Some authors attribute the Sudden Infant Death Syndrome to cardiac conduction impairment [1-3]. Others, having studied the neurophysiology of the carotid baroreceptors and of the peripheral chemoreceptors, feel that impaired responses to hypoxia and arterial hypotension in animal fetuses during the final stage of pregnancy may be more relevant. Although many paediatricians consider Sudden Infant Death Syndrome to have its roots in a long QT syndrome type of disorder, we believe that it might more appropriately be described as the Sudden Respiratory Infant Death syndrome.
The term Sudden Infant Death Syndrome is misleading since the illness is characterized by sudden death as a result of failure to take into account some specific symptoms and causes. It is important to analyse the different events that precede onset of the syndrome (the course of pregnancy, any drugs taken by the mother, etc.), histological slides of bulbo-mesencephalic sections of any fetuses miscarried before the current pregnancy, or infants who died of Sudden Infant Death Syndrome, the pathogenic mechanisms related to the sequence of histological features, and any possible pre-existing causes that can be lethal even some days after birth.
Much research has focused on the prenatal, peripartum and post-partum periods, examining the possibility that such deaths could have been caused by a long-lasting inhibition of the activity of the respiratory muscles. At the end of pregnancy, physiological apoptosis eliminates the surplus number and the power of the inhibitory interneurones allowing the rhythms of the infant's physiological respiration to start up. This apoptosis occurs as a result of fatigue of the mother during the expulsive period. It is enhanced by hypoxia, hypoglycaemia, stress, hypotension, allergic reactions and hyperthermia, and is decreased by prematurely induced delivery, deep narcosis, abuse of alcohol and neurotropic drugs. A different aetiological process underlies sudden death in infants and in young athletes previously considered healthy.
Among the different aetiologies and genetic or acquired pathologies that can cause the sudden death of apparently healthy subjects, we have considered those regarding the specialist fields of the anaesthetist, the obstetrician and the paediatrician. In deceased fetuses and infants referred to our Centre ('Lino Rossi' Research Centre for the study and prevention of the unexpected perinatal and infant death, University of Milan), we have analysed histological changes in the motor neurones and in the inhibiting interneurones of the respiratory centres, and their connections with the respiratory muscles.
Sudden infant death has been described as 'an abrupt and inexplicable death of an apparently healthy infant'. Over the years, various theories have been advanced to explain such deaths including sleep-induced apnoea, laryngospasm and overwhelming infectious disease [1,2]. These were all classified as Sudden Infant Death Syndrome, and often attributed to cardiac arrest due to a long QT syndrome [3-6].
The first to come to a different conclusion was Bruni [7-9]. After three years of research, he came to "a general view slightly different from that based on theoretic conceptions and having today the highest support in Italy" . Bruni demonstrated that during the differentiating process of the mesenchymal cells, alterations in the subject and its environment could alter the cell's destinations. For example, the fibrocytes of scars can move and penetrate foreign bodies, phagocytose bacteria, destroy elements of damaged tissue, etc. Endothelial cells of blood-vessels, marrow, spleen, thymus, etc., may also undergo modifications in their morphology and function under the influence of different stimuli [7-10].
Bruni pointed out the importance of the connective tissue as a defensive organ, and the need for further study to increase knowledge in the field of immunology, but also proposed: "that the epithelial and nervous tissues, derived from the external and internal layer of the embryo, in particular events, can cause modifications" similar "to those of the tissues originating from the mesoderm" [7-9]. In addition, he advocated research into the possibility of revealing, in adults in particular spontaneous or artificial situations, the phenomenon of differentiation and the multiplication capacity of cells originating from myoblasts or neuroblasts, normally considered unable to reproduce [7-10].
In 1929, to better clarify all the functions of the Tropho-Defensive System, instead of only the morphological aspects, Bruni instead defined it as the Reticulo-Endothelial System [7-9], terminology which is still used today . At the end of the 1950s, the first Department of Resuscitation and Intensive Care in Europe was founded and anaesthesiologists became involved in the problems of respiratory insufficiency caused by neurological events (tetanus, spinal shock, intoxication by alcohol, curare, carbon monoxide, neurotropic drugs, pontobulbar viral polio, etc.).
Research on animals elicited the suggestion that spinal shock and pontobulbar poliomyelitis might be managed by the tropho-defensive system in a similar way. When the excitatory stimuli no longer reach the respiratory centres, the motor neurones do not receive inhibitory antidromic activity (from the interneurones), that normally imparts their rhythmic work and rest pattern. If the fibres of the respiratory muscles lose the synchronisation of their contractions, they become functionally ineffective (analogous to cardiac muscle in the case of fibrillation). If this persists, further deterioration due to hypoxia and glucose depletion ensues, producing a life-threatening condition due to respiratory overwork, hyperthermia and apoptosis of their inhibiting interneurones.
In the 1960s and 1970s, other research considering the plasticity of the perceptive mechanisms of pain and the treatment of traumatic shock of the spinal cord through tubocurarine was performed at the Universities of Milan [11,12], Massachusetts , Paris [14,15] and New York [16,17]. Experimental research conducted by Johnston and Gluckman in 1989  and Hirooka and colleagues in 1997  is still far from conclusive. Their studies were restricted to animals and in addition, the invasive techniques they used produced artifacts which make extrapolation to man inappropriate.
In the last two decades, the anatomist and pathologist Rossi has conducted in-depth research on sudden coronary death, on the structures of the human baroreflex and on cardiac arrhythmias, particularly in relation to sport medicine [20-25]. With respect to neurocardiac sudden death of adults, Rossi described a bulbo-spinal pathology with prominent life-threatening derangements of the oxygen-conserving cardio-inhibitory reflex (the dive-reflex and its subsets), and reconsidered the histopathology of the bulbo-spinal and the sympatho-vagal abnormalities and a possible underlying arrhythmogenic prolongation of the QT interval .
It is known that when divers lose their sense of direction, as a consequence of forced hyperventilation and/or dramatic anxiety, cardiac arrest can occur. Moreover, we have observed several cardiac arrests in subjects who have ingested a long, icy, fizzy drink after underwater fishing and correct emersion [26,27].
In 1999, Rossi published a Review 'Bulbo-spinal pathology in neurocardiac sudden death of adults: a pragmatic approach to a neglected problem' . He had the opportunity to study the bulbo-pontine interneurons of the Kölliker-Fuse nucleus, from the brain of fetuses and infants deceased before or after delivery [28,29].
Interest has shifted towards research on the genetic causes and attention was paid to the issue of an autosomal-recessive and an autosomal-dominant inheritance [30-33]. Keating [34-36] has identified the relationship of Long QT Syndrome with the Harvey ras-1 gene. In 1999 Rossi studied the neuropathology of unexpected death in adults , while in 2001 Towbin and colleagues [37-39] identified 5 genes coding for myocardial membrane potassium and sodium channels and the effects of mutations in these genes. It would be useful for anaesthesiologists and obstetricians to collect genetic data from the parents and the ancestors of infants and healthy sportsmen dying suddenly.
Our hypothesis reverts to the original works of Bruni, whose contributions [7-9] are useful to clarify the mechanisms involved, in our view, in sudden respiratory death of infants. The hypothesis considers the aetiological and pathogenic findings and implicates the following structures and mechanisms: the nervous centres of respiration (Kölliker-Fuse nucleus), the respiratory muscles, the tropho-defensive system, any administration of neurotropic drugs at the end of the embryonic period, deliberately anticipated delivery, general anaesthesia and insufficient apoptosis at the end of delivery of the inhibitory interneurones involved in impeding contractions of the respiratory muscles during the fetal period. The interested reader may refer to the excellent review 'Long QT syndrome and anaesthesia' by Wisely and Shipton .
Over the course of many years, we have examined embryos and human fetuses that died at different intrauterine periods or during delivery, as well as infants who died some weeks after birth. Invasive experiments on animals were deliberately eschewed because, since 1956, we have been involved in research in two main areas:
(a) The histopathological and aetiopathogenetic basis of some congenital malformations of the respiratory muscles revealing insufficient development or differentiation of the muscular tissues and other tissues derived from the mesenchyme (cartilage, tendons, ligaments, bony tissues, etc.)
(b) The effects produced by fatigue, hypoxia, hypoglycaemia, stress, and neurotropic drugs on the activity of the inhibitory centres and of the respiratory motor neurons.
The human respiratory centres have different features compared to those of animals. In man, each respiratory centre can have or assume various different features. The cerebral cortex motor centres also modulate breathing for vocal requirements. The bulbo-mesencephalic centres manage the movements of the diaphragm but also play a role in emotional situations (crying, laughing) and in the acts of coughing, sneezing and hiccupping. The cervical spinal cord controls the respiratory auxiliary muscles, but their inhibiting system is also deputed to coordinate the precision movements of the segments of the upper limb and the hands. The centres of the thoracoabdominal muscles are involved in breathing and contribute to bladder and bowel peristalsis. The lumbosacral interneurones inhibiting the motor neurons do not have a direct relationship with respiratory function, but their activity changes according to whether the subject is engaged in walking and running automatically on a treadmill or else is completing a cross country run, crowded with unforeseen events.
Today most researchers have 'rediscovered', after more than 70 years, that the human central nervous system does not stop growing at the age of 10 years but at the age of 20 and that brain activity can increase even in the mentally active elderly. The human central nervous system is much more complicated and plastic than the tenacious reductionism theories proposed. The functions of the nervous system and its survival are strictly dependent on the tropho-defensive system.
It could be hypothesized that when the tropho-defensive system is unable to modulate the activity of the respiratory inhibiting systems at birth, the newborn infant may die from inhibition of the movements of the respiratory muscles. In fetuses dying before delivery, apoptosis can be observed in the neurons and/or inhibiting centres of the respiratory muscles that have impeded respiration throughout pregnancy. In newborns dying during labour or postnatally, the number and the normal histological aspect of the inhibiting interneurones of the respiratory muscles did not present the signs of initial apoptosis which are essential to trigger spontaneous respiration at birth. Four important points have emerged.
1. At the 8th gestational week, designated as the start of the fetal period, there is a great increase in the number of myoblasts migrating to their destination in the skeleton. Only the myocytes reached by nerve motor fibres, modulated by nerve growth factor, will survive [41,42].
2. The interneurones with the task of inhibiting respiration continue to grow in number and power, while the other striated muscles develop the physiological activity of normal contractions followed by normal intervals for rest.
3. In fetuses who died of other pathological events at the end of delivery, a different number of inhibitory interneurones and/or of the respiratory centres was observed with respect to the number recorded at the start of delivery.
4. In the bulbo-mesencephalic slides of infants with a respiratory cause of death, we have observed the same number of respiration inhibitory interneurones as in fetuses who died at the beginning of delivery [28,29].
Histology has demonstrated that some deaths are produced by mechanisms of the tropho-defensive system producing, at the end of gestation, an adequate apoptosis of the inhibitory interneurones of the respiratory centres, in particular of the nucleus of Kölliker-Fuse and of the motor neurones of the respiratory muscles. The nucleus of Kölliker-Fuse is made up of an area of clustered neurons (subnucleus compactus) and an adjacent area with dispersed neurons (subnucleus dissipatus) [28,29,43].
During gestation the activity of the respiratory muscles is inhibited by the growing number of inhibitory interneurones, a defence system preventing the amniotic liquid from invading the respiratory tree. The inhibition is dramatically increased when the baby passes through the vagina. At the end of delivery the inhibition of respiration must decrease to a physiological level and take up the appropriate rhythm for correct respiration of the infant. The mechanism is induced by the tropho-defensive system. During physiological delivery, the inhibitory interneurones are generally stressed and will consume oxygen and glucose. They will be eliminated by apoptosis, following the concept demonstrated by Bruni in 1929.
In Sudden Respiratory Infant Death the event and the mechanisms involved can be slow to develop and death can occur some days after birth, when other factors intervene (neurotropic drugs, allergy, wrong blood-transfusions, etc.) and postpone apoptosis of the inhibitory interneurones of respiration. Our study of Sudden Respiratory Infant Death introduces some considerations:
1. There are many different aetiologies of Sudden Infant Death Syndrome.
2. Sudden Respiratory Infant Death can occur also as a consequence of genetic causes such as malformations of the respiratory muscles.
3. Sudden Respiratory Infant Death may have a different aetiopathogenesis from the one investigated in animals (sheep) submitted to invasive techniques.
4. It is difficult to compare the complex, different respiratory mechanisms in man with those of other mammals.
5. Aggravation of the situation can also depend on the mother, environment, cultural habits, as well as on doctors' decisions.
Based on our histopathological observations and on some clinical observations by anaesthetists, it can be deduced that some sudden deaths of newborns and infants are attributable to the persistence, after birth, of the respiratory interneurones and/or the inhibiting centres that developed during pregnancy to prevent the activity of the respiratory muscles and the consequent risk that the fetus could inhale amniotic fluid or other polluting substances in the birth canal. We may hypothesize, therefore, that the best way to prevent Sudden Respiratory Infant Death is not to interfere, at the end of delivery, with the fatigue of the mother, which seems to be important in reducing the level of glucose and oxygen in the infant's blood and so reducing the activity of the inhibitory interneurons of respiration. The neurons of the respiratory centres and muscles, not affected by fatigue, are then ready to start the physiological activity of the baby's respiratory muscles.
Sudden Respiratory Infant Death can also occur after several days as a consequence of other events (coughing, hiccupping, convulsions, pulmonary diseases, cardiac failure, intoxications, etc.). It has not yet been demonstrated whether absence of inhibition of the motor neurones or of the expiratory centres can result in Sudden Infant Death Syndrome, or whether the expiratory centres can cause Sudden Respiratory Infant Death.
To conclude, we believe that the mechanisms involved in Sudden Respiratory Infant Death are:
(a) Insufficient inhibition of the activity of the centres and/or the respiratory muscles during fetal life.
(b) Excess fatigue of the inhibitory interneurones of respiration of the fetus during delivery.
(c) Death induced by fatigue and apoptosis of the surplus inhibitory respiratory interneurones.
(d) Adequate oxygen and glucose availability for the neural mechanisms as soon as the child needs to start physiological respiration.
(e) A correct balance between the central nervous systems and the tropho-defensive systems of mother and child.
C. V. Morpurgo
Dipartimento di Anestesia e di Rianimazione; Istituto Ortopedico G. Pini e Clinica Ortopedica; Milano, Italy
A. M. Lavezzi
Istituto di Anatomia Patologica; Università degli Studi di Milano; Milano, Italy
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