Sleep influences on homeostatic functions: implications for sudden infant death syndrome
Introduction
Infants who later succumb to the sudden infant death syndrome (SIDS), although exhibiting no major signs of physiological distress, show a variety of altered state-related respiratory, cardiovascular and arousal characteristics prior to death. Some of these patterns are manifest shortly after birth, suggesting deficits originating in fetal life. Epidemiologic evidence of enhanced risk from prenatal exposure to tobacco use (Sawczenko and Fleming, 1996) and maternal anemia (Bulterys et al., 1990) also supports the hypothesis that damage early in development underlies risk for the syndrome. That possibility does not exclude the potential that specific postnatal environmental conditions, e.g. second-hand smoking, overheating, airway obstruction, etc., may act in concert with existing deficiencies to further enhance risk for a fatal event.
The approaches to determining the mechanisms of death in SIDS are multifaceted, and include the identification of neural sites recruited in response to breathing and cardiovascular challenges, deficient anatomic sites in infants who have succumbed, and physiological characteristics of infants exposed to homeostatic challenges during sleep. The latter issue is of particular interest, because appropriate responses to a breathing or cardiovascular challenge within sleep may necessitate a state change or arousal, and deficiencies within state-switching mechanisms must be explored, in addition to systems which regulate routine breathing or cardiac patterns.
Section snippets
Neurotransmitters: the role of acetylcholine and nicotinic receptor binding
Among the risk factors for SIDS, prime consideration must be given to the role of nicotine exposure. Both pre- and postnatal exposure substantially increases the risk for SIDS, with a remarkable dose-dependent risk increase with postnatal exposure. The mechanism operating with nicotine exposure is obscure; however, preliminary evidence suggests that, compared to controls, infants with prenatal exposure who later succumb show a failure to up-regulate nicotinic binding in defined brainstem areas
Sleeping position
Any discussion of mechanisms operative in SIDS must account for the enhanced risk for SIDS from the prone position (Fleming et al., 1990, Ponsonby et al., 1993). Several pathophysiological mechanisms could underlie the enhanced risk. These mechanisms include rebreathing of expired gases and suffocation from facial proximity to bedding (Kemp and Thach, 1991, Bolton et al., 1993, Kemp et al., 1993), enhanced arousal thresholds in the prone position (Franco et al., 1996, Franco et al., 1998) which
Thermal and other sleeping environment considerations
In the prone position, the infant is potentially at greater risk from the adverse effects of heat stress from a warm environment, or, more importantly, from heavy wrapping (Fleming et al., 1993, Tuffnell et al., 1995). In the supine position, the adverse effects of heavy wrapping are less important than in the prone position, unless the head is completely covered (Fleming et al., 1996). SIDS victims are found to have been more heavily wrapped than controls, and the homes are more likely to have
Arousal
Infants at risk for SIDS show a relative inability to arouse to afferent stimuli (Newman et al., 1989), and infants who later succumb tend to remain asleep in the early morning hours; i.e. the normal momentary arousals which emerge as infants pass from one sleep state to another, occur less frequently (Schechtman et al., 1992b). The prone sleeping position raises the arousal threshold (Franco et al., 1996, Franco et al., 1998). Thus, ventilatory or other challenges, to which the normal
Antecedent physiologic signs
Physiologic patterns found prior to death in SIDS infants indicate subtle disturbances; however, these differences are small, and require careful partitioning of state, time-of-day, and age for detection. The differences include a relatively fixed breathing pattern during sleep, with a diminution of the normal occurrences of short apnea (Schechtman et al., 1991), periods of tachycardia, and less pronounced changes in heart rate that normally accompany inspiration and expiration (Kluge et al.,
Potential for cardiovascular failure
Evidence from several sources (Meny et al., 1994, Fox et al., 1996) indicates that some infants who succumb while on monitors can show a sudden-onset, profound bradycardia while breathing movements continue and, in some subjects, continued heart rate slowing, even if ventilation is supported. As loss of perfusion continues, gasping efforts may emerge. Thus far, the sleep state in which the fatal sequence occurs is uncertain, and interpretation of the patterns is made difficult by sparse data
Neural sites
Multiple neural sites mediate respiratory/blood pressure compensatory interactions. Some of the sites are well described, but other interactions remain obscure. The peripheral aortic and carotid blood pressure sensors, afferent projections to the nucleus of the solitary tract, and projections from the dorsal medulla to ventral medullary areas have been well described. Other interactions between somatic musculature and vestibular sensory transducers, acting in coordination with breathing action
Gasping, eupnea and autoresuscitation
The pattern of heart rate and breathing variability in infants who later succumb suggests deficits in eupnea and routine cardiac patterning. Considerable evidence exists that neural areas controlling eupnea differ from those mediating autoresuscitative responses, such as gasping (Fung et al., 1994, St. John, 1996), although localizing the particular structures involved in eupnea versus gasping is controversial (Ramirez et al., 1998). When hypoxia and/or hypotension are sufficiently severe to
Experiments of nature
To determine neural areas which mediate cardiovascular and breathing control, it is often useful to turn to pathology. Children with Congenital Central Hypoventilation Syndrome (CCHS) show a loss of breathing drive during sleep and a failure of appropriate respiratory responses to central chemoreception, although peripheral chemoreception appears to remain at least partially intact (Gozal et al., 1993). The physiological characteristics of these patients provide useful models to assess
Summary
The findings suggest that neural deficits in particular regions, or a developmental delay in particular systems, underlie the fatal event in SIDS. The evidence from the prenatal environment suggests that the neural handicap is established in fetal life, although the precipitating event during the fatal sequence may result from a unique set of circumstances in the compromised infant during a critical developmental period (Filiano and Kinney, 1993). Continuing postnatal neural damage from
Acknowledgements
Supported by RO1-HD-22506, RO1-HL-22418 and P50-HL-60296 (RMH), the SIDS Alliance, RO1-HD-20991 and PO1-HD36379 (KCH), RO1-HD-10993 (BBT), the Foundation for the Study of Infant Deaths, and the US National Institutes of Health (PJF).
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