Ventilation and ventilatory pattern during sleep in aborted sudden infant death syndrome

To assess ventilatory control during sleep in infants at risk for the sudden infant death syndrome (SIDS), we made serial measurements of resting tidal volume (Vt), respiratory cycle time (Ttot), and the ventilatory changes resulting from inhalation of 2% CO2 in aborted SIDS infants in rapid eye movement and quiet sleep and compared them to a group of normal infants during the first 4 months of life. Ventilation was measured by the barometric method, and sleep was staged using electroencephalogram, electrooculogram, and electromyogram and behavioral criteria. Although resting instantaneous minute ventilation (Vt/Ttot) was virtually the same in both groups of infants, Vt tended to be smaller (by up to 50% in the first 2 months) and Ttot tended to be shorter in aborted SIDS than in normal infants in both rapid eye movement and quiet sleep. The increase in the mean Vt/Ttot with 2% CO2 is greater by about 5 to 20% in aborted SIDS than in normal infants at 3 and 4 months of age in both sleep states. These findings, together with our previous findings that aborted SIDS infants have an increase in heart rate and a shortening of the QT interval, provide indirect evidence that infants at high risk for SIDS may have increased sympathoadrenal activity.     

Sudden infant death syndrome and prolongation of the QT interval

A standard lead II ECG was recorded during either the first or the fourth week of life or at both ages from 30 neonates whose sibling had died of the sudden infant death syndrome (SIDS). Electrocardiographic recordings also were obtained from 75 control neonates and from 52 adults who had had an infant who died of SIDS. The neonatal data revealed that the QT interval, corrected for heart rate (QTC), was longest during NREM (vs rapid eye movement [REM]) sleep. Furthermore, the QTC interval was longer within the fourth week than in the first week of life. However, the QTC interval of siblings of SIDS victims did not differ from that of the control infants, nor did the QT interval of parents of SIDS victims differ from published normal values. One neonate who subsequently died of SIDS did not have an abnormally long QTC interval. These data do not support the hypothesis that genetically determined prolongation of the QT interval plays a major role in SIDS.     

Effect of sleep state on the QT interval in normal infants.

Twenty QT intervals selected at random from the middle periods of rapid eye movement (REM) and quiet sleep were measured in 12 normal infants studied at 2 weeks and 1, 2, 3, and 4 months of life. A digitizing system, consisting of a precision rotational potentiometer mounted on a pair of calipers and an A/D converter, was used for measurements. An accuracy of +/- 2 msec was achieved by high resolution of the digitized signal and calibration of each QT measurement with an accurately generated time code. Sleep staging was done visually using an electroencephalogram (EEG), an electrooculogram (EOG), a submental electromyogram (EMG), and behavioral criteria. Our results show that the QT index (QTc = QT/square rootRR) was significantly greater during quiet sleep (mean = 0.439) than during REM sleep (mean = 0.433) (P less than 0.01) and that this difference existed at all ages studied.     

Heart rate variation in normal infants and victims of the sudden infant death syndrome

Infants who later succumb to the sudden infant death syndrome (SIDS) exhibit lower overall heart rate variability during waking than do other infants. This study attempts to determine which type or types of heart rate variation are reduced in SIDS victims. Long-term recordings of heart rate and respiration were obtained from normal infants and infants who later died of SIDS, and heart rate variation in three frequency bands was examined: respiratory sinus arrhythmia (periods 0.9-3.0 s), 'mid-frequency' (periods 4.0-7.5 s) and 'low-frequency' (periods 12-30 s). All three types of heart rate variation were diminished in SIDS victims under 1 month of age during waking and rapid eye movement (REM) sleep compared with controls. Partitioning heart rate effects showed that in waking, and to a lesser extent in REM sleep, the reduction in all types of heart rate variation exceeded that which would have been predicted based on higher heart rates in SIDS victims. No heart rate-independent reduction in any type of heart rate variation was observed in quiet sleep. This state-dependent reduction in three types of heart rate variation could indicate an abnormality of autonomic control mechanisms during waking and REM sleep in infants who later succumb to SIDS.     

Responses to partial nasal obstruction in sleeping infants

Partial nasal obstruction was performed during a morning of quiet sleep (QS: non-REM) and active sleep (AS: REM) at ages 1 week, 2 weeks, 1, 2, 3, 4 and 6 months on 12 normal infants, 15 subsequent siblings of victims of the Sudden Infant Death Syndrome (SIDS) and 12 infants admitted for investigation of infant apnoea ('near-miss' SIDS). In all three groups the numbers failing to arouse after 240 s (FTA-240) in QS were significantly greater than those in AS. After 2 months of age all groups showed a decrease in the number FTA-240 in AS, whereas in QS the number did not change significantly. Subsequent siblings of SIDS had a significantly higher number FTA-240 in QS than controls. There was no significant difference in FTA-240 in QS between controls and infant apnoeas, although there was a trend for this to be higher in subsequent siblings of SIDS than infant apnoeas.
It was concluded that arousal from AS is more marked than from QS, that after 2 months of age the ability to arouse from AS increases, and that in relation to SIDS, QS is the sleep state in which the infant is less able to arouse. Furthermore, subsequent siblings of SIDS differ from normal infants in their ability to arouse from QS.     

Responses to partial nasal obstruction in sleeping infants

Partial nasal obstruction was performed during a morning of quiet sleep (QS: non-REM) and active sleep (AS: REM) at ages 1 week, 2 weeks, 1, 2, 3, 4 and 6 months on 12 normal infants, 15 subsequent siblings of victims of the Sudden Infant Death Syndrome (SIDS) and 12 infants admitted for investigation of infant apnoea ('near-miss' SIDS). In all three groups the numbers failing to arouse after 240 s (FTA-240) in QS were significantly greater than those in AS. After 2 months of age all groups showed a decrease in the number FTA-240 in AS, whereas in QS the number did not change significantly. Subsequent siblings of SIDS had a significantly higher number FTA-240 in QS than controls. There was no significant difference in FTA-240 in QS between controls and infant apnoeas, although there was a trend for this to be higher in subsequent siblings of SIDS than infant apnoeas. It was concluded that arousal from AS is more marked than from QS, that after 2 months of age the ability to arouse from AS increases, and that in relation to SIDS, QS is the sleep state in which the infant is less able to arouse. Furthermore, subsequent siblings of SIDS differ from normal infants in their ability to arouse from QS.     

Measures of cardiac repolarization and body position in infants

Sudden Infant Death Syndrome (SIDS) is the most common cause of death in children between 1 and 6 months of age. Recent data suggest that a prolonged QTc interval on the 12-lead electrocardiogram (ECG) is associated with SIDS. Prone body position during sleep is also known to be a risk factor for SIDS; this has prompted the American Academy of Pediatrics to promote the "Back to Sleep" campaign. We postulated that the QTc interval in infants might change as a function of body position, linking the observations relating body position and QTc interval to SIDS. We recorded ECGs in a group of infants in both the supine and prone position to determine if the QTc interval and QT dispersion differ between the 2 positions. Forty-seven standard 12-lead EGGs and high-amplitude, rapid-sweep 12-lead EGGs were performed on 45 healthy infants (mean age 26 +/- 40 days) in both the supine and prone positions. The infants were asleep in a quiet, restful state. The ECGs were reviewed by 2 investigators blinded to the position of the infants during recording. Measurements included the average QTc interval (using Bazett's correction) and QT dispersion (the difference between the longest and the shortest QT intervals on a standard 12-lead EKG). The study was designed to detect a 3% difference in QTc interval with 80% power and alpha = 0.05. All subjects had telephone or clinical follow-up at 1 year. The average QTc interval was 403 +/- 20 milliseconds (msec) in the supine position and 405 +/- 27 msec in the prone position (p = NS). The QT dispersion was 20 +/- 12 msec in the supine position and 22 +/- 13 msec in the prone position (p = NS). One infant in the study group died of SIDS at the age of 3 months. The EGG of this patient revealed a QTc interval of 382 msec in the supine position and 407 msec in the prone position; the QT dispersion was 34 msec in the supine position and 34 msec in the prone position. We found no difference in QTc interval or QT dispersion as a function of body position in healthy infants resting quietly. Prolongation of the QTc interval is unlikely to explain the increased risk for SIDS associated with prone body position in the general population of healthy infants, unless patients with long QT syndrome are somehow more influenced by body position than normal patients are.     

Transepidermal water loss during sleep in infants at risk for sudden death

To search for excessive sweating during sleep in infants considered at risk for sudden infant death syndrome (SIDS), we studied 258 infants during one night. There were 134 normal infants (controls), 85 siblings of SIDS victims (siblings), and 39 infants who survived an apparent life-threatening event (ALTE) with no cause found for the incident. Mean postnatal ages were between 10 and 16 weeks. Transepidermal water evaporation rate was measured from the forehead using an evaporimeter during one night's polygraphic sleep recording. Measurements were made before feedings, during the first part of the night, and evaporation rate values were expressed as grams per square meter of body surface area per hour. In the three groups of patients evaporation rates were significantly lower during rapid eye movement (REM) sleep, compared with values measured during quiet wakefulness or nonrapid eye movement (NREM) sleep. Infants with an ALTE had significantly higher evaporation rate values during NREM sleep than the two other groups (20.1 +/- 1.93, 11.3 +/- 0.68, and 11.5 +/- 0.98 for the ALTE, control, and sibling infants, respectively). The differences were not related to age, sex, weight, or rectal temperature. During NREM sleep, evaporation rate values greater than 25 mg/m2/h were seen in 10/190 (5.3%) of the asymptomatic infants and in 11/36 (30.6%) of the infants with an ALTE. The results are in agreement with reports in the literature of repeated night sweating in infants who eventually died of SIDS. Although we are unable to conclude why evaporation rate values are higher in the ALTE group than in the two other groups, we cannot exclude that it reflects differences in autonomous system activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered arousal response in infants exposed to cigarette smoke.

AIMS: A failure of the arousal mechanism is a key feature in the apnoea theory for sudden infant death syndrome (SIDS). In infants studied at an age when the incidence of SIDS is highest, we evaluated whether in utero smoke exposed infants have altered arousal response to standardised auditory stimuli, and/or sleep pattern, as recorded on overnight complex sleep polysomnography. METHODS: A standardised sequence of audiology stimuli was applied binaurally to 20 in utero smoke and non-smoke exposed infants aged 8-12 weeks during a rapid eye movement (REM) and NREM epoch, in a controlled (temperature, position, pacifier use, noise) sleep environment. Infants were monitored for 10-12 hours using complex sleep polysomnography. RESULTS: Five infants exposed to in utero tobacco smoke did not have behavioural arousal response, whereas all non-smoke exposed infants aroused during NREM (p = 0.016). There was, however, no difference in REM sleep, and the groups did not differ in routine overnight complex sleep polysomnography parameters. CONCLUSION: At the age when the incidence of SIDS is at its peak, infants of smoking mothers are less rousable than those of non-smoking mothers in NREM sleep; this may partly explain why such infants are more at risk of SIDS.     

Altered arousal response in infants exposed to cigarette smoke

Aims: A failure of the arousal mechanism is a key feature in the apnoea theory for sudden infant death syndrome (SIDS). In infants studied at an age when the incidence of SIDS is highest, we evaluated whether in utero smoke exposed infants have altered arousal response to standardised auditory stimuli, and/or sleep pattern, as recorded on overnight complex sleep polysomnography. Methods: A standardised sequence of audiology stimuli was applied binaurally to 20 in utero smoke and non-smoke exposed infants aged 8–12 weeks during a rapid eye movement (REM) and NREM epoch, in a controlled (temperature, position, pacifier use, noise) sleep environment. Infants were monitored for 10–12 hours using complex sleep polysomnography. Results: Five infants exposed to in utero tobacco smoke did not have behavioural arousal response, whereas all non-smoke exposed infants aroused during NREM (p = 0.016). There was, however, no difference in REM sleep, and the groups did not differ in routine overnight complex sleep polysomnography parameters. Conclusion: At the age when the incidence of SIDS is at its peak, infants of smoking mothers are less rousable than those of non-smoking mothers in NREM sleep; this may partly explain why such infants are more at risk of SIDS.     

Determination of sleep state in infants using respiratory variability

Sleep staging has been conventionally performed using neurophysiologic and behavioral criteria. However, these criteria may not always be available. Since it is known that cardiorespiratory variables in rapid eye movement (REM) sleep are different from those in quiet sleep, we asked whether such variables can be used for the determination of sleep state. We studied nine normal full-term infants at 1 and 4 months of life. Ventilation was measured using barometric plethysmography and the RR interval using a high accuracy R wave detector. Electroencephalogram, electrooculogram, and postural muscle electromyogram were recorded using surface electrodes and behavioral criteria applied. Means of RR interval, respiratory cycle time and tidal volume, and coefficients of variation of the same variables, were obtained for 30-s intervals throughout each sleep study. The Kolmogorov-Smirnov distances between REM and quiet sleep were larger for the coefficients of variation than for the means at both ages for all variables. Moreover, coefficient of variation of respiratory cycle time was found to provide the largest separation between REM and quiet sleep. In view of this result, we developed a statistical decision rule using coefficient of variation of respiratory cycle time for the classification of REM and quiet sleep in blocks of 5-min periods. Each study was divided into 5-min epochs and this rule was applied to each epoch. Of 85 epochs staged as quiet sleep by neurophysiologic and behavioral criteria, 79 epochs (or 93%) were classified correctly as quiet sleep using our decision rule. Of 85 epochs staged as REM sleep, 84 were classified as REM sleep and only one misclassified as quiet sleep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pneumograms in infants who subsequently died of sudden infant death syndrome

Victims of sudden infant death syndrome (SIDS) have occasionally been reported to have had prolonged apnea or an increased frequency of short apnea prior to their deaths. To examine the extent of these abnormalities, we compared pneumograms obtained in 17 infants who subsequently died of SIDS (10 with history of apnea) with those of 34 age- and sex-matched controls. The recordings were analyzed by a computer program that avoided observer bias. SIDS infants had significantly greater mean heart rate (P less than 0.05) and periodic breathing during quiet time (P less than 0.003) than control infants had. The apnea in SIDS infants tended to be more periodic than in control infants (P less than 0.002). In addition, the incidence of bradycardia was greater in SIDS (three infants) than in controls (none) (P less than 0.03). These differences suggest a disturbance of autonomic function prior to death in some victims of SIDS.     

Sleep apnea in infants who succumb to the sudden infant death syndrome

Previous studies have shown the frequency of respiratory pauses to be altered in groups of infants at risk for the sudden infant death syndrome (SIDS). In this study, we assess the frequency of apneic pauses during quiet sleep and rapid eye movement sleep in control infants and infants who subsequently died of SIDS. Sleep states were identified in 12-hour physiological recordings of SIDS victims and matched control infants, and the number of respiratory pauses from 4 to 30 seconds in duration was computed for quiet sleep and rapid eye movement sleep. SIDS victims 40 to 65 days of age showed significantly fewer apneic pauses than did age-matched control infants across the two sleep states. Fewer short respiratory pauses accounted for most of the reduction in number of apneic events in the SIDS victims during both sleep states. During the first month of life, SIDS victims did not differ significantly from control neonates on this measure. The finding that this respiratory difference exists during the second month of life, just before the period of maximal risk for SIDS, but not earlier, may have implications for the etiology of SIDS deaths.     

Maturation of cardiac control in full-term and preterm infants during sleep

ECG and respiration were recorded from 13 full-term and 8 preterm infants at 2–5-week intervals during sleep at home in the first year of life. Average pulse interval in both quiet and active sleep was minimum at postnatal ages between 4 and 10 weeks, with the minimum during quiet sleep being significantly smaller for preterm (409 ±22 (SE) msec) than for full-term (445 ±9 msec) infants. The minimum average pulse interval of preterm infants was smaller than the pulse interval of full-term infants at any postconceptional age, and a smaller average pulse interval and smaller variations in pulse interval in preterm infants during quiet sleep persisted until a postnatal age of 7 months. The pulse interval variations attributable to respiration varied substantially with age. The results indicate that developmental changes in cardiac rate control are functions of both postnatal and postconceptional age, with the post-conceptional age at birth setting the mean level of pulse interval, a level which is then altered by development linked to postnatal age.     

Motility and arousal in near miss sudden infant death syndrome

Developmental sleep patterns were compared in infants at known risk for "near-miss" sudden infant death syndrome and age-matched normal infants. Near-miss SIDS infants had significant differences suggestive of a temporary developmental delay. They retained rapid eye movement (REM) sleep at neonatal proportions, and stage 2 non-REM sleep appeared later. They also had a significantly increased apnea index. Twenty-four-hour recordings of sleep and respiratory patterns in near-miss SIDS infants from 3 weeks through 6 months of age showed a significant reduction in number of body movements in REM, non-REM, and total sleep time and in percentage of movement time at 3 weeks through 3 months of age. These findings can be used to address the role of arousal threshold in infants at risk for SIDS.     

Central hypoventilation during quiet sleep in two infants.

Expired ventilation (VE), tidal volume (VT), frequency (f), and alveolar PCO2 (PACO2) were examined in six normal infants at 41 to 52 weeks post-conceptional age and in two infants who were apneic at birth. Their response to breathing 5% carbon dioxide in air and to 100% oxygen in quiet sleep were compared to those in rapid eye movement (REM) sleep. VE in normal infants was 259 ml/kg/min in REM and 200.2 ml/kg/min in quiet sleep with the difference being due to decreased carbon dioxide production and to decreased dead space. VE increased 34.4 ml/kg/min/mm Hg of PCO2 elevation with 5% carbon dioxide breathing during REM and was not significantly different during quiet sleep. During oxygen breathing VE fell by 32.7% at 30 seconds before increasing again. In the affected infants, VE and PACO2 during REM at 1 and 4 months were normal. At 1 month, during quiet sleep, each infant became apneic and PACO2 rose 9 and 8 mm Hg/min respectively. At this time mechanical ventilation was begun. At 4 months, during quiet sleep, VE was 0.064 and 0.063 ml/kg/min at PACO2 of 66 mm Hg in each infant. The change was due entirely to a decrease in VT to 2.3 and 2.5 ml/kg. At this time 5% carbon dioxide breathing given during normal ventilation in REM produced an abrupt fall in VT to 2.0 and 2.2 ml/kg with no change in frequency. Oxygen breathing during REM at one month had no effect but at 4 months produced apnea requiring mechanical ventilation after one minute. The findings suggest that the ventilatory response to carbon dioxide is (1) important in initiation of extrauterine ventilation and (2) in sustaining ventilation particularly in quiet sleep. It is not necessary in sustaining ventilation awake or in REM sleep and it represents a balance between the stimulatory and depressant effects of carbon dioxide on the central nervous system.     

Sudden infant death syndrome: abnormalities in short term fluctuations in heart rate and respiratory activity

In order to test the hypothesis that a defect in cardiorespiratory regulation contributes to death of infants from sudden infant death syndrome (SIDS), we analyzed the power spectra of heart rate and respiratory activity during 256-sec epochs of quiet sleep. Data were obtained from pneumogram recordings performed for 12 h at night on eight infants who subsequently died from SIDS and 22 age-matched control infants. We computed the heart rate and respiratory power spectra from a single epoch on each infant using an algorithm developed for an 8085 microprocessor system dedicated to this investigation. There was no statistically significant difference between SIDS and controls based on mean respiratory and heart rates. Spectral analysis revealed enhancement of low frequency power in the 0.02 to 0.1 Hz band in the heart rate power spectrum in the SIDS group compared to control (p less than 0.002) and dispersion in respiratory frequency as determined by the respiratory band width (p less than 0.00001). These data suggest that a predisposition to SIDS manifests itself in an abnormal pattern of fluctuations in heart rate and respiratory activity.     

Respiratory control in infants at increased risk for sudden infant death syndrome.

There is much debate relating to possible abnormalities in respiratory control mechanisms in infants considered at increased risk for sudden infant death syndrome (SIDS). The P0.1 occlusion technique was used to assess the central respiratory response to hyperoxic hypercapnia during quiet sleep in 21 normal infants, 13 siblings of SIDS victims, and 17 infants with apparent life threatening events. The slope of P0.1 plotted against carbon dioxide concentration increased exponentially with age, independent of body weight in each group. Birth weight has a significant effect on slope with a lower weight predisposing to a lower slope. Siblings as a group had a significantly lower slope at any given age than normal infants, whereas the infants who had had apparent life threatening events were not significantly different from the controls. As intragroup variation in both siblings and control groups greatly exceeded the significant intergroup differences observed, the technique cannot identify individual infants as belonging to one or other group.     

The diagnosis of sleep apnea--possibility for the prevention of SID?

Groups of children with a statistically enhanced risk for SIDS: siblings of SIDS-victims and other full-term and preterm infants with anamnestic signs for an enhanced risk of SIDS and a control group of healthy infants without anamnestic signs of risk were polysomnographically investigated in the first year of life. The mean apnoea duration (MA-value estimated by frequency and length of apnoeas greater than or equal to 3s) in the sleep states active and quiet sleep was calculated. During active sleep there is a significant inverse correlation between MA and postnatal age in the full-term and preterm SIDS-risk infants but not in the controls and siblings of SIDS-victims. In all age groups there are some children in the full-term and preterm infants with extremely enhanced MA-values. For 6 age groups of the first year of life the 90% percentile of the MA-value was calculated separately in the sleep states active and quiet sleep to select infants with an abnormal breathing pattern. This limit could be a help for the decision on therapy.     

Incidence and significance of primary abnormalities of cardiac rhythm in infants at high risk for sudden infant death syndrome

Summary The exact relationship between cardiac arrhythmias and sudden infant death syndrome (SIDS) is uncertain. Several reports have implicated both ventricular and supraventricular arrhythmias in isolated cases, but there have been no studies of the incidence or type of arrhythmias that occur in populations at risk for SIDS. Of 1699 infants at high risk for SIDS, 60 (4%) were found to have a primary cardiac arrhythmia (i.e., not associated with disordered respiration or apnea). The incidence of atrial and ventricular premature beats, supraventricular tachycardia, and Wolff-Parkinson-White syndrome was similar to the incidence found in normal infants. Primary bradycardia (defined as a heart rate less than 60 for greater than 10 s not associated with abnormal respiration) was the most common arrhythmia, occurring with a frequency and severity not seen in normal infants. Thirty-two infants experienced periodic bradycardia. In 19 of these latter infants, there were symptoms associated with these bradyarrhythmias that necessitated treatment. Heart rates as low as 20 beats/min were recorded. One infant presented with an episode of ventricular fibrillation and on further evaluation was noted to have recurrent bradyarrhythmias. In no infant was there abnormal prolongation of the QT interval. Primary bradyarrhythmias are seen at an increased incidence in infants at high risk for SIDS and may play a causal role in this syndrome. Most symptomatic infants can be adequately controlled with sympathomimetic or parasympatholytic therapy. Other cardiac arrhythmias occur at a rate similar to that in normal infants and are therefore unlikely to play a major role in SIDS.