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.     

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.     

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.     

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.     

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.     

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.     

Sleeping Like a Baby—Does Gender Influence Infant Arousability?

Introduction:

Victims of the sudden infant death syndrome (SIDS) may have preexisting abnormalities in their arousal pathways, inhibiting the progression of subcortical activation (SCA) to full cortical arousal (CA). Approximately 60% of SIDS victims are male, and it has been suggested that male infants have delayed cortical maturation compared to females. We hypothesized that CA frequency would be lower and CA threshold would be higher in male infants during both active (AS) and quiet (QS) sleep.

Methods:

50 healthy term infants (21 male, 29 female) were studied with daytime polysomnography at 2–4 weeks and 2–3 months after birth. Arousal from sleep was induced using a pulsatile air-jet to the nostrils at increasing pressures.

Results:

At 2–4 weeks, arousability from AS was similar in males and females, however during QS, male infants required a lower stimulus to induce SCA and CA. This gender difference in arousal threshold was not observed at 2–3 months. CA frequencies were similar between genders during both sleep states at both ages, though overall, CA was more frequent in AS than in QS.

Conclusions:

This study demonstrated that at 2–4 weeks, male infants were easier to arouse than female infants during QS. There were no significant effects of gender on total arousability or SCA and CA frequencies at 2–3 months, the age of peak SIDS incidence. Thus, although male infants are at greater risk of SIDS than female infants, this difference is unlikely to be associated with gender differences in CA threshold or frequency.

Citation:

Richardson HL; Walker AM; Horne RSC. Sleeping like a baby—does gender influence infant arousability? SLEEP 2010;33(8):1055-1060.     

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.     

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.     

The carotid body and arousal in the fetus and neonate

Arousal from sleep is a major defense mechanism in infants against hypoxia and/or hypercapnia. Arousal failure may be an important contributor to SIDS. Areas of the brainstem that have been found to be abnormal in a majority of SIDS infants are involved in the arousal process. Arousal is sleep state dependent, being depressed during AS in most mammals, but depressed during QS in human infants. Repeated exposure to hypoxia causes a progressive blunting of arousal that may involve medullary raphe GABAergic mechanisms. Whereas CB chemoreceptors contribute heavily to arousal in response to hypoxia, serotonergic central chemoreceptors have been implicated in the arousal response to CO₂. Pulmonary or chest wall mechanoreceptors also contribute to arousal in proportion to the ventilatory response and decreases in their input may contribute to depressed arousal during AS. Little is known about specific arousal pathways beyond the NTS. Whether CB chemoreceptor stimulation directly stimulates arousal centers or whether this is done indirectly through respiratory networks remains unknown. This review will focus on arousal in response to hypoxia and CO₂ in the fetus and newborn and will outline what we know (and do not know) about the involvement of the carotid body in this process.     

Effect of infant sleeping position on sleep spindles

Sleep spindles play an active role in inducing and maintaining sleep and may affect arousal by blocking the transmission of external stimuli through the thalamus to the cortex. Previously we have demonstrated that sleeping in the prone position impairs arousal in infants at 2-3 months of age, but not at 5-6 months. We aimed to examine if sleeping position and postnatal age affected duration and/or density of sleep spindles. Twenty-one healthy term infants were studied using daytime polysomnography at 2-3 months and 16 were again studied at 5-6 months. Infants slept both prone and supine at each study. The mean duration of non-rapid eye movement (NREM) sleep was not different between the two studies in either position. At 2-3 months both spindle density (P < 0.001) and proportion of NREM sleep (P < 0.025) with spindles were significantly greater in the supine than in the prone position. At 5-6 months spindle duration was longer in the supine than in the prone position (P < 0.03). Spindle density in the supine position was not different between the two studies, however, when infants slept prone, it was significantly increased at 5-6 months compared with 2-3 months (P < 0.001). Arousal threshold was not correlated with either spindle density or percentage of NREM sleep with spindles in either position at either study. In this study spindle density and the percentage time spent with spindles were not well correlated with infant arousability, and hence may not be able to be used as markers of depressed arousal responses in infants.     

Sleep position alters arousal processes maximally at the high‐risk age for sudden infant death syndrome

An impaired ability to arouse from sleep may play an important role in the pathogenesis of sudden infant death syndrome (SIDS). This study aimed to investigate the effects of prone sleeping on the nature of both induced and spontaneous arousal responses in infants. Thirteen healthy term infants were studied longitudinally at 2–4 weeks, 2–3 months and 5–6 months postnatal age. A pulsatile jet of air to the nostrils was used to induce arousal from both active sleep and quiet sleep in both prone and supine positions. For each stimulus, arousals were classified as sub‐cortical activations and cortical arousals, scored using physiological and electroencephalogram changes and expressed as a percentage of the total number of arousals. Spontaneous arousals were similarly analysed. Increased proportions of cortical arousals, hence decreased proportions of sub‐cortical activations, were observed in the prone position at 2–3 months. This distinct peak in the proportion of cortical arousals occurred regardless of sleep state and regardless of whether the arousal occurred spontaneously or was induced by air‐jet stimulation. The nature of arousal responses in healthy term infants is altered in the prone sleeping position at 2–3 months after birth, the age where SIDS incidence is highest. We postulate that a greater propensity for cortical arousal may be a protective mechanism to promote complete arousal in a vulnerable sleeping position and/or a vulnerable period of maturation. Inadequate or incomplete cortical arousals may explain the increased risk of SIDS associated with the prone position at this age.     

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.     

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.     

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.     

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.     

Ambient temperature is associated with changes in infants' arousability from sleep

STUDY OBJECTIVE: To evaluate the influence of ambient temperature on infants' arousability from sleep. DESIGN: Two groups of healthy infants with a median age of 11 weeks were recorded polygraphically during one night: 31 infants were studied at 24 degreesC and 31 infants at 28 degreesC. To determine their arousal thresholds, the infants were exposed to white noises of increasing intensities during REM and NREM sleep. Arousal thresholds were defined by the auditory stimuli needed to induce arousals. SETTING: N/A. PATIENTS or PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS and RESULTS: The arousal thresholds decreased across the night in the infants sleeping at 24 degreesC (p=.017). The finding was not found for the infants sleeping at 28 degreesC. When analyzing the arousal responses according to time of the night, it was found that the auditory thresholds were significantly higher at 28 degreesC than at 24 degreesC between 03:00 hr and 06:00 hr (p=.003). These findings were only seen in REM sleep. CONCLUSION: High ambient temperature could add to the difficulty to arouse from REM sleep in the late hours of the night.     

Behavioural and EEG responses to auditory stimuli during sleep in newborn infants and in infants aged 3 months

Two studies were conducted in order to assess EEG and behavioural responsiveness to auditory stimuli as a function of sleep state in infants. The subjects in the first experiment were 11 infants aged 3 months, and in the second study the responsiveness of 8 infants aged 3 months was compared with that of 8 newborn infants. The stimuli ranged in intensity from 36 to 90 dB and were presented using a modification of the method of constant stimuli. The occurrence and intensity of behavioural responses were recorded by a trained observer. Electroencephalogram (EEG) responses were defined as EEG desynchronization and were identified by a Fast Fourier Transform algorithm. The results of the two studies showed that infants were more responsive during active sleep (AS) than during quiet sleep (QS) and gave behavioural responses at lower stimulus intensities than EEG responses. Behavioural responsiveness and EEG responsiveness during AS increased as a function of age, while EEG responsiveness during QS decreased. The marked suppression of EEG responsiveness during QS at 3 months of age is thought to be a consequence of developmental changes in sleep mechanisms--an effect which may have clinical implications.     

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.     

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.