Intrathoracic Petechiae in Sudden Infant Death Syndrome
Copyrightã 2001 by James Michael Howard.
I think a connection of reduced dehydroepiandrosterone (DHEA) and intrathoracic petechiae in sudden infant death syndrome (SIDS) may be demonstrated. I intend to show this symptom occurs because of a disconnection in a cycle which stimulates DHEA during sleep. It is my hypothesis that levels of DHEA too low to support brainstem function in these infants may be the cause of SIDS. My explanation of sleep suggests DHEA declines during sleep, the lowest levels are reached during deep (non-REM) sleep. Normally these low levels of DHEA are sufficient to maintain brainstem activity. As DHEA levels decline, I think norepinephrine increases to stimulate DHEA so brainstem activity does not cease. Once DHEA levels reach sufficient levels, norepinephrine levels are reduced in a cycle. This cycle maintains brainstem activity during deepest sleep. (Support follows.)
Norepinephrine is directly connected to wakefulness. Dodt, et al., (Hypertension 1997; 30: 71-6) reported the following: "low activity of the noradrenergic branches depends mainly on horizontal body position during nocturnal sleep" and "standing up at the end of the experiment sharply increased norepinephrine concentrations by 180%, whereas epinephrine levels were less enhanced (46%) by the change of body position." and "During rapid eye movement sleep, both epinephrine and norepinephrine concentrations were significantly lower than during sleep stages 1 and 2 and slow-wave sleep." Osaka and Matsumura found that: "These results suggest that NA [noradrenaline, norepinephrine] promotes wakefulness by inhibiting sleep-active neurons and by exciting waking-active neurons" (Neurosci Res 1995; 21: 323-30). Norepinephrine is involved in wakefulness and is strongly affected by body position. Effects of DHEA are also affected by body position. "Changes in supine and standing systolic and standing diastolic blood pressures also related to changes in dehydroepiandrosterone sulphate." (Eur Heart J. 1998; 19: 1743-4). Increased norepinephrine is directly connected to blood pressure. Dodt, et al., found low levels of norepinephrine during REM sleep. This is to be expected since, according to my model of sleep, norepinephrine should stimulate DHEA. (It is also part of my explanation of sleep that REM sleep is the result of increased brain activity when DHEA rises slightly during sleep.) Once DHEA reaches sufficient levels, DHEA should reduce norepinephrine production. This is supported. "Our results suggest that the inhibitory effects of DHEA on secretion [of norepinephrine] mainly occur at nicotinic receptors as well as at the voltage-dependent Na+ channels." (Neurosci Lett 1996; 204: 181-4). The increase in DHEA reduces norepinephrine production, so during REM sleep, norepinephrine is reduced. Once DHEA reaches a certain level, norepinephrine production is inhibited, so sleep may continue. This is cycling of norepinephrine and DHEA during sleep.
It is my hypothesis that SIDS results from levels of DHEA too low to maintain brainstem function. A sign of this may reside in an ineffective stimulation of DHEA production by norepinephrine during deep sleep, that is, overproduction of norepinephrine if DHEA does not respond and subsequently inhibit norepinephrine production. This may be observed in sleep apnea. (At this point, for sake of clarity, I will take a brief aside to show a connection between sleep apnea and reduced DHEA. In other work, I have suggested that sleep apnea results from too little DHEA production to stimulate the nerves which maintain the structure of the throat, obstructive sleep apnea. An example in support: It is part of my theory that testosterone adversely affects the availability of DHEA, so testosterone and male sex should increase obstructive sleep apnea, even in infants. Testosterone administration to male, gonadectomized infant primates, significantly depressed hypercapnic ventilatory drive. "These results support the hypothesis that testosterone depresses hypercapnic ventilatory drive during sleep in the infant primate." (J Appl Physiol 1994; 76: 1786-93). This could account for increased occurrence of SIDS in male infants.) "There are cases in which subtle morphologic evidence suggests SIDS represents the termination of a chronic hypoxic/hypoxemic disorder such as recurrent apnea." (Pathol Annu 1984; 19: 1-14). I suggest low DHEA results in obstructive sleep apnea and cessation of brainstem function in SIDS.
A number of reports find sleep apnea is directly connected to increased norepinephrine. (According to this model, increased norepinephrine implies reduced DHEA stimulation.) This increase is quite dramatic in apnea in infants. "They also had serum norepinephrine levels that were elevated threefold while awake (P less than .05), 5.3-fold during quiet sleep (P less than .001), 3.2-fold during hypoxia (P less than .02), and 12-fold during recovery from hypoxia (P less than .001) in comparison with the corresponding levels in the four (23%) infants who aroused normally to hypoxia. It is speculated that elevated circulating catecholamines are associated with abnormal hypoxic arousal responses in children with apnea of infancy." (Pediatrics 1987; 79: 269-74). I suggest these infants survived for measurement of norepinephrine because they were eventually able to stimulate DHEA. However, these infants were close to death, following their recovery from hypoxia; their norepinephrine increased "12-fold." I suggest those "who aroused normally to hypoxia" were able to stimulate DHEA in a normal manner.
If an infant is not able to respond with DHEA production, I suggest norepinephrine production increases, because the norepinephrine-DHEA cycle is disconnected. As pointed out in the foregoing quotation, norepinephrine levels increase dramatically during hypoxia in some infants who do not arouse normally from hypoxia. SIDS is characterized by symptoms which are also produced by excessive norepinephrine, intrathoracic petechiae. "Petechial haemorrhages were identified at one or more intrathoracic site in 90% of SIDS and in 55% of explained cot deaths." (J Clin Pathol 1998; 51: 689-94). "These petechiae occur in more than 80% of SIDS cases, suggesting that abnormal intrathoracic pressure, perhaps caused by breathing against an obstructed airway, is a common terminal event." (Arch Pathol Lab Med 1984; 108: 77-9) Excessive norepinephrine may be the cause of these petechiae. This was reproduced in an animal model. "In a rat model, norepinephrine (0.02 mg/kg) caused systemic hypertension and numerous pulmonary petechiae, the latter a common finding in SIDS." (Pediatr Pathol 1984; 2: 115-22). The norepinephrine response to hypoxia may cause these petechiae prior to brainstem failure due to reduced DHEA. It should be noted that a single event does not produce petechiae. "A single fatal episode of apnoeic asphyxia did not produce any petechiae. In contrast, many lung petechiae resulted from the repeated obstructive apnoeic episodes." (Pathology 1980; 12: 181-8). DHEA produces a protective effect for nervous tissue during anoxia. "Our data indicate that pretreatment with DHEA and DHEAS at physiologically relevant concentrations promotes neuronal survival following anoxia in embryonic rat cerebral cortical cultures." (Brain Res 2000; 871: 104-12). I suggest periodic apneas result in damaged brainstem activity in infants of low DHEA in those infants who exhibit petechiae. That is, as each event occurs, DHEA response declines, resulting in increased norepinephrine production and petechiae until an event ends life. Prone sleeping may increase the incidence of SIDS. If this is the case, prone sleeping may increase the lethality of apnea and therefore the development of petechiae. That is, death occurs before significant effects of norepinephrine accrue. This is supported. "There was a decreased frequency of pleural petechiae in infants placed prone for their final sleep." (Pediatr Dev Pathol 1998; 1: 200-9). DHEA is proven to protect against bacterial and viral infections. Therefore, infections should increase the incidence of petechiae. This is supported in an animal model (Am J Dis Child 1980; 134: 364-6). Infections do not cause SIDS, but can increase the incidence of SIDS.
It is my hypothesis that sudden infant death syndrome results from insufficient dehydroepiandrosterone production to maintain brainstem function during sleep. Norepinephrine production stimulates DHEA during times of reduced DHEA during sleep. Disruption of various parts of a norepinephrine-DHEA-cycle should produce loss of brainstem function and, therefore, death. However, the findings that intrathoracic petechiae are common in SIDS suggests that the most common lost event in SIDS is DHEA production.