Sudden infant deaths: stress, arousal and SIDS.

The prevalence of the Sudden Infant Death Syndrome (SIDS) has dropped in most countries following the development of education campaigns on the avoidance of preventable risk factors for SIDS. These include factors in the infant's micro environment, such as prenatal passive smoking, administration of sedative drugs, prone sleep, high ambient temperature or sleeping with the face covered. Sleep laboratory studies have shown that these risk conditions contribute to the development of respiratory and autonomic disorders and reduce the child's arousability. The opposite effects were seen when studying factors protective from SIDS, such as breastfeeding or the use of a pacifier. In victims of SIDS, similar breathing, autonomic and arousal characteristics were recorded days or weeks before their death. It is concluded that in some infants, already immature control mechanisms can be aggravated by environmental factors.

Sudden infant deaths: from epidemiology to physiology.

The incidence of sudden infant death syndrome (SIDS) has dropped significantly in most countries following the development of education campaigns on the avoidance of risk factors for SIDS. However, questions have been raised about the physiological mechanism responsible for the effects of these environmental risk factors. Since 1985, a series of prospective, multicentric studies have been developed to address these questions; over 20,000 infants were recorded during one night in a sleep laboratory and among these, 40 infants eventually died of SIDS. In this review, the following methods were employed: sleep recordings and analysis, monitoring procedure, data analysis of sleep stages, cardiorespiratory and oxygen saturation, scoring of arousals, spectral analysis of the heart rate and the determination of arousal thresholds, and statistical analysis and the results including sleep apneas, arousals and heart rate and autonomic controls in both future SIDS victims and normal infants were introduced separately. In addition, the physiological effect of prenatal risk factors (maternal smoking during gestation) and postnatal risk factors (administration of sedative drugs, prone sleeping position, ambient temperature, sleeping with the face covered by a bed sheet, pacifiers and breastfeeding) in normal infants were analyzed. In conclusion, the physiological studies undertaken on the basis of epidemiological findings provide some clues about the physiological mechanisms linked with SIDS. Although the description of the mechanisms responsible for SIDS is still far from complete, it appears to involve both arousal responses and cardiac autonomic controls during sleep-wake processes.

Vasomotor reactivity in premature neonates at term.

In order to assess the specific sympathetic reactivity in premature infants at term, we designed a study to evaluate the peripheral vasomotor response of such infants when exposed to auditory challenges. Testing was performed in 29 premature neonates at term in both quiet and active sleep during a morning session. Two types of noises were used (click and continuous tones) at three frequencies (250, 1,000 and 6,000 Hz) and at three intensities (60, 85 and 110 dBA). Vasomotor response was studied by analyzing with Mathlab software the variability of the plethysmographic wave of the oxymetric pulse. No behavioral awakening was observed in response to any stimulation. When a tachycardia or a bradycardia reaction to the stimuli was observed, all neonates responded with a vasoconstriction. The global mean of the vasoconstrictive response was 18.45%. The overall ANOVA on the vasomotor response revealed significant effects for sleep stages (t: 1.98; p < 0.05), for frequency (t: 3.3; p < 0.001) and for intensity of noise (t: 3.01; p < 0.03) but no significant response with heart rate variability. From these results, we could conclude that the assessment of the vasomotor response is a very sensitive procedure to determine the reactivity of the autonomic nervous system in neonates, and could be used to study such vegetative responses in other stressful situations with good accuracy.

Developmental characteristics of apnea in infants who succumb to sudden infant death syndrome.

We compared the breathing characteristics of 40 infants who subsequently died of sudden infant death syndrome (SIDS) with those of 607 healthy infants matched for sex and age. The infants were between 2 and 19 wk old at the time of recording. Compared with the control group, the infants who died of SIDS experienced significantly more frequent episodes of obstructive and mixed sleep apnea. The duration of the apneic episodes did not exceed 15 s. Moreover, the SIDS group had a greater proportion of infants with obstructive and mixed apneic episodes than did the control group. In both groups, the frequency of episodes among male infants with apnea was greater than that among female infants. After the age of 9 wk, the proportion of male infants with episodes of obstructive apnea was greater in the SIDS group than in the control group. The frequency of apneic episodes decreased with age. The rate of decrease was significantly greater in the control subjects than in the SIDS group. This finding was made mainly in male infants. The present study provides further indirect evidence for a slower maturation of respiratory control in some infants who ultimately die of SIDS.

Maternal education and risk factors for sudden death in infants. Working Group of the Groupe Belge de Pédiatres Francophones.

UNLABELLED: To monitor infant care practices associated with risks for sudden infant death, 400 Belgian families with infants less than 6 months old were questioned by 21 paediatricians during routine visits to local paediatric practices and well baby services (11 in urban centres, 10 in rural areas). Because of incomplete information, 35 families were excluded. Of the 365 mothers included in the study, 36.1% had under 7 years of schooling, 38.4% less than 13 years, and 25.5% had a professional school or a university degree. Risk factors for sudden infant death were found in 208 (56.9%) families: a usual non-supine sleep position (31.5% of the infants); sleeping under a duvet (24.1%); mothers smoking during and after gestation (16.4%); a high room temperature (6.6%); use of sedatives (3.8%); necklaces or plastic film in the cot (2.5%); and soft beddings (2.2%). Maternal education, but not the fathers' profession was significantly related to the number of risk factors (mean odds ratio of 4.4; 95% CI: 1.5 to 5.3; P = 0.001). A stepwise logistic regression analysis identified the mother's length of schooling as the single most significant independent factor for the presence of risk (P < 0.005). CONCLUSION: Less educated mothers reported having been informed of risk-reducing recommendations as frequently as better educated mothers. It can be concluded that future reduction in risks for sudden infant death syndrome should include new strategies designed to modify infant care practices.

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.

Reduced arousals following obstructive apneas in infants sleeping prone.

A decreased arousability and an increased risk for sudden infant death syndrome (SIDS) have been shown in infants sleeping prone. Obstructive apnea, a known risk factor for SIDS, is less often terminated by an arousal reaction in infants than in adults. The effect of body position on the arousal reaction to spontaneous respiratory events had not been previously studied in infants. The aim of our study was to see if body position has an influence on the frequency and delay of the arousal reaction to obstructive apnea. All obstructive events recorded during two successive nights in 20 infants sleeping one night prone and one night supine were studied. During the supine recording 153 obstructive events were detected, and 217 were detected during the prone session. Prone sleep was not associated with an increased frequency of obstructive apneas. Total sleep time was 382 min (range, 283-456) supine and 423 min (range, 325-521) prone (p = 0.003). Obstructive events duration was 6.5 s (range, 3-21.5) when sleeping supine and 8 s (range, 3.5-30.5) when prone (p = 0.002). Behavioral arousal were found in 57.5 % of obstructive events recorded supine and in 31.3 % of those seen prone (p < 0.001). Arousal occurred after 8 s (range, 0-21) from the start of the obstructions when supine and 10.5 s (range, 3.5-23.5) when prone (p = 0.001). Sighs were found in 34 % of supine obstructive events and in 44.7 % of those prone (p = 0.040). A reaction, i.e. arousal or sigh, was found in 91.5 % of supine events and 76 % of those prone (p < 0.001). We conclude that when sleeping supine, infants arouse to obstructive events more often and after shorter delay than when prone.

Factors influencing the determination of arousal thresholds in infants - a review.

Objective: To review the major confounding factors that influence the determination of arousal thresholds in infants.Review of confounding factors: The determination of arousal thresholds in infants measures their arousability from sleep. The evaluation is influenced by various conditions. The infant's arousability is decreased by maternal factors, such as exposure to cigarette smoke, alcohol, illegal drugs or medications during gestation or breastfeeding. The levels of arousal thresholds also depend on the age of the infant and on experimental conditions, such as previous sleep deprivation, type of arousal challenges, time of administration of the arousal challenge, sleep stage, body position, room temperature, use of a pacifier, bed sharing, or type of feeding. In addition, spontaneous arousals can occur and modify the infant's response to external arousal challenges.Conclusions: Factors known to modify infants' arousability from sleep should be controlled during studies designed to determine arousal thresholds.

The influence of a pacifier on infants' arousals from sleep.

OBJECTIVE: The risk of sudden infant death during sleep was postulated to decrease with the use of a pacifier and by conditions facilitating arousals from sleep. We evaluated the influence of a pacifier on arousal from sleep in healthy infants. STUDY DESIGN: Fifty-six healthy infants were studied with polygraphy during 1 night; 36 infants used a pacifier regularly during sleep, and 20 never used a pacifier. Thumb users or occasional pacifier users were not included in the study. The infants were recorded at a median age of 10 weeks (range 6 to 19 weeks). To evaluate auditory arousal thresholds, the infants were exposed to white noise of increasing intensity during rapid eye movement sleep. RESULTS: Polygraphic arousals occurred at significantly lower auditory stimuli in pacifier users than in nonusers (P =.010). Compared with nonusers, pacifier users were more frequently bottle-fed than breast-fed (P =. 036). Among infants sleeping without a pacifier, breast-fed infants had lower auditory thresholds than bottle-fed infants (P =.049). CONCLUSIONS: Infants using pacifiers during sleep had lower auditory arousal thresholds than those who did not use a pacifier during sleep. Breast-feeding could be a further factor contributing to lower arousal thresholds. These findings could be relevant to the occurrence of sudden infant deaths during sleep.

Prenatal exposure to cigarette smoking is associated with a decrease in arousal in infants.

OBJECTIVE: Sudden infant death syndrome has been related to both exposure to prenatal cigarette smoke and impaired arousability from sleep. We evaluated whether healthy infants born to mothers who smoked during pregnancy had higher auditory arousal thresholds than those born to mothers who did not smoke and whether the effects of smoking occurred before birth. STUDY DESIGN: Twenty-six newborns were studied with polygraphic recordings for 1 night: 13 were born to mothers who did not smoke, and 13 were born to mothers who smoked (>9 cigarettes per day). Other infants with a median postnatal age of 12 weeks were also studied, 21 born to nonsmoking mothers and 21 born to smoking mothers. White noise of increasing intensity was administered during rapid eye movement sleep to evaluate arousal and awakening thresholds. RESULTS: More intense auditory stimuli were needed to induce arousals in newborns (P =.002) and infants (P =. 044) of smokers than in infants of nonsmokers. Behavioral awakening occurred significantly less frequently in the newborns of smokers (P =.002) than of nonsmokers. CONCLUSIONS: Newborns and infants born to smoking mothers had higher arousal thresholds to auditory challenges than those born to nonsmoking mothers. The impact of exposure to cigarette smoke occurred before birth.

Development of cardiopulmonary integration and the role of arousability from sleep.

The recent literature on cardiopulmonary integration in infants is surveyed here, focusing on arousals from sleep. Recent studies reported that the ontogenicity of cardiopulmonary integration cannot be evaluated independently from that of sleep-wake cycles. The issue is of importance for researchers and clinicians evaluating cardiorespiratory characteristics in infants. It also has significant implications in the understanding of clinical conditions, such as parasomnias, obstructive sleep apneas, or some cases of sudden infant death syndrome. The propensity to arouse can be evaluated by exposing the sleeper to awakening challenges. Arousal thresholds are determined by measuring the intensity of the stimulus needed to induce arousals. However, these studies are complicated by factors such as the scoring of the arousal responses. Another difficulty lies in the choice and modality of the arousal stimulus. Noise, gases, light, and nociceptive, mechanical, chemical, or temperature stimuli have all been used to induce arousals. Confounding factors modify the sleeper's responses to a given stimulus. Prenatal drug, alcohol, or cigarette use and the infant's age or, previous sleep deprivation also modify thresholds. Other confounding factors include time of the night, sleep stages, the sleeper's body position, and sleeping conditions. Arousal can also occur spontaneously because of endogenous stimuli. The literature surveyed here also covers such unresolved issues as the clinical significance of aborted arousals, or the mechanisms responsible for the arousal reactions.

Erythrocyte Ca2(+)-ATPase: activation by enzyme oligomerization versus by calmodulin.

The subject of our studies is the mechanism of activation of the erythrocyte Ca2(+)-ATPase. Using purified, detergent solubilized enzyme it was found that equivalent maximal Ca2(+)-ATPase activity is obtained either upon addition of calmodulin or upon increase of enzyme concentration. Three independent methods, including Ca2(+)-ATPase activity, polarization of the enzyme modified with an external fluorescent probe, and efficiency of fluorescence resonance energy transfer between enzyme molecules have established that the concentration dependent activation is due to enzyme oligomerization. The oligomers bind calmodulin with a lower stoichiometry (0.5 mol calmodulin/mol Ca2(+)-ATPase), higher Ca2+ affinity (KCa = pCa 7.4), and higher cooperativity for Ca2+ (nH = 2.6) than the monomeric form (stoichiometry = 1 mol calmodulin/mol Ca2(+)-ATPase, KCa = pCa 7.0, nH = 1.1). The Ca2+ dependence of calmodulin binding and activation of monomers indicates that calmodulin binds before the Ca2(+)-ATPase activity is exhibited, demonstrating that the activation of this enzyme form is totally dependent on calmodulin. In contrast, oligomers reveal very similar Ca2+ dependence for calmodulin binding and for Ca2(+)-ATPase activity as well as for Ca2+ binding (assessed by tryptophan fluorescence), and for the oligomerization process (assessed by fluorescence energy transfer). The calmodulin antagonist drug 48/80 inhibits the calmodulin dependent activity of the monomers (I50 = 1.4 micrograms/ml) but has no effect on the activity of oligomers, confirming that calmodulin plays no role in the activation of the oligomeric enzyme. Our studies indicate that the erythrocyte Ca2(+)-ATPase can be activated by its high affinity, Ca2+ dependent binding of calmodulin or by a Ca2+ dependent oligomerization process which may involve calmodulin binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

The partial reactions in the catalytic cycle of the calcium-dependent adenosine triphosphatase purified from erythrocyte membranes.

A preparation of purified erythrocyte membrane ATPase whose activation by Ca2+ is or is not dependent on calmodulin depending on the enzyme dilution was used in the low dilution state for these studies. In appropriate conditions, the purified ATPase in the absence of calmodulin exhibited a Ca2+ concentration dependence identical to that of the native enzyme in the erythrocyte membrane ghost in the presence of calmodulin. Accordingly, an apparent Kd approximately equal to 1 X 10(-7) M was derived for cooperative calcium binding to the activating and transport sites of the nonphosphorylated enzyme. The kinetics of enzyme phosphorylation in the transient state following addition of ATP to enzyme activated with calcium were then resolved by rapid kinetic methods, demonstrating directly that phosphoenzyme formation precedes Pi production, consistent with the phosphoenzyme role as an intermediate in the catalytic cycle. Titration of a low affinity site (Kd approximately equal to 2 X 10(-3) M) with calcium produced inhibition of phosphoenzyme cleavage and favored reversal of the catalytic cycle, indicating that calcium dissociation from the transport sites precedes hydrolytic cleavage of the phosphoenzyme. The two different calcium dissociation constants of the nonphosphorylated and phosphorylated enzyme demonstrate that a phosphorylation-induced reduction of calcium affinity is the basic coupling mechanism of catalysis and active transport, with an energy expenditure of approximately 6 kcal/mol of calcium in standard conditions. From the kinetic point of view, a rate-limiting step is identified with the slow dissociation of calcium from the phosphoenzyme; another relatively slow step following hydrolytic cleavage and preceding recycling of the enzyme is suggested by the occurrence of a presteady state phosphoenzyme overshoot.