than NS infants. Maternal smoking did not affect ventilatory responses preceding hypoxia-induced arousal in either sleep-state at any age. We conclude that mild hypoxia stimulates ventilation and arousal in infants up to 6 months and that arousability is depressed in SM infants at 5-6 months; however, ventilatory responses preceding arousal are not adversely affected by smoking.     

Methodological issues in coding sleep states in immature infants

Thirty-five healthy, premature infants, ranging from 30–39 weeks postconceptional age, were observed continuously for 6 to 24 hr. Behavioral state and electroencephalographic patterns were coded for each minute. Using these data, three questions regarding coding of states of sleep were addressed: What is the concordance between behavioral codes and specific EEG patterns? Does the concordance between behavioral codes and EEG patterns change with postconceptional age? What range of error can be expected when observation periods shorter than 24-hr are used to estimate the daily distribution of quiet sleep (QS) and active sleep (AS)? With behavioral codes as the standard, concordances of EEG patterns for QS and AS were 72.5 and 92.1% respectively. With EEG patterns as the standard, behavioral codes for QS and AS agreed 83.0 and 88.9%. Agreement between behavioral codes and EEG patterns for QS increased with age. Finally, variation in estimates of the daily distribution of QS and AS decreased dramatically as the length of observation increased from 3 to 24 hr. © 1995 John Wiley & Sons, Inc.     

Arousal and ventilatory responses to mild hypoxia in sleeping preterm infants

A failure to adequately respond to hypoxia has been implicated in the Sudden Infant Death Syndrome (SIDS). Preterm infants are at increased risk for SIDS, thus we compared ventilatory and arousal responses to mild hypoxia [15% oxygen (O₂)] in preterm and term infants. Eight preterm and 15 term infants were serially studied with daytime polysomnography during which nasal airflow was monitored by pneumotachograph at 2–5 weeks, 2–3 and 5–6 months. At each age, in both groups, hypoxia induced a significant decrease in oxygen saturation (SpO₂) during both active sleep (AS) and quiet sleep (QS). Infants invariably aroused in AS; and in QS either aroused or failed to arouse. In preterm infants arousal latency in AS was longer than in term infants ( P  < 0.05) at 2–5 weeks. Compared with term infants, preterm infants reached significantly lower SpO₂ levels at 2–5 weeks in both AS and QS non-arousing tests and at 2–3 months in QS. A biphasic hypoxic ventilatory response was observed in QS non-arousing tests in both groups of infants at all three ages. We conclude that the greater desaturation during a hypoxic challenge combined with the longer arousal latency in preterm infants could contribute to greater risk for SIDS.     

Polysomnographic sleep and waking states are similar in subsequent siblings of SIDS and control infants during the first six months of life

Twenty-five subsequent siblings of infants who died of Sudden Infant Death Syndrome (SIDS) underwent 12-h overnight polygraphic recordings during the first week of life and at 1, 2, 3, 4, and 6 months of age. The polygraphic tracings from these infants were compared with those from 25 infants without a family history of SIDS. One dozen sleep and waking parameters were examined including state transition probabilities, the ratio between quiet sleep (QS) and active sleep (AS), the incidence and duration of sustained states and the stability of an infant's sleep and waking during the first half year of life. Variability within and between infants was marked with a reduction of variability in measures of QS at 3 months and of AS at 4 months of age. The similarities between subsequent siblings of SIDS and control infants far outweighted the differences. However, subsequent siblings exhibited a tendency, once asleep, to remain asleep longer than controls. This finding was observed in a comparison of 20 infants in each group. When five infants were added to each group, infants in both groups tended to awaken equally from QS, but once in AS the subsequent siblings tended to proceed into QS instead of awaken as the controls did.     

Prone sleeping impairs circulatory control during sleep in healthy term infants: implications for SIDS

STUDY OBJECTIVES: To determine the effects of sleeping position on development of circulatory control in infants over the first 6 months of postnatal age (PNA). DESIGN: Effects of sleeping position, sleep state and PNA on beat-beat heart rate (HR) and mean arterial pressure (MAP) responses to a head-up tilt (HUT) were assessed during sleep in infants at 2-4 wks, 2-3 mo and 5-6 mo PNA. MEASUREMENTS: Daytime polysomnography was performed on 20 full-term infants (12 F/8 M) and MAP was recorded continuously and noninvasively (Finometer). HUTs of 15 degrees were performed during active sleep (AS) and quiet sleep (QS) in both the prone and supine sleeping positions. MAP and HR data were expressed as the percentage change from baseline, and responses were divided into initial, middle and late phases. RESULTS: In the supine position HUT usually resulted in an initial increase (P < 0.05) in HR and MAP, followed by decreases (P < 0.05) in HR and MAP in the middle phase; subsequently HR and MAP returned to baseline in the late phase. By contrast, in the prone position the initial HUT-induced rises in HR and MAP were usually absent, and at 2-3 mo MAP actually decreased (P < 0.05); subsequently HR but not MAP returned to baseline. At 2-3 mo, MAP was lower (P < 0.05) in prone than supine sleeping throughout the HUT. CONCLUSIONS: Prone sleeping alters MAP responses to a HUT during QS at 2-3 mo PNA. Decreased autonomic responsiveness may contribute to the increased risk for SIDS of infants sleeping in the prone position.     

Postnatal development of ventilatory and arousal responses to hypoxia in human infants

During the first year of life there is significant maturation of the hypoxic ventilatory response (HVR) in human infants. Compared with adults, healthy term infants have an immature HVR until at least 6 months of age. There are few studies in infants on the effects of sleep state on the HVR but these suggest that at early postnatal ages there is initially no sleep-state related difference; this is followed by a developmental trend towards the adult situation in which the response is depressed in REM sleep compared with NREM. Maternal cigarette smoking is a major risk factor for SIDS and the mechanism for this may involve a depressed HVR in the exposed infant; however studies are limited and the wide variation in cigarette consumption makes interpretation of results difficult. Arousal responses to hypoxia are of vital importance and a failure to arouse has been implicated in SIDS. Sleeping infants frequently fail to arouse in response to hypoxia in QS, whereas in AS they invariably arouse; furthermore arousal latency is longer in QS compared with AS. The oxygen saturation at which infants arouse is not different between sleep states, suggesting that desaturation is more rapid in AS. In QS younger infants arouse more readily than at older ages and arousal is depressed by maternal smoking. These findings suggest that depression of the arousal response to hypoxia in AS may have life-threatening consequences. Infants at increased risk for SIDS have been shown to have both depressed ventilatory and arousal responses to hypoxia, thus they may be at even greater risk.     

Development of sleep states in normal premature and full-term newborns

The aims of our study were: 1) to answer the question "Do sleep states exist in normal premature infants;" 2) to analyze the development of sleep cycle and sleep state characteristics in premature and full-term newborns. Polygraph recordings were done on 38 normal, appropriate for gestational age newborns, born at 30 to 41 weeks (w) of gestation. All infants fell asleep in active sleep (AS). Postwaking AS was significantly shorter than the next AS. Mean sleep cycle duration increased from approximately 46 min at 31-34 w of conceptional age (CA) to 70 min. at 35-36 w CA. In all infants we observed stable, greater than 5 min AS and quiet sleep (QS) periods, as defined by EEG and REM criteria. Indeterminate sleep was about 30% of the total sleep cycle at 31-34 w; it decreased to 12% at 35-36 w. Both duration and percentage of AS and QS significantly increased at 35-36 w and remained stable up to 39-41 w CA. Values of QS were significantly reduced when defined by additional criteria (respiratory rate, tonic chin EMG or motility). Concordance of QS criteria was not significantly better in older versus younger groups of infants. At all ages, AS values were insensitive to changes in the criteria chosen to define them. The contrast, starting from 31-34 w CA, between AS and QS as defined by EEG and REM criteria could account for state differences in the control of many physiological variables in prematures.     

Ventilatory responses preceding hypoxia-induced arousal in infants: effects of sleep-state

Augmented ventilation and/or arousal in response to hypoxia are important protective mechanisms during sleep. We aimed to quantify ventilatory responses preceding hypoxia-induced arousal in infants and determine the effects of sleep-state. Fifteen term infants were studied at 2-4 weeks, 2-3 and 5-6 months of age. Ventilatory responses to 15% oxygen inhalation were expressed as breath-by-breath changes from normoxic levels and averaged over 5, 10 and 15 breaths preceding arousal. Minute ventilation preceding arousal significantly increased above normoxic levels only in AS at 5-6 months. There were no sleep-state related differences in minute ventilation, oxygen saturation or carbon dioxide levels (expressed as changes from normoxic values) at 5, 10 or 15 breaths preceding arousal. However, the rate of oxygen desaturation during hypoxia in AS was two to four times faster than in QS at each age. We conclude that the ventilatory responses preceding hypoxia-induced arousal do not differ between sleep-states and that arousal occurs at similar levels of desaturation in both states.     

Between-sleep states transitions in premature babies

To assess the manner in which between-sleep state transitions occur in infants, we examined polysomnography (PSG) studies in 25 clinically and neurologically normal, appropriate-for-gestational-age, 30-to-36-week-gestational age (GA) infants. Twenty infants underwent paper PSG and five infants digitised PSG. Sleep states were coded based on concordance of REMs and the electroencephalogram (EEG) pattern. Data were analysed using a multivariate linear model, with the subject factor as a cluster. Duration of active sleep (AS) to quiet sleep (QS) transitions (median 4.8 min) was significantly longer than duration of QS to AS transitions (1.7 min) and was independent from GA and from the recording method (paper vs. digitized PSG). The sequence of modifications in parameters (REM and EEG) was invariable: REM cessation was the first change in AS to QS transitions, and REM appearance was the last change in the QS to AS transitions. Our study demonstrates a stable, well-organized pattern of between-sleep-states transitions in healthy 30-to-36-week GA premature infants. These findings are similar to those described in full-term newborns and are in agreement with our previous observations of well-defined sleep states at the age investigated here.     

Sleep and waking states in infancy: normative studies

Twelve-hour polygraphic recordings were obtained in 20 normal healthy term infants at 1 week of age, at monthly intervals up to 4 months, and at 6 months of age. Each minute of these recordings was coded into active sleep (AS), quiet sleep (QS), wakefulness (AW), or indeterminate (IN) based on polygraphic and behavioral variables. For each state, a dozen variables were computed with the help of a laboratory computer. Together these variables describe trends in the development of sleep and wakefulness in the laboratory: an increase in QS and a concomitant decrease in AS, an increase in sustained episodes of these states, and continuous sleep onset in AS throughout this time span. Considerable variability appears to characterize immature sleep patterns, but a reduction in variability was noted between 3 and 4 months of age. The number of sustained sleep-state episodes and the percentage of AS and IN proved to be stable characteristics of individual infants. The large variability among and within infants sheds doubt on the usefulness of polygraphic monitoring of sleep states for early detection of abnormalities.     

Rhythms and complexity of respiration during sleep in pre-term infants.

The aim of this study is to test rhythmic and complex properties of respiratory control in former ventilated, pre-term infants during quiet and active sleep. The children had a higher risk for sudden infant death due to bronchopulmonary dysplasia (BPD). Twelve infants suffering from BPD and 12 control infants, matched regarding their post-conceptional age, were examined polygraphically during quiet (QS) and active sleep (AS). The respiratory rate (RR), the ratio (LF/HF) between the low-frequency power (LF) and the high-frequency power (HF) of the spectra of the thoracic respiratory effort, and the frequency of the dominant peak within LF (LFF) and HF (HFF) were computed. The correlation dimension (D2) of the respiratory signal was calculated to determine the complexity of the respiratory control. The transcutaneous pO2 (tcpO2) and pCO2 and the oxygen saturation (sO2) were analysed. Infants with BPD had significantly higher RR and HFF during QS (median: BPD 48 breaths min-1; control 32 breaths min-1). tcpO2 and sO2 were significantly lower in the BPD group. No differences were found in LF/HF, LFF or D2 between groups, either in QS or in AS. D2 ranged between 1.8 and 3.8, showing significantly higher values during AS. LFF was found to be lower during active sleep (AS 0.04-0.05 Hz; QS about 0.06 Hz). We propose that in infants with BPD the lower lung compliance and the higher resistance, and possibly also the hypoxaemia, contribute to the acceleration of breathing. The behaviour of RR, spectral parameters and D2 indicates a specific, functional setting rather than a regulatory impairment in infants with BPD.     

Polygraphic investigation of 24-h waking distribution in infants

An evening forbidden zone for sleep has been shown for adults. This research was aimed to ascertain the prevalence of waking in the evening in early development. Twelve infants, aged between 2 weeks and 11 months 3 weeks, were each recorded once over a 24-h period. Recordings included EEG, EOG, EMG, respiration, ECG, and behavioural observation. Four states were defined by combining behavioural and electrophysiological data. Wakefulness was defined by the presence of eyes open, eye movements and additionally body movements, and irregular respiration. In infants younger than 12 months and a half, a greater amount of wakefulness was observed in the time interval between 17 and 20. Older infants show uniform high amount of wakefulness during daytime. Our data corroborate the hypothesis that evening hours are those most frequently characterised by the behavioural waking state, suggesting that a forbidden zone for sleep exists in development and that its time placement corresponds to the one observed in the adult.     

Development of sinus arrhythmia during sleeping and waking states in normal infants.

The development of variability in heart rate (HR) due to respiration (sinus arrhythmia; SA) has been examined in normal infants from birth through the first 6 months of life. Two aspects of HR variation were examined: the absolute variation at the median respiratory frequency, or extent of sinus arrhythmia (XSA), and the degree to which HR follows respiration regardless of the absolute amount of variation, or coherence of sinus arrhythmia (CSA). Extent of sinus arrhythmia tended to be highest in quiet sleep (QS), lower in active or REM sleep (AS), and lowest in waking (AW), especially after 2 months of age. Extent declined at 1 month of age in QS, but rose over the first 6-month period in all states. During this same period, CSA was also highest in QS, lower in AS, and lowest in AW. Coherence in QS also declined at 1 month and rose between 1 and 6 months; however, no age effects were found in other states. Heart rate was negatively correlated with XSA, but less so with CSA. Sleep state appears to have a significant effect on cardiorespiratory coupling, and this coupling undergoes dramatic changes at 1 month in QS.     

The role of slow-wave sleep on the duration of quiet sleep in infants

The duration of quiet sleep (QS) phases has been shown to increase during the first year of life. Slow-wave sleep (SWS) appears in about half of the QS phases beyond 20 weeks. In order to evaluate the role of SWS in the lengthening of QS phase duration during the first year of life, we looked at 48 normal full-term infants (aged between 1 and 54 weeks), recorded for a whole-night period. Records included electro-encephalogram (EEG) and other polygraphic parameters. Infants were separated into two groups: (1) those who did not show SWS episodes at all, and (2) those who show both QS phases with (QS SWS+) and without (QS SWS-) SWS episodes. In group 2 the duration of QS SWS+ was longer than that of QS SWS, as well as longer than that of QS of group 1. Group 1 had a duration of QS phases similar to that of QS SWS-. The duration of QS SWS+ depended both on the SWS latency and SWS duration. The lengthening of QS phases with age is accounted for by those phases containing SWS episodes, reflecting a maturational restructuring of QS.     

新生儿睡眠期的脑电非线性分析方法

目的脑电（electroencephalogram,EEG）是新生儿脑功能监护中重要的生理信号,近年研究发现基于非线性动力学的复杂度分析能够客观反映大脑成熟度、睡眠周期和惊厥状态等。方法本文针对神经系统发育正常的早产新生儿组和足月新生儿组,采用近似熵（approximate entropy,ApEn）和样本熵（sample entropy,SampEn）两种非线性参数,对新生儿在安静睡眠期（quiet sleep,QS）和活动睡眠期（active sleep,AS）的脑电信号进行分析。结果神经系统发育正常的新生儿中,AS期的ApEn和SampEn均高于QS期,且具有显著性差异;随着受孕后年龄（postmenstrual age,PMA）的增大,新生儿QS期的ApEn和SampEn的值均随之增加,且波动逐渐减弱,而AS期的ApEn和SampEn的值并无显著变化;绝大多数新生儿在AS期与QS期的SampEn之差高于ApEn之差。结论AS期新生儿EEG的复杂度大于QS期的复杂度;随着PMA的增大,新生儿EEG的复杂度提高,脑功能发育趋于成熟;ApEn与SampEn在表现新生儿脑电信号复杂度上趋势一致,但SampEn在区分AS与QS方面更具优势。     

Effects of age and sleeping position on arousal from sleep in preterm infants

STUDY OBJECTIVES: Preterm infants are at increased risk of sudden infant death syndrome (SIDS). We investigated whether the prone sleeping position impaired arousal from sleep in healthy preterm infants and whether this impairment was related to cardiorespiratory variables, temperature or postnatal age. DESIGN: Longitudinal SETTING/PARTICIPANTS: 14 healthy preterm infants (mean 32 +/- 0.4 weeks) were studied using daytime polysomnography on 4 occasions: 36-38 weeks postconception age, 2 to 3 weeks postterm, 2 to 3 months postterm, and 5 to 6 months postterm. Interventions: N/A. MEASUREMENTS: Multiple measurements of arousal threshold (cm H2O) in response to air-jet stimulation applied alternately to the nares were made in both active sleep and quiet sleep when infants slept both prone and supine. RESULTS: Arousal thresholds were significantly higher in both AS and QS when infants slept prone at 36 to 38 weeks postconception age and 2 to 3 months postterm but not at 2 to 3 weeks or 5 to 6 months postterm. These increases were independent of any sleep position-related changes in either rectal or abdominal skin temperature, respiratory rate, oxygen saturation or heart rate. CONCLUSIONS: At the age when the risk of SIDS is highest, the prone position significantly impairs arousal from both active sleep and quiet sleep in healthy infants born prematurely. This impairment in arousability occurred with no clinically significant changes in cardiorespiratory parameters or body temperature. Decreased arousability from sleep in the prone position may explain its role as a risk factor for SIDS.