Tissue mineral levels in victims of sudden infant death syndrome II. Essential minerals: copper, zinc, calcium, and magnesium

Deficiencies of various vitamin and minerals per se have been suggested as possible causes of sudden infant death syndrome (SIDS). Further, a deficiency of essential minerals may lead to enhanced toxicity of toxic elements, in particular, lead and cadmium to explore the possibility of mineral deficiencies or interactions with the toxic metals, lead and cadmium, lung, liver, kidney, and rib specimens were obtained at autopsy from 66 SIDS infants and 23 infants who died suddenly from other cases. Tissue copper, zinc, calcium, and magnesium were measured by atomic absorption spectroscopy. No differences were found between SIDS and non-SIDS for any element in any tissue except for more magnesium in the liver (P less than 0.0001) and less copper in the lungs (P less than 0.02) in the SIDS group. Only sporadic interactions between toxic and essential elements could be found. We found no evidence of any essential mineral deficiencies per se or significant interactions of essential and toxic minerals that might potentiate the effects of toxic metals. The physiologic significance, if any, of the higher liver magnesium and lower lung copper found in SIDS is unclear.     

Increased muscularity of the pylmonary circulation in victims of sudden infant death syndrome.

It has recently become apparent that some victims of sudden infant death syndrome (SIDS) are chronically hypoxemic before death. In this study, the structural alterations in the pulmonary circulation of 15 victims of SIDS were examined using precise quantitative morphometric techniques applied to the injected and inflated lung. Increased muscularity of the pulmonary circulation has been demonstrated, as evidenced by the extension of muscle into arteries not usually muscularized during the first year of life, and by an increased thickness of the medial wall in some patients. This confirms the findings of Naeye and further justifies the shift of investigative efforts from the events immediately surrounding death to a search for chronic abnormalities.     

Elevated levels of hypoxanthine in vitreous humor indicate prolonged cerebral hypoxia in victims of sudden infant death syndrome

Hypoxanthine levels in vitreous humor from 32 infants who died of sudden infant death syndrome (SIDS) were determined and compared with levels found in eight children who died of trauma, drowning, or hanging and with levels from seven neonates dying suddenly without long-standing antemortem hypoxia. Determination of hypoxanthine level was done with either a PO2 electrode method or high-performance liquid chromatography. The results obtained by both methods were significantly correlated; therefore they were pooled. The median hypoxanthine level in victims of SIDS (380 mumol/L) was significantly higher (P less than .001) than in the children who died violently (118 mumol/L). Moreover, the levels from the SIDS victims were significantly higher (P less than .001) than those from the neonates who died without long-standing hypoxia (53 mumol/L). It is concluded that SIDS is probably not a sudden event but may be preceded by a relatively long period of respiratory failure and hypoxia.     

Control of ventilation in subsequent siblings of victims of sudden infant death syndrome

To learn whether the ventilatory responses to hypoxia (17% O2) and hypercapnea (4% CO2) differ in the subsequent siblings of sudden infant death victims (SIDS), we studied seven normal control infants, nine infants who had had a prolonged apneic spell (apneic infants), and 10 subsequent siblings of SIDS (mean ages 10.4 weeks, 15 weeks, and 10 weeks, respectively). With inhalation of 17% O2, one of seven controls, two of nine apneic infants, and seven of 10 siblings of SIDS breathed periodically (controls vs siblings, P less than 0.04). Heart rate and end-tidal PCO2 did not change, but respiratory rate decreased in the siblings (45 to 31 breaths per minute, P less than 0.001). Arousal occurred during 25% of the hypoxic challenges in the controls and apneic infants but was not seen in the siblings of SIDS (control vs siblings P less than 0.08, apneic vs siblings P less than 0.05). With inhalation of 4% CO2 there was a similar increase in estimated ventilation among the three groups. Arousal occurred 33% of the time in all three groups. Our findings show that, after 5 weeks of age, siblings of SIDS have a normal response to hypercapnea but respond to mild hypoxia with periodic breathing.     

Abnormal patterns of pulmonary neuroendocrine cells in victims of sudden infant death syndrome

Ventilatory dysfunction has become the main focus of current research in sudden infant death syndrome (SIDS). This has been correlated with structural abnormalities in the carotid body and respiratory nuclei of the brainstem. In recent studies, the denervating effect of asphyxial brainstem dysfunction on the pulmonary neuroendocrine cells, which probably function as chemoreceptors, was demonstrated and prompted the following study. The pulmonary neuroendocrine system was evaluated in 25 victims of SIDS and 20 control infants, ranging in age from 3 weeks to 7 months and 1 to 12 months, respectively. The pulmonary neuroendocrine cells were stained by the Churukian-Schenk method and the neuroendocrine cell-positive airway values expressed as a percentage of the total number of airways. The range of positive airway values for victims of SIDS was 2% to 97% with a median of 73%. In contrast, the range for the control infants was 1% to 44% with a median of 25.5%. The SIDS victims' percentage was significantly greater than the control infants' percentage (P less than .0001). The number of pulmonary neuroendocrine cells in positive airway was also increased among SIDS victims compared with control infants. The altered pulmonary neuroendocrine cell pattern could be attributable to either brainstem dysfunction or chronic hypoxia. These explanations are not, however, mutually exclusive of one another; in fact, it is possible that both mechanisms may be operative.     

Hypothermia and sudden infant death syndrome.

We recently reported an association between recurrent episodes of severe apnoea requiring vigorous resuscitation for which no cause could be found and episodic hypothermia. Two similar cases are now reported that give further evidence of a link between hypothermia and acute life threatening episodes of apnoea.     

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.     

Hypercapnic and hypoxic ventilatory and cardiac responses in school-aged siblings of sudden infant death syndrome victims.

Siblings of sudden infant death syndrome (SIDS) victims have been shown to have abnormal ventilatory patterns and altered responses to respiratory stimuli during infancy. To evaluate whether these abnormalities persist, we studied ventilatory responses in 20 older SIDS siblings (9.8 +/- 0.9 (mean +/- SEM) years of age) and 20 control subjects (10.2 +/- 0.9 years of age). To evaluate hypercapnic ventilatory responses, we had subjects rebreathe 5% carbon dioxide and 95% oxygen until end-tidal carbon dioxide tension reached 65 mm Hg. Instantaneous minute ventilation, mean inspiratory flow, and respiratory rate were calculated breath by breath. Hypercapnic responses did not differ between SIDS siblings (2.08 +/- 0.14 L/min per mm Hg) and control subjects (1.90 +/- 0.10 L/min per mm Hg; not significant). To assess hypoxic ventilatory responses, we asked subjects to rebreathe 13% oxygen and 7% carbon dioxide, with the balance nitrogen, at mixed-venous end-tidal carbon dioxide tension, until arterial oxygen saturation by pulse oximetry fell to 75%. No differences in hypoxic ventilatory responses were found between the SIDS siblings (-1.39 +/- 0.15 L/min/% saturation) and the control subjects (-1.22 +/- 0.17 L/min/% saturation; not significant). The mean inspiratory flow, tidal volume, respiratory rate, and heart rate responses to hypercapnia and hypoxia were also similar in the two groups. We conclude that there is no difference in hypercapnic and hypoxic ventilatory and cardiac responses, as assessed by rebreathing techniques, between school-aged SIDS siblings and control subjects. We speculate that in SIDS siblings the control of breathing is immature during infancy and that they achieve maturity of control and resolution of breathing abnormalities with time.     

Response to acute hypercapnia in the parents of victims of sudden infant death syndrome

The ventilatory response to acute hypercapnia was studied in 68 parents of victims of sudden infant death syndrome and 56 control subjects. Tidal volume, inspiratory time, and total respiratory cycle time were measured before and immediately after a vital capacity breath of 13% CO2 in oxygen. Instantaneous minute ventilation, mean inspiratory flow (tidal volume/inspiratory time), and respiratory timing (inspiratory time/total respiratory cycle time) were calculated. Both groups of subjects showed a marked increase in tidal volume (48.4% +/- 26.5%), instantaneous minute ventilation (56% +/- 35%), and tidal volume/inspiratory time (56.8% +/- 33.5%) after inhalation of the test gas, with little change in inspiratory time/total respiratory cycle time. There were no significant differences between the two groups for ventilation before or after inhalation of the test gas. The ventilatory response to acute hypercapnia is mediated by the peripheral chemoreceptors. These results suggest that an inherited abnormality of peripheral chemoreceptor function is unlikely to be a factor leading to sudden infant death syndrome.     

Microanatomy of vagal body paraganglia in infancy including victims of sudden infant death syndrome

The microanatomy of vagal body paraganglia (VBP) in the cephalic segment of both vagus nerves was evaluated in an autopsy study of 32 infants one year of age or younger. The study group included 14 victims of sudden infant death syndrome (SIDS) and 18 non-SIDS cases. VBP in both groups were located at or below the lower border of the ganglion nodosum, and were histologically identical to carotid body chemoreceptors, although spatially dispersed and much smaller in size. Using a combined step and serial sectioning technique, there were no significant differences between the two groups (i.e. SIDS vs. non-SIDS) with regard to microanatomy, number, distribution and size of VBP. The proportion of chief and sustentacular cells was similar to carotid body paraganglia. For the study group as a whole, VBP were present in 89% of vagus nerves, and were typically multiple with good correlation between the number of separate paraganglia on the two sides. Small collections of ectopic parathyroid chief cells were identified in 6% of nerve segments, and histologically should be distinguished from VBP. Although the microanatomy of VBP in the SIDS group was identical to that of non-SIDS, one cannot exclude an underlying functional abnormality with autonomic malregulation.     

Decreased autonomic responses to obstructive sleep events in future victims of sudden infant death syndrome.

To evaluate changes in autonomic nervous system controls in response to obstructive events in future victims of sudden infant death syndrome (SIDS), we studied the polysomnographic sleep recordings of 18 future SIDS infants and those of 36 matched control infants. A heart rate autoregressive power spectral analysis was performed preceding and after the obstructive apneas. The low-frequency to high-frequency power ratio was computed to evaluate sympathovagal balance. Future SIDS victims had significantly more obstructive apneas (p = 0.001) and mixed apneas (p = 0.005) than control infants. Obstructive events occurred mainly during rapid eye movement sleep in the two populations (84.5% in future SIDS victims and 95.8% in control infants; p = NS). Comparing heart rate power spectral analysis before and after obstructive apneas in rapid eye movement sleep, high-frequency power values were significantly lower and low-frequency to high-frequency power ratios higher in future SIDS victims than in control infants. Compared with preapnea values, low-frequency to high-frequency power ratios significantly decreased after obstructive apneas in control infants (p < 0.001) but not in the future SIDS victims. When the obstructive apneas were divided according to duration, the findings were seen mainly for long apneas. In conclusion, future SIDS victims were characterized by different autonomic status and responses to obstructive apneas during sleep. These findings could be relevant to mechanisms implicated in some cases of SIDS.     

Dummies and the sudden infant death syndrome.

The association between dummy use and sudden infant death syndrome (SIDS) was investigated in 485 deaths due to SIDS in the postneonatal age group and compared with 1800 control infants. Parental interviews were completed in 87% of subjects. The prevalence of dummy use in New Zealand is low and varies within New Zealand. Dummy use in the two week period before death was less in cases of SIDS than in the last two weeks for controls (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.57 to 1.02). Use of a dummy in the last sleep for cases of SIDS or in the nominated sleep for controls was significantly less in cases than controls (OR 0.44, 95% CI 0.26 to 0.73). The OR changed very little after controlling for a wide range of potential confounders. It is concluded that dummy use may protect against SIDS, but this observation needs to be repeated before dummies can be recommended for this purpose. If dummy sucking is protective then it is one of several factors that may explain the higher mortality from SIDS in New Zealand than in other countries, and may also explain in part the regional variation within New Zealand.     

Febrile convulsions and sudden infant death syndrome.

It has been suggested that sudden infant death syndrome (SIDS) and febrile convulsions are related aetiologically. We compared the risk of SIDS in 9877 siblings of children who had had febrile convulsions with that of 20 177 siblings of children who had never had febrile convulsions. We found no support for the shared susceptibility hypothesis.