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 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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Magnesium deficiency promotes muscle weakness, contributing to the risk of sudden infant death (SIDS) in infants sleeping prone.

A review was published (1991) of 19 retrospective case-control studies that had investigated the relationship between prone sleeping position (on the stomach) and the sudden infant death syndrome (SIDS). These studies, which had been conducted between 1965 and 1990 in New Zealand, Australia, England, France and the Netherlands, showed an overall higher rate of SIDS in infants who usually slept prone. In those countries, vigorous community intervention to change babies' sleep position away from the prone has resulted in marked declines of 50 per cent or more in the rate of SIDS. Such encouraging reports from many countries prompted the American Academy of Pediatrics to recommend that infants be placed to sleep on their backs to reduce the risk of SIDS. This was followed by a successful campaign in the United States between mid-1994 and 1998. Despite the decreased incidence, SIDS remains the leading cause of death in infants 1 month to 1 year of age of industrialized nations of the world. Studies have been conducted in human infants, mechanical models and animal models to learn the role of risk factors in prone sleeping infants. Soft bedding, thermal stress and biologic risk factors such as impaired ventilatory and arousal responsiveness are among many factors that have been investigated. Hunt states that there is not a single unifying factor that explains increased SIDS in prone sleeping infants. Two major studies conducted in the 1970s showed: (1) muscle weakness in the upper half of the body in infants who subsequently died of SIDS, and (2) shoulder hypotonia in near-miss for SIDS infants. An infant sleeping face-down in the prone position could be jeopardized if he lacked the muscle strength to shift his position or turn his head to rescue himself from a life-threatening situation. In contrast, recent studies in neonates sleeping in the prone position report that normal infants can spontaneously arouse and turn their heads. Some data support the hypothesis that magnesium deficiency contributes to SIDS. Muscle strength is seriously impaired in the young magnesium deficient subject, while magnesium rapidly reverses muscle weakness. In rats, marginal deprivation in dietary magnesium reduces exercise capacity, an early effect of magnesium deficiency which is preventable by consuming magnesium-enriched mineral water. It is concluded that magnesium deficiency is at least one major unifying factor that explains increased SIDS in prone sleeping infants.     

Intrauterine hypoxia and sudden infant death syndrome

Sudden infant death syndrome (SIDS) or crib or cot death are synonyms for the sudden, unexpected and unexplained death of an infant. The incidence of SIDS has been estimated to be from 1-2% to 3%. Protracted intrauterine hypoxia or recurrent hypoxic insults during fetal life undoubtedly influence the development of the central nervous structures as a tissue most susceptible to hypoxia, although well developed mechanisms of defense against hypoxia exist during the fetal life. The mechanisms underlying SIDS include neurologically compromised infants who are deprived of compensatory mechanisms during sleep, sustaining a hypoxic insult with alterations in neurotransmitter receptors within the regions involved in chemoreception and cardiovascular control. Changes in the brain result from perinatal prolonged hypoxia (persistent reticular pathways in the pons and medulla, astroglia in the brainstem, gliosis of brain nerve nuclei, defects in neurotransmitter receptors, neuronal apoptosis, microthrombosis, and hypoxic ischemic lesion). Hypoxic perinatal risk factors for SIDS included passive and active exposure to cigarette smoking in pregnancy, abuse of drugs, alcohol, coffee and medication in pregnancy, intrauterine growth retardation, perinatal hypoxia with or without resuscitation, preeclampsia, anemia in pregnancy, prematurity, multiparity, multiple pregnancy, pregnant women aged < 20 years and > 35 years, cardiocirculatory, pulmonary and endocrine diseases in pregnancy, and short time interval between two pregnancies. As cigarette smoking has been demonstrated to lead to fetoplacental insufficiency, which result in fetal hypoxia, it is concluded that hypoxia is a precondition for the occurrence of SIDS. Prenatal exposure to cigarette smoke decreases maternal red blood cell count, and concentrations of tyrosine and selenium, reduces fetal and neonatal cerebral blood flow, and increases maternal MCV, leukocytosis, especially neutrophils, monocytes and lymphocytes, maternal and fetal heart rate, systolic and diastolic blood pressure, resistance index in umbilical artery, fetal hemoglobin, cytokine, serotonine, dopamine, catecholamine, hypoxanthine, endorphin and interleukin-6. Pregnancy at a risk of hypoxia, especially in heavy smokers, is a major risk factor for SIDS, and such pregnancy requires close and intensive antenatal monitoring.     

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.     

Depression of hypoxic arousal response in adolescent mice following antenatal vasoactive intestinal polypeptide blockade

Late-gestation blockade of vasoactive intestinal polypeptide (VIP) activity in pregnant mice produces discrete morphological abnormalities in the somatosensory cortex of offspring. We investigated the functional implications of this lesion on the behavioural arousal response to moderate hypoxia. Pregnant mice received twice-daily injections of 200 μl saline (control), or saline + 50 μg VIP antagonist (anti-VIP) on embryonic days 17 and 18. Offspring were studied unrestrained at 6–7 weeks after birth, in a bias-flow whole-body plethysmograph during behavioural quiet sleep. Arousal was defined by movement (MVT) lasting >1 s. Hypoxic ventilatory (HVR) and arousal responses were measured during a 5 min exposure to 10 % O₂-3 % CO₂ (hypoxia); peripheral chemoreflex drive was estimated by transient hyperoxia administered at rest and end-hypoxia (Dejours-type test). MVTs increased in all mice during hypoxia, but in anti-VIP mice: (a) MVT onset was delayed (174 ± 90 vs. 108 ± 59 s from the start of hypoxia, anti-VIP vs. control;   P = 0.008  ); and (b) MVTs were less frequent, and total MVT time in hypoxia was less (8 ± 7 vs. 15 ± 9 %;   P = 0.03  ). The HVR, and peripheral drive at rest and end-hypoxia were comparable in control and anti-VIP mice. In conclusion, a significant arousal deficit was evident in anti-VIP mice. This was not associated with obviously deranged peripheral or brainstem-mediated responses to hypoxia during sleep. This may signal a general deficit in the way hypoxic distress is monitored and processed, and arousal initiated and sustained in these mice.     

Periodic breathing at high altitude and ventilatory responses to O2 and CO2

To determine the relationship between periodic breathing (PB) during sleep at high altitude and ventilatory chemosensitivities, we studied nine Japanese climbers who participated in the expedition to the Kunlun Mountains (7,167 m) in China in 1986. At sea level, ventilatory response to hypoxia (HVR) by isocapnic progressive hypoxia test and to hypercapnia (HCVR) by Read's method were examined. At altitude 5,360 m, respiratory movements of the chest and abdominal wall, SaO2, ECG, and HR were monitored. Seven climbers manifested PB during sleep. There was a significant correlation between PB during sleep and HVR and HCVR (p less than 0.05). All the climbers showed severe desaturation during sleep. There was a significant negative correlation between degree of desaturation during sleep and HVR (p less than 0.05). A negative correlation was also detected between PB and the degree of desaturation during sleep. We concluded that ventilatory chemosensitivities play an important role in eliciting PB and that climbers with high HVR can maintain their arterial oxygenation during sleep, due to hyperventilation induced by PB, which is considered an advantageous adaptation for lowland sojourners.     

Peripheral arterial chemoreceptors and sudden infant death syndrome

Sudden infant death syndrome (SIDS) is the major cause of death in infants between 1 month and 1 year of age. Two particular concerns are that (1) premature or low birth weight (<2500-g) infants have a 2- to 40-fold greater risk of dying of SIDS (depending on the sleep position) than infants born at term and of normal birth weight, and that (2) the proportion of premature infants dying of SIDS has increased from 12 to 34% between 1988 and 2003. Hypo- and hypersensitivity of peripheral arterial chemoreceptors (PACs) may be one biological mechanism that could help to explain the epidemiological association between the increased incidence of SIDS in formerly premature infants. Because premature infants are often exposed to the extremes of oxygen stress during early postnatal development, they are more likely to have a maladaptive response of PACs later in their lives. As the first line of defense that mediates an increase in ventilation to a hypoxic challenge during wakefulness and sleep, PACs also mediate arousal responses during sleep in response to an asphyxial event that is often associated with upper airway obstruction. In most mammalian species, PACs are not fully developed at birth and thus are vulnerable to plasticity-induced changes mediated by environmental exposures such as the extremes of oxygen tension. Hypoxic or hyperoxic exposure during early postnatal development can lead to hyposensitive or hypersensitive PAC responses later in life. Although baseline chemoreceptor activity may not be the cause of an initial hypoxic or asphyxial event, the level of peripheral chemoreceptor drive does modulate the (1) time to arousal, (2) resumption of airflow during airway obstruction, (3) escape behaviors during rebreathing, and (4) cardiorespiratory responses that result from activation of the laryngeal chemoreflex. The laryngeal chemoreflex can be stimulated by reflux of gastric contents above the upper esophageal sphincter, or an increase in nasopharyngeal secretions from upper respiratory tract infections--events that contribute to some cases of SIDS. In this review, evidence is presented that both hypo- and hypersensitivity of PACs may be disadvantageous to the premature infant who is placed in an at risk environment for the occurrence of hypoxemia/asphyxia event thereby predisposing the infant to SIDS.     

Is Tourette syndrome a cause of sudden infant death syndrome and childhood obstructive sleep apnea?

The cause of sudden infant death syndrome (SIDS) is unknown. Sleep-related impairment of respiratory control and arousal are postulated; hyperdopaminergic and hyposerotonergic dysfunction may contribute to events leading to infant apnea and SIDS. Psychosocial adversity and impulsive and compulsive behaviours characterize some families of SIDS victims. Tourette syndrome (TS) is a common hereditary neurobehavioral disorder characterized by the frequent presence of impulsive and compulsive behaviors. Sleep disorders are common and include sleep apnea and abnormal arousal. Hyperdopaminergic and hyposerotonergic abnormalities are postulated to contribute to the pathophyusiology of the disorder. The following is a report of the presence of incidents of infant apnea and SIDS in families in which TS was present. In an additional TS family, a child had obstructive sleep apnea syndrome (OSAS). Results of a preliminary survey suggest that TS gene carriers are at increased risk of life-threatening apneas of infancy and that the prevalence of SIDS in such families may be 2 to 5 times the prevalence in the general population. The presence in some pedigrees of sleep apnea in children and adults suggest that in some instances disorders of sleep-related ventilatory control and arousal occurring throughout the life-span share common pathophysiological mechanisms. © 1993 Wiley-Liss, Inc.     

Brainstem mechanisms underlying the sudden infant death syndrome: Evidence from human pathologic studies

The brainstem hypothesis is one of the leading hypotheses concerning the sudden infant death syndrome (SIDS). It states that SIDS, or an important subset of SIDS, is due to abnormal brainstem mechanisms in the control of respiration, chemosensitivity, autonomic regulation, and/or arousal which impairs the infant's response to life‐threatening, but often occurring, stressors during sleep (e.g., hypoxia, hypercarbia, asphyxia, hyperthermia) and leads to sudden death in a vulnerable developmental period. In this review, we summarize neuropathologic evidence from SIDS cases that support this hypothesis, beginning with the seminal report of subtle brainstem gliosis three decades ago. We focus upon recent neurochemical studies in our laboratory concerning the neurotransmitter serotonin (5‐HT) and its key role in mediating protective responses to homeostatic stressors via medullary circuits. The possible fetal origin of brainstem defects in SIDS is reviewed, including evidence for adverse effects of prenatal exposure to maternal cigarette smoking and alcohol upon the postnatal development of human brainstem 5‐HT pathways. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 223–233, 2009