Potential Central Nervous System Involvement in Sudden Unexpected Infant Deaths and the Sudden Infant Death Syndrome Bradley T. Thach*1 ABSTRACT Sudden unexpected infant death (SUID) in infancy which includes Sudden Infant Death Syndrome (SIDS) is the commonest diagnosed cause of death in the United States for infants 1 month to 1 year of age. Central nervous system mechanisms likely contribute to many of these deaths. We discuss some of these including seizure disorders, prolonged breath holding, arousal from sleep and its habituation, laryngeal reflex apnea potentiated by upper airway infection, and failure of brainstem-mediated autoresuscitation. In the conclusions section, we speculate how lives saved through back sleeping might result in later developmental problems in certain infants who otherwise might have died while sleeping prone. © 2015 American Physiological Society. Compr Physiol 5:1061-1068, 2015.

Introduction In spite of recent public health measures to reduce the incidence of SIDS such as the promotion of back sleeping and removal of soft bedding from the sleep environment, it remains one of the commonest causes of death in infants under a year of age (47). It has long been proposed that the most likely cause of death in SIDS is either acute respiratory or cardiovascular failure (29, 47) SIDS is diagnosed when a previously healthy infant suddenly dies and the medical history, death scene investigation and postmortem examination do not indicate a cause of death. Lately, a broader diagnosis, Sudden Unexpected Infant Death (SUID) which includes SIDS, is being used more often by medical examiners particularly in situations where evidence suggests that infants died of accidental suffocation, positional asphyxia, or accidental overlaying when infants share a bed with others (48). However, there is still a lack of consensus among medical examiners with many preferring .the traditional diagnosis “SIDS” or “cause of death undetermined in these cases.” There is abundant evidence that central nervous system functions can play a causal role in sudden infant deaths (47). We view any cause of acute severe hypoxia leading to loss of consciousness as a potential cause of an infant’s death, since in this situation, an infant’s airway protective behaviors no longer function and survival depends on brainstem reflexes coordinating autoresuscitation (AR) which can fail for a variety of reasons (72, 83). In this review, we discuss several central nervous system mechanisms that potentially could precipitate an infant’s death. These include seizures, infantile breath holding spells, laryngeal reflex apnea and its potentiation by infections, inadequate motor learning of

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airway protective behaviors, failure of arousal from sleep and failure of AR mechanisms.

Seizures as a Potential Cause of SUID/SIDS It is well known that seizures may be a cause of sudden unexplained death in over a broad age range of individuals with epilepsy (82). Both cardiac and respiratory compromise has been suggested as causal mechanisms. Specifically, a history of febrile seizures have been associated with sudden death in infants and toddlers (31, 45, 46, 95). Febrile seizures are rare in children under 6 months old but may be associated with death in older infants (46, 95). Compromised respiration causing severe hypoxemia is a well-known characteristic of grand mal seizures. Prolonged apnea as a primary manifestation of seizures occurs in both neonates (term and preterm) and older children (3, 73). In addition, Oren and colleagues reported that seizures may have been causal in the deaths of 4 of 76 infants who presented with prolonged apnea during sleep (64). Furthermore, death has been reported in an infant treated with a drug whose side effects included seizures and whose death was sudden, unexpected, and unexplained at autopsy, although seizures were not witnessed (75). This case * Correspondence

to [email protected] of Pediatrics Emeritus, Washington University School of Medicine, St. Louis, Missouri, USA Published online, July 2015 (comprehensivephysiology.com) DOI: 10.1002/cphy.c130052 Copyright © American Physiological Society. 1 Professor


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along with the other reports suggests a possible relationship between SIDS/SUID and seizures. However, at the present time the limited available information prevents the determination of a definitive role for seizures in SIDS.

Apnea and Asystole Associated with Infantile “Breath holding” Breath holding spells have long been known to be a cause of sudden severe asphyxia and/or asystole in infants (56). The usual stimulus is sudden pain, fear, or anger (19,20,56,58,87). Such spells are believed to be based on primitive reflexes originating from the limbic system and related pathways in the forebrain since they may be precipitated by extreme emotions (20, 56). In infants breath-holding results in severe cerebral asphyxia, opisthotonic posturing, sometimes termed “hypoxic seizures” (19, 20, 56, 58, 87). When decerebrate posturing occurs, the infant is apneic (“hypoxic apnea”). In virtually all breath holding spells the infants recover rapidly when hypoxic gasping initiates AR without short term or long-term sequelae (19, 20, 56, 87). Formerly breath holding spells were thought to be rare in infants under a year of age. However, it is now known that infants under observation in neonatal intensive care units have frequent episodes of severe desaturation and apnea precipitated by noxious stimuli similar to breath holding spells in older infants (2). Particularly relevant to SIDS/SUID are observations in infants with chronic lung disease and pulmonary hypertension. Breath holding episodes preceded by pain or irritating stimuli are common in these infants and are not uncommonly associated with sudden death during the episode in spite of vigorous resuscitation efforts (1). This results from failure of timely restoration of lung perfusion following hypoxic pulmonary arteriolar vasoconstriction. Sudden death has been reported in two awake infants occurring in the presence of their parents (97, 101). Both infants began to cry inconsolably during or just after bottle feedings. As with a typical breath holding spells this was rapidly followed by pallor or cyanosis and loss of muscle tone. Then the infants began to gasp. Resuscitation efforts were of no avail. A standard autopsy did not reveal preexisting pathological findings in the lungs or other organs. Subsequently, however, a more detailed microscopic examination of their lungs, performed later, found evidence of latent pulmonary hypertension with arteriolar muscular hyperplasia in peripheral regions of the lung. In both cases, the pregnancy was uncomplicated. Both infants were referred at birth to neonatal intensive care units briefly for ill-defined respiratory distress. Following hospital discharge, cyanosis and other symptoms of pulmonary hypertension prior to death were absent in both cases. Genetic and EKG studies in the parents of both infants did not reveal genetic mutations or EKG abnormalities associated with prolonged QT syndrome. Accordingly, it seems possible that there are some SIDS cases in which breath holding complicated by asymptomatic pulmonary hypertension can


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precipitate death. Conceivably such deaths might occur during sleep transitions and arousals when an infant is presumed to be sleeping.

Arousal from Sleep and SUID/SIDS That infants who succumb to SIDS have defective arousal mechanisms is a long held hypothesis. Specifically, failure to arouse to hypercapneic or hypoxic stimuli associated with apnea or while rebreathing expired air from bedding covering the infant’s airway may be present in SIDS infants (43, 47). Arousal involves progressive activation of specific subcortical and cortical brain structures. This process is complex. Cortical arousal is preceded by noradrenergic, serotonergic (5-HT), dopaminergic, cholinergic, and histaminergic neurons in the rostral brainstem, basal forebrain, and hypothalamus, which excite neurons in the cerebral cortex and cause EEG activation (30,32,59,79,80,88,89). Subcortical arousal, on the other hand, is mediated mainly by brainstem sites that increase heart rate, blood pressure, respiration, and postural tone. Thus, subcortical arousals involve autonomic and respiratory brainstem-mediated changes without changes in cortical (EEG) activity. Serotonergic and GABAergic neurons in the brainstem are critical in this arousal pathway (59,79). Serotonergic neurons respond to hypercapnea, which in turn helps initiate cortical and subcortical arousals (29, 58). In response to hypoxic, hypercapneic, or tactile stimuli, normal infants demonstrate an “arousal sequence” that consists of a spinal withdrawal reflex (tactile stimuli to the feet) followed by an augmented breath (sigh), a startle, then “thrashing limb” movements, all of which are mediated in the brainstem (53, 62). Finally a change in the EEG and behavior indicating full cortical arousal occurs (61). Relevant to the SIDS arousal failure hypothesis is a prospective study of infants who subsequently died of SIDS (40). The affected infants had more frequent and longer subcortical arousals and fewer cortical arousals than controls, possibly indicating subclinical deficits in the arousal pathway. Cortical arousal as reflected by EEG changes is not a prerequisite for termination of obstructive and mixed apnea in infants and adults (60, 76, 109). Also, other studies of infants who were placed in asphyxiating environments or were subjected to brief airway occlusion indicate that subcortical arousals accompanied by a sleep startle can cause a change in infants head position allowing access to fresh air (53,65,109). It is also noteworthy that in some situations arousal may be harmful. Thus, it has been observed in some infants during rebreathing that when a startle and brief arousal fail to cause head repositioning, rapid respiratory decompensation and desaturation can result (66). As shown by Wulbrand and colleagues stimuli initiated sighs and startles terminate the occurrence of EEG sleep spindle activity in thalamic reticular cells confirming the sequence of the arousal pathway from brainstem to midbrain to cortex (108). Whereas some

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degree of cortical activation may be needed to escape from an asphyxial environment, its effect on terminating other asphyxial events (e.g., prolonged apnea) is uncertain.

Elimination of Arousal Responses due to Habituation The basic mechanisms in the brain causing habituation to repeated stimuli have been defined (36). As regards human infants, it is known that exposure to elevated CO2 in sleeping infants first causes brainstem arousal and finally cortical arousal when inspired CO2 concentrations are gradually increased (53). Likewise it has been shown that arousal to a nonrespiratory tactile stimulus tactile occurs in a sequence of events that begins with spinal, followed by brainstem, responses, then thalamic activity, and finally by cortical electroencephalographic (EEG) activity (53, 61). Repeated tactile stimuli depressed all arousal responses (62). Spinal, brainstem, and cortical responses occurred on the first stimulus trial. Repeated trials, however, during both nonrapid eye movement (NREM) and rapid eye movement (REM) sleep, resulted in sequential decreases in the incidence of each individual response and eventually resulted in elimination of all responses. Cortical arousal was eliminated first, followed by brainstem arousals, and finally spinal responses (62). The elimination of each of the responses occurred more rapidly during REM than NREM sleep. Clearly, suppression of this arousal pathway by habituation could leave an infant vulnerable to life-threatening events. It is particularly important to note the effects of habitation to asphyxic stimuli, since arousal is crucial in recovery from obstructive apnea or in initiation of protective (escape) maneuvers in infants who are rebreathing expired air (e.g., face covered by bedding) (7, 43, 67). Johnston and colleagues and also Waters and Tinworth showed that exposure to repeated hypoxia in lambs and piglets results in elimination of cortical arousals (37, 106). In addition, Fewell and Kondurii found that repeated exposure to rapidly developing hypoxemia produces an arousal response decrement in sleeping lambs (18). They also found that after exposure to acute hypoxia, the time taken to achieve cortical arousal increases. As well, the delay in arousal is significantly greater after repeated exposures to hypoxemia in days prior to the actual arousal studies. Also, Darnall and colleagues reported blunted arousal from sleep when young rats were exposed to intermittent hypoxia (10). These findings are particularly relevant to asphyxial deaths, since Waters and colleagues found in studies of healthy prone sleeping infants that they repeatedly turned to the face down position during the night causing a brief exposure to asphyxia due to rebreathing expired air (107). Habituation to some degree may have occurred in one infant whose expired CO2 level reached 87 mmHg [arousal threshold for normal infants = 48.4 mmHg (53)] before she changed her head position. In this infant, repeated exposure to asphyxial stimuli could have ultimately eliminated arousal altogether.

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Theoretically, this deficiency could have resulted in death due to failure to escape from the face down position. With regard to an infant’s susceptibility to SIDS/SUID, habituation of the arousal sequence may have both beneficial and detrimental consequences. Rapid habituation to innocuous stimuli such as noise is probably beneficial in avoiding frequent detrimental sleep cycle disruptions that may lead to excessive fatigue and consequent depression of arousal pathways (24). However, in situations requiring the protective functions of arousal, habituation clearly could be detrimental, for example, if the arousal responses to an asphyxial environment are gradually suppressed in infants who prefer to sleep face down and return to this position often for prolonged periods of time (7, 107).

Motor Learning Young infants are able to learn behaviors in studies of classical conditioning and operant learning (96). Lipsitt showed that young infants can be conditioned to reinforce avoidance responses to oral occlusion by reinforcing existing reflexes (6, 55). The protective subcortical occlusion reflex begins to wain and transitions to a midbrain and/or cortically mediated learned response at 2 and 4 months of age, the peak age range for SIDS deaths. He suggested that deficiencies in motor learning sites in the brain during this critical transition period which is also the peak age for SIDS could play a role in some unexpected deaths. Similarly, studies in primates have shown that they can learn and perfect reflex-like subconscious beneficial motor behaviors. Such motor learning is not thought to primarily involve the cortex, but to involve cerebellar and midbrain sites (23, 102). Many activities, such as crawling and walking, are finally learned as a result of trial and error at which time those activities become subconscious reflexive behaviors. Specifically Lipsitt, proposed that a defect in acquisition of learned head turning and other avoidance behaviors may underlie the increased risk for SIDS when the airway is occluded in prone sleeping infants (6, 55). In fact, failure to acquire protective escape behaviors, such as head turning, has been documented in infants who are inexperienced in prone sleeping. These infants who are accustomed to back sleeping have a great deal of difficulty in gaining access to fresh air when sleeping face down on soft bedding (65). Epidemiologic studies have also shown that such inexperienced infants are very much at increased risk for accidental suffocation if they are placed prone by a caretaker or roll to prone when sleeping on their sides (63). An infant’s ability to lift and turn his/her head to the side is dependent on prior experience (65). Infants who have experience in prone sleeping frequently have brief exposures to rebreathing when they turn to a face down position during sleep (22, 107). Therefore, it is likely that majority of prone sleeping infants “learn” how to avoid asphyxiation. However, it is noteworthy that some infants who are experienced in prone sleeping have not acquired adequate escape maneuvers when exposed to asphyxia (65).


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Therefore, inadequate motor learning may underlie the welldocumented increased risk for sudden death in prone sleeping infants. Studies have shown that learned escape behaviors are independent of postnatal age, which confirms the importance of learning through prior experience rather than acquisition of this escape ability simply as a result of normal maturation (65). In summary, developmental deficits in central neural pathways that contribute motor learning might increase the risk of accidental suffocation in infants.

Obstructive Sleep Apnea and SUID/SIDS A wealth of circumstantial evidence suggests that obstructive sleep apnea combined with failure of AR could be a cause sudden death in infants (99, 100). Although the pathophysiology of sleep apnea involves central nervous system regulation of upper airway maintaining muscles, anatomical factors in the upper airway, such as nasal resistance and pharyngeal compliance, are believed to be etiologiclally more important (33, 41). It should be noted, however, that infant apnea, especially in preterm infants, is typically “mixed apnea” with both central and obstructive apnea components (11, 12).

The Potential Role of Upper Airway Infection, Laryngeal Chemoreflex Apnea and Brain Cytokines in SUID/SIDS Storey, Harding and Johnson, and later Downing and colleagues, suggested that prolonged apnea associated with the normally airway protective laryngeal chemoreflex (LCR) reflexes might be causal in SIDS (14, 27, 28, 50, 92). The LCR combined responses are initiated when low chloride or acidic liquids stimulate intraepithelial receptors localized to the interarytenoid space of the larynx (5, 28, 71). This stimulation results in swallowing, apnea, vocal cord constriction, cough, increased blood pressure, and arousal (12,27,71). The apnea component of the LCR is strongest in the neonate, particularly in preterm infants, and later diminishes with maturation (71, 91). Stimulation of the LCR can cause prolonged apnea especially in preterm infants (11, 70). The interaction between the LCR, infection, and circulating cytokines are particularly relevant to SIDS causal theories. Hypothetically, upper airway infection, particularly with the respiratory syncytial virus (RSV), can result in a fatal course of events that lead to SIDS. RSV-infected infants that are brought to the hospital occasionally require mechanical ventilation for prolonged apnea; otherwise, presumably, they would have expired. RSV-related prolonged apnea is characterized by central apnea associated with obstructed inspiratory efforts like LCR apnea or prolonged central apnea during periodic breathing (69). Infants between 2 and 4 months of age are at highest risk for SIDS and normally have transient “physiologic” anemia at this age due to the transition from a fetal to adult


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hemoglobin synthesis. This is likely to be more prominent in preterm than term infants. Three findings are particularly relevant to SIDS pathogenesis in this regard. First, anemia increases activity of LCR associated prolonged apnea (16). Second, St-Hilaire and coworkers have shown that neonatal exposure to cigarette smoke, a risk factor for SIDS, prolongs LCR Apnea in a lamb model (90). Third, the age span for first acquiring an RSV infection coincides with the peak in SIDS incidence. Thus several risk factors for SIDS including prematurity are associated with enhancement of LCR apnea. As regards infection with fever, it is noteworthy that elevated body temperature abolishes the ability to autoresuscitate in young hypoxic mice (39). Also, Curran and associates found that increased body temperature prolongs LCR related apnea in piglets (9). Prolongation of LCR apnea in rat pups with elevated temperature is further increased by prenatal nicotine exposure (110). This effect may be mediated via the nucleus of the solitary tract in the brainstem and appears to involve GABAergic inhibitory mechanisms (15). These studies lend credence to the theory proposed by Fleming and colleagues that infants who over wrapped or in a hot environment may be more susceptible to SIDS when elevated body temperature is present (62). Premature infants with a history of apnea of prematurity are at increased risk for reoccurrence of prolonged apnea when infected with RSV (69). Also, relevant is that the risk for both SIDS and for RSV infection peaks during the winter. Together, these findings suggest that viral infection with RSV or other viruses could be a cause of SIDS by virtue of the effects of infection on potentiating LCR apnea (54). Several studies in infants and animal models indicate links between upper respiratory viral infection, LCR reflexes, brainstem, or CSF cytokines and SIDS. A recent study of a relatively small number of infants found that cytokines (1L-1B) are increased in the brainstems of SIDS as compared with control (accidental death) infants (38). Yet another study showed that interleukin cytokines associated with laryngeal inflammation are on average elevated in the cerebrospinal fluid of SIDS infants compared to control infants (105). The mechanisms involved underlying the increased interleukin cytokines are unclear since Interleukins in the brain are produced by CNS neurons. Also, they can be transported to the brain from peripheral tissues by a hematogenous route or retrograde axonal transport (4, 57). Studies in animal models have found that intravenous or intrathecal injection of cytokines (1L-1B) augment LCR reflexes and the associated prolonged apnea (92). All of these studies reinforce the theory that effects of local viral infection on potentiating LCR prolonged apnea could be involved in the sequence if events leading to SIDS. As regards the finding of increased cytokines levels in the brainstem in SIDS Infants, a crucial question concerns the origin of these cytokines (83). Could the increased levels come from axonal transport of cytokines from the inflamed upper airway to abnormal brainstem neurons with decreased receptors cause increased LCR activity or does this observation represent abnormal function of brainstem cytokine metabolism? If the former were the case, it would be a clue to the source

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of the underlying SIDS vulnerability envisioned in the “SIDS triple-risk model” (47). However, if the latter is true, then these findings would indicate that an intrinsic alteration in brainstem cytokine metabolism is the precursor to SIDS vulnerability and also could be considered consistent with the triple risk model.

Failure of Autoresuscitation and SUID/SIDS Severe progressive asphyxia leads to a loss of consciousness, areflexia, and apnea when a critical level of the partial pressure of arterial oxygen is reached (approximately 10 mmHg) or when hypoperfusion results in extreme brain hypoxia. When the critical level of hypoxemia is reached, prolonged apnea (“hypoxic apnea”) and severe bradycardia as well as decreased blood pressure occur (50). After a variable time span, neurons presumed to be located in the pre-B˝otzinger nucleus in the rostral medulla and/or related nuclei initiate a maximum inspiratory efforts known as “hypoxic gasps” (74, 77, 84). These neurons are stimulated by hypoxia. Immediately following a gasp the larynx constricts, limiting expiratory air flow from the lungs thereby maintaining increased lung volume (81). Studies in animal models indicate that this facilitates AR. Additionally airway protective components of the LCR (swallowing) appear to be intact at the onset of gasping and this may be effective in avoiding aspiration of oral and pharyngeal fluids (44). As first suggested by Guntheroth and Kawabori, the final event in SIDS, could be failure to autoresuscitate from “hypoxic coma” (26). Gasping may be present but is ineffective in causing recovery (72,83). For successful AR gasps must introduce oxygen into the lung, and then oxygen must reach the heart and reverse the bradycardia. Finally, to restore normal respiration oxygenated blood must reach the brain (13, 21, 22, 26, 34, 35). Neurotransmitter and receptor influences on gasping have been characterized in the past by St. John, Leiter, and others (52, 85, 86, 103, 104). Tryba and coworkers found that total blockage of serotonergic receptors eliminates gasp like activity in mouse brainstem slices in vitro (104). However, in perfused juvenile rat brains when serotonin receptors are blocked or in gene knockout mice with an 85% to 90% reduction in serotonin neurons only minor changes in gasping pattern were seen (52, 85, 86, 103, 104). In these studies when Alpha 1-adrenergic receptors were blocked in addition to serotonergic receptors gasping duration was decreased and recovery of eupnea when oxygen was reintroduced was delayed indicating the importance of adrenergic and possibility other receptors in the maintenance of gasping. In another study indicating the importance of brainstem serotonin neurons in successful AR, Cummings and co-workers found that whereas Pet 1 knockout mice with a 70% deficiency in serotonin neurons, autoresuscition following repeated exposure to anoxia was diminished due to failure to increase heart rate following prolonged gasping (8).

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The progression of events during successful and failed AR has been seen in cardio respiratory recordings in infants who were being monitored at home at the time of death from SIDS (72, 83). Importantly, infants dying of known causes including seizures and cardiac defects either completely or partially autoresuscitate prior to finally dying due to AR failure (83). This suggests that some SIDS infants, at least, have a specific defect in AR mechanisms. Studies in animal models indicate potential sources of this defect. Fewell and Smith noted that perinatal nicotine exposure impaired the ability to newborn rats to AR (17). Notably gasping was intact but the increase in heart rate phase of AR was aberrant resulting in AR failure. Also potentially relevant are the studies of Gozal and colleagues who found that exposure of the rat fetus or neonate to intermittent hypoxia impaired ability to autoresusciate (25). Additionally, as already mentioned, elevated body temperature can impair AR. (39,78). Finally, in studies of AR in mice it was discovered that a certain inbred strain (Swiss Webster and related strains) failed to successfully autoresuscitate after exposure to hypoxia even though normal gasping occurred (13, 21, 22, 34, 35, 98). Gasping may fail to cause adequate blood oxygenation for various reasons. Regulation of cardiac function and circulation by the autonomic nervous system may have a critical role. Pulmonary edema fluid is commonly seen in SIDS cases and this could make gasping ineffective in introducing air into the lungs. Moreover, postmortem findings in SIDS infants often indicate focal intrapulmonary aspiration of gastric contents. Formerly, this was believed to be a postmortem artifact of attempted artificial resuscitation, however a recent study by Krous and colleagues found that aspiration was sometimes found in the lungs of SIDS infants with no history of resuscitation attempts (49). This suggests that terminal focal aspiration may have compromised lung function to the extent that AR was impaired. Also, persistent pulmonary hypertension, a result of acute hypoxia, could reduce pulmonary perfusion and limit the efficacy of gasps to reoxygenate the lungs. Abnormal vagal regulation of heart function during hypoxemia or faulty autonomic nervous system-mediated redistribution of perfusion from the extremities to several critical central organs during hypoxia, which is normally beneficial for survival, could interfere with the sequence of events leading to successful AR. Finally AR will fail if the infant is unable to escape from an asphyxiating environment. Heart failure during attempted AR in mice is suggested by decreased cardiac glycogen stores resulting in decreased glycogenolysis during the 20 to 22-day critical period when inbred Swiss Webster mice (SWR/J) are unable to AR (13). In other studies it was found that an epinephrine injection improves the ability of your Swiss Webster (SWR/J) mice to autoresusciate (Thach BT and Song A, personal observations). The mechanism for this beneficial effect is unclear. Other inbred mouse strains are competent in AR at all ages (13, 21, 22, 34, 35, 98). This mouse model is relevant to SIDS in that there is a developmental window in time in which Swiss Webster mice cannot autoresuscitate (20-22 days old)


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(21, 22, 34, 35). Given that young mice can be weaned at this time and that human infants may be weaned as early as five months suggests that the mouse model may have some relevance for the critical age of vulnerability in SIDS. Recent, genetic studies in Swiss Webster mice and related inbred strains indicate that regions on one or two chromosomes have mutations contributing to failure of AR. Whether or not some SIDS or SUID infants have similar gene mutations remains to be seen, however these studies in mice offer promise for better understanding the genetic basis of SIDS (98). All in all, these multiple studies suggest that hypoxic gasping is a very robust reflexive mechanism and failure of AR in SIDS is not likely due to failure of gasping per se. Failure of other AR components such as effective LCR protective responses, the action of laryngeal constricting muscles following a gasp or mechanisms preventing pulmonary edema may play a role. Future research might well be directed to aspects of lung pathology, autonomic nervous system regulation of pulmonary and peripheral circulation as well as cardiac function that play a critical role in the sequence of events leading to successful AR.

Comprehensive Physiology


5. 6. 7. 8.

9. 10. 11. 12. 13.

14. 15.

Conclusion We have discussed a number of central nervous system mechanisms that might mediate sudden unexpected deaths in infants. Many of these could result in fatal cessation of breathing but others might not. Some deaths such as those that might be precipitated by breath holding spells might not be diagnosed as SIDS due to the general belief that SIDS always occurs during sleep, an unsupported assumption. A question that frequently is asked is what might be the long-term disabilities of infants who might have died while sleeping prone but survived due to adaption of back sleeping. Since many prone sleeping infants die when they are unable to escape from asphyxiating environments (e.g., Face down on soft bedding) one might assume that they failed to “learn” airway protective from sleep in an asphyxiating environment. With maturation these infants might have difficulties with motor learning such as learning to walk or ride a bicycle. For those with arousal deficits, they might be more susceptible to sleep apnea in later life. In summary, a number of central nervous mechanisms that potentially could cause SUDI/SIDS have been identified.

16. 17. 18.


20. 21. 22. 23. 24. 25. 26.

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Banks WA, Ortiz L, Plotkin SR, Kastin AJ. Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism. J Pharmacol Exp Ther 259(3): 988-96, 1991. Boggs DF, Bartlett D, Jr. Chemical specificity of a laryngeal apneic reflex in puppies. J Appl Physiol 53(2): 455-62, 1982. Burns B, Lipsett LP. Behavioral factors in crib death: Toward an understanding of the sudden infant death syndrome. J Appl Dev Psychol 12(2): 159-184, 1991. Chiodini BA, Thach BT. Impaired ventilation in infants sleeping facedown: Potential significance for sudden infant death syndrome. J Pediatr 123(5): 686-92, 1993. Cummings KJ, Commons KG, Hewitt JC, Daubenspeck JA, Li A, Kinney HC, Nattie EE. Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: Implications for SIDS. J Appl Physiol 111(3): 826-33, 2011. Curran AK, Xia JC, Bartlett D. Elevated body temperature enhances the laryngeal chemoreflex in decerebrate piglets. J Appl Physiol 98: 780-786, 2005. Darnall RA, McWilliams S, Schneider RW, Tobia CM. Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat. J Appl Physiol 109: 1686-1696, 2010. Davies AM, Koenig JS, Thach BT. Characteristics of upper airway chemoreflex prolonged apnea in human infants. Am Rev Respir Dis 139(3): 668-73, 1989. Davies AM, Koenig JS, Thach BT. Upper airway chemoreflex responses to saline and water in preterm infants. J Appl Physiol 64(4): 1412-20, 1988. Deshpande P, Khurana A, Hansen P, Wilkins D, Thach BT. Failure of autoresuscitation in weanling mice: Significance of cardiac glycogen and heart rate regulation. J Appl Physiol 87(1): 203-10, 1999. Downing SE, Lee JC. Laryngeal chemo sensitivity: A possible mechanism for sudden infant death. Pediatrics 55: 640-649, 1975. Duy P, Xia L, Bartlett D, Leiter JC. An adenosine A(2A) agonist injected in the nucleus of the solitary tract prolongs the laryngeal chemoreflex by a GABAergic mechanism in decrebrate piglets. Exp Physiol 95: 774-87, 2010. Fagenholz SA, Lee JC, Downing SE. Association of anemia with reduced central respiratory drive in the piglet. Yale J Biol Med 52(3): 263-70, 1979. Fewell JE, Smith FG. Perinatal nicotine exposure impairs ability of newborn rats to autoresuscitate from apnea during hypoxia. JAP 85: 2066-2074, 1998. Fewell JE, Konduri GG. Repeated exposure to rapidly developing hypoxemia influences the interaction between oxygen and carbon dioxide in initiating arousal from sleep in lambs. Pediatr Res 24(1): 28-33, 1988. Gastaut H. A physiopathologic study of reflex anoxic cerebral seizures in children (syncopes, sobbing, spasms, and breatholding spells). In: Kellaway P, Peterson I, editors. Clinical Electroencephalopathy of Children. New York: Grune and Stratton, 1968, pp. 257-274. Gauk EW, Kidd L, Prichard JS. Mechanism of seizures associated with breath-holding spells. N Engl J Med 268: 1436-41, 1963. Gershan WM, Jacobi MS, Thach BT. Maturation of cardiorespiratory interactions in spontaneous recovery from hypoxic apnea (autoresuscitation). Pediatr Res 28(2): 87-93, 1990. Gershan WM, Jacobi MS, Thach BT. Mechanisms underlying induced autoresuscitation failure in BALB/c and SWR mice. J Appl Physiol 72(2): 677-85, 1992. Gilbert PF, Thach WT. Purkinje cell activity during motor learning. Brain Res 128(2): 309-28, 1977. Goncalves MA, Paiva T, Ramos E, Guilleminault C. Obstructive sleep apnea syndrome, sleepiness, and quality of life. Chest 125(6): 2091-6, 2004. Gozal D, Gozal E, Reeves SR, Lipton AJ. Gasping and autoresuscitation in the developing rat: Effect of antecedent intermittent hypoxia. JAP 92: 1141-1144, 2002. Guntheroth WG, Kawabori I. Hypoxic apnea and gasping. J Clin Invest 56: 1371, 1975. Harding R, Johnson P, Johnston BE, McClelland ME, Wilkerson AR. Proceedings: Cardiovascular changes in newborn lambs induced by stimulation of laryngeal receptors with water. J Physiol 256: 35-36, 1976. Harding R, Johnson P, McClelland ME. Liquid-sensitive laryngeal receptors in the developing sheep, cat and monkey. J Physiol 279: 409-422, 1978. Harper RM, Kinney HC, Fleming PJ, Thach BT. Sleep influences on homeostatic functions: Implications for sudden infant death syndrome. Respir Physiol 119: 123-132, 2000. Haxhiu MA, Tolentino-Silva F, Pete G, Kc P, Mack SO. Monoaminergic neurons, chemosensation and arousal. Respir Physiol 129(1-2): 191209, 2001.

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31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

43. 44. 45.


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Brain Function in Sudden Infant Death

59. McCormick DA, Wang Z. Serotonin and noradrenaline excite GABAergic neurones of the guinea-pig and cat nucleus reticularis thalami. J Physiol 442: 235-55, 1991. 60. McNamara F, Issa FG, Sullivan CE. Arousal pattern following central and obstructive breathing abnormalities in infants and children. J Appl Physiol 81(6): 2651-7, 1996. 61. McNamara F, Wulbrand H, Thach BT. Characteristics of the infant arousal response. J Appl Physiol 85(6): 2314-21, 1998. 62. McNamara F, Wulbrand H, Thach BT. Habituation of the infant arousal response. Sleep 22(3): 320-6, 1999. 63. Mitchell EA, Thach BT, Thompson JM, Williams S. Changing infants’ sleep position increases risk of sudden infant death syndrome. New Zealand Cot Death Study. Arch Pediatr Adolesc Med 153(11): 113641, 1999. 64. Oren J, Kelly D, Shannon OC. Identification of a high-risk group from sudden infant death syndrome among infants who were resuscitated for sleep apnea. Pediatrics 77(4): 495-499, 1986. 65. Paluszynska DA, Harris KA, Thach BT. Influence of sleep position experience on ability of prone-sleeping infants to escape from asphyxiating microenvironments by changing head position. Pediatrics 114(6): 1634-9, 2004. 66. Patel AL, Paluszynska D, Harris KA, Thach BTT. Sudden respiratory decompensation in sleeping infants while rebreathing. Pediatrics 111(4) e328, 2003. April. 67. Patel AL, Harris K, Thach BT. Inspired CO(2) and O(2) in sleeping infants rebreathing from bedding: Relevance for sudden infant death syndrome. J Appl Physiol 91(6): 2537-45, 2001. 68. Paton JF, Abdala AP, Koizumi H, Smith JC, St-John WM. Respiratory rhythm generation during gasping depends on persistent sodium current. Nat Neurosci 9(3): 311-3, 2006. 69. Pickens DL, Schefft GL, Thach BT. Characterization of prolonged apneic episodes associated with respiratory syncytial virus infection. Pediatr Pulmonol 6(3): 195-201, 1989. 70. Pickens DL, Schefft G, Thach BT. Prolonged apnea associated with upper airway protective reflexes in apnea of prematurity. Am Rev Respir Dis 137(1): 113-8, 1988. 71. Pickens DL, Schefft GL, Thach BT. Pharyngeal fluid clearance and aspiration preventive mechanisms in sleeping infants. J Appl Physiol 66(3): 1164-71, 1989. 72. Poets CF, Meny RG, Chobanian MR, Bonofiglo RE. Gasping and other cardiorespiratory patterns during sudden infant deaths. Pediatr Res 45(3): 350-4, 1999. 73. Ramelli GP, Donati F, Bianchetti M, Vassella F. Apnoeic attacks as an isolated manifestation of epileptic seizures in infants. Eur J Paediatr Neurol 2(4): 187-91, 1998. 74. Ramirez JM, Richter DW. The neuronal mechanisms of respiratory rhythm generation. Curr Opin Neurobiol 6(6): 817-25, 1996. 75. Randall B, Gerry G, Rance F. Dicyclomine in the sudden infant death syndrome (SIDS)—A cause of death or an incidental finding? J Forensic Sci 31(4): 1470-4, 1986. 76. Rees K, Spence DP, Earis JE, Calverley PM. Arousal responses from apneic events during non-rapid-eye-movement sleep. Am J Respir Crit Care Med 152(3): 1016-21, 1995. 77. Rekling JC, Feldman JL. PreBotzinger complex and pacemaker neurons: Hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol 60: 385-405, 1998. 78. Serdarevich C, Fewell JE. Influence of core temperature on autoresuscitation during repeated exposure to hypoxia in normal rat pups. JAP 87: 1346-53, 1999. 79. Sinton CM, McCarley RW. Neurophysiological mechanisms of sleep and wakefulness: A question of balance. Semin Neurol 24(3): 211-23, 2004. 80. Sofroniew MV, Priestley JV, Consolazione A, Eckenstein F, Cuello AC. Cholinergic projections from the midbrain and pons to the thalamus in the rat, identified by combined retrograde tracing and choline acetyltransferase immunohistochemistry. Brain Res 329(1-2): 213-23, 1985. 81. Song Z, Harris KA, Thach BT. Laryngeal constriction during hypoxic gasping and its role in improving autoresuscitation in two mouse strains. JAP 106: 1223-1226, 2009. 82. Sperling MR. Sudden unexplained death in epilepsy. Epilepsy Curr 1: 21-23, 2001. 83. Sridhar R, Thach BT, Kelly DH, Henslee JA. Characterization of successful and failed autoresuscitation in human infants, including those dying of SIDS. Pediatr Pulmonol 36(2): 113-22, 2003. 84. St John WM. Medullary regions for neurogenesis of gasping: Noeud vital or noeuds vitals? J Appl Physiol 81(5): 1865-77, 1996. 85. St. John WM, Leiter JC. Genesis of gasping is independent of levels of serotonin in the Pet-1 knockout mouse. JAP 107: 679-685, 2009. 86. St. John WM, Leiter JC. Maintenance of gasping and restoration of eupnea after hypoxia is impaired following blockers of α1-adrenergic receptors and serotonin 5-HT2 receptors. JAP 104: 665-673, 2008.


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Comprehensive Physiology

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Volume 5, July 2015

Potential Central Nervous System Involvement in Sudden Unexpected Infant Deaths and the Sudden Infant Death Syndrome.

Sudden unexpected infant death (SUID) in infancy which includes Sudden Infant Death Syndrome (SIDS) is the commonest diagnosed cause of death in the U...
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