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

Bradley T. Thach

10.1002/cphy.c130052

Source: Volume 5, Issue 3, July 2015

Published online: June 2015

Full Article on Wiley Online Library



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.

References
 1. Abman SH , Burchell MF , Schaffer MS , Rosenberg AA . Late sudden unexpected deaths in hospitalized infants with bronchopulmonary dysplasia. Am J Dis Child 143(7): 815‐9, 1989.
 2. Abu‐Osba YK , Brouillette RT , Wilson SL , Thach BT . Breathing pattern and transcutaneous oxygen tension during motor activity in preterm infants. Am Rev Respir Dis 125(4): 382‐7, 1982.
 3. Amir J , Ashkenazi S , Schonfeld T , Weitz R , Nitzan M . Laryngospasm as a single manifestation of epilepsy. Arch Dis Child 58(2): 151‐3, 1983.
 4. 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.
 5. Boggs DF , Bartlett D, Jr . Chemical specificity of a laryngeal apneic reflex in puppies. J Appl Physiol 53(2): 455‐62, 1982.
 6. 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.
 7. Chiodini BA , Thach BT . Impaired ventilation in infants sleeping facedown: Potential significance for sudden infant death syndrome. J Pediatr 123(5): 686‐92, 1993.
 8. 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.
 9. Curran AK , Xia JC , Bartlett D . Elevated body temperature enhances the laryngeal chemoreflex in decerebrate piglets. J Appl Physiol 98: 780‐786, 2005.
 10. 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.
 11. 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.
 12. 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.
 13. 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.
 14. Downing SE , Lee JC . Laryngeal chemo sensitivity: A possible mechanism for sudden infant death. Pediatrics 55: 640‐649, 1975.
 15. 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.
 16. 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.
 17. Fewell JE , Smith FG . Perinatal nicotine exposure impairs ability of newborn rats to autoresuscitate from apnea during hypoxia. JAP 85: 2066‐2074, 1998.
 18. 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.
 19. 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.
 20. Gauk EW , Kidd L , Prichard JS . Mechanism of seizures associated with breath‐holding spells. N Engl J Med 268: 1436‐41, 1963.
 21. Gershan WM , Jacobi MS , Thach BT . Maturation of cardiorespiratory interactions in spontaneous recovery from hypoxic apnea (autoresuscitation). Pediatr Res 28(2): 87‐93, 1990.
 22. 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.
 23. Gilbert PF , Thach WT . Purkinje cell activity during motor learning. Brain Res 128(2): 309‐28, 1977.
 24. Goncalves MA , Paiva T , Ramos E , Guilleminault C . Obstructive sleep apnea syndrome, sleepiness, and quality of life. Chest 125(6): 2091‐6, 2004.
 25. 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.
 26. Guntheroth WG , Kawabori I . Hypoxic apnea and gasping. J Clin Invest 56: 1371, 1975.
 27. 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.
 28. Harding R , Johnson P , McClelland ME . Liquid‐sensitive laryngeal receptors in the developing sheep, cat and monkey. J Physiol 279: 409‐422, 1978.
 29. 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.
 30. Haxhiu MA , Tolentino‐Silva F , Pete G , Kc P , Mack SO . Monoaminergic neurons, chemosensation and arousal. Respir Physiol 129(1‐2): 191‐209, 2001.
 31. Holm IA , Podui A , Crandall L , Hass E , Grafe MR , Kinney HC , Krous HF . Inheritance of febrile seizures in sudden unexplained death in toddlers. Pediatr Neurol 46: 235‐239, 2012.
 32. Hu B , Steriade M , Deschenes M . The effects of brainstem peribrachial stimulation on neurons of the lateral geniculate nucleus. Neuroscience 31(1): 13‐24, 1989.
 33. Ishikawa I , Isono S , Aiba J , Tanaka A , Nishino T . Prone positioning increases collapsibility of the passive pharynx in infants and small children. Am J Respir Crit Care Med 166: 760‐764, 2002.
 34. Jacobi, MS , Gershan WM , Thach BT . Effect of pentobarbital on spontaneous recovery from hypoxic apnoea in mice. Respir Physiol 84(3): 337‐49, 1991.
 35. Jacobi MS , Gershan WM , Thach BT . Mechanism of failure of recovery from hypoxic apnea by gasping in 17‐ to 23‐day‐old mice. J Appl Physiol 71(3): 1098‐105, 1991.
 36. Jasper H , Sharpless S . Habituation of the arousal reaction. Brain 79(4): 655‐80, 1956.
 37. Johnston RV , Grant DA , Wilkinson MH , Walker AM . Repetitive hypoxia rapidly depresses arousal from active sleep in newborn lambs. J Physiol 510 (Pt 2): 651‐9, 1998.
 38. Kadhim H , Kahn A , Sebire G . Distinct cytokine profile in SIDS brain: A common denominator in a multifactorial syndrome? Neurology 61(9): 1256‐9, 2003.
 39. Kahraman L , Thach BT . The inhibitory effects of hyperthermia on mechanisms involved autoresuscitation from hypoxic apnea in mice. J Appl Physiol 97: 669‐674, 2004.
 40. Kato I , Franco P , Groswasser J , Scaillet S , Kelmanson I , Togari H , Kahn A . Incomplete arousal processes in infants who were victims of sudden death. Am J Respir Crit Care Med 168(11): 1298‐303, 2003.
 41. Katz ES , Mitchell RB , D'Ambrosio CM . Obstructive sleep apnea in infants. Am J Respir Crit Care Med 185: 805‐816, 2012.
 42. Kemp JS , Kowalski RM , Burch PM , Graham MA , Thach BT . Unintentional suffocation by rebreathing: A death scene and physiologic investigation of a possible cause of sudden infant death. J Pediatr 122(6): 874‐80, 1993.
 43. Kemp JS , Thach BT . Sudden death in infants sleeping on polystyrene‐filled cushions [see comments]. N Engl J Med 324(26): 1858‐64, 1991.
 44. Khurana A , Thach BT . Effects of upper airway stimuli on swallowing, gasping and autoresuscitation in hypoxic mice. J Appl Physiol 80: 472‐481, 1996.
 45. Kinney HC , Armstrong DL , Chadwick AE , Crandall LA , Hilbert C , Belliveau RA , Kupsky WJ , Krous HF . Sudden Death in toddlers associated with developmental abnormalities of the hippocampus: A report of five cases. Pediatr Dev Pathol 10: 208‐223, 2007.
 46. Kinney HC , Chadwick AE , Crandall LA , Grafe M , Armstrong DL , Kupsky WJ , Trachtenberg FL , Krous HF . Sudden death febrile seizures and hippocamal and temporal lobe maldevelopment in toddlers: A new entity. Pediatr Dev Pathol 12: 455‐463, 2009.
 47. Kinney HC , Thach BT . The sudden infant death syndrome. N Engl J Med 361(8): 795‐805, 2009.
 48. Krous HF , Beckwith JB , Byard RW , Rognum TO , Bajanowski T , Corey T , Cutz E , Hanzlick R , Keens TG , Mitchell EA . Sudden infant death syndrome and unclassified sudden infant deaths: A definitional and diagnostic approach. Pediatrics 114(1): 234‐8, 2004.
 49. Krous HF , Masoumi H , Haas EA , Chadwick AE , Stanley C , Thach BT . Gastric aspiration in cases of Sudden Infant Death Syndrome for which Cardiopulmonary resuscitation was not attempted. J Pediatr 150: 241‐24, 2007.
 50. Lawson EE , Thach BT . Respiratory patterns during progressive asphyxia in newborn rabbits. J Appl Physiol 43(3): 468‐74, 1977.
 51. Lee JC , Stoll BJ , Downing SE . Properties of the Laryngeal chemoreflex in neonatal piglets. Am J Physiol 233: 30‐36, 1977.
 52. Leiter JC . Serotonin, gasping, autoresuscitation and SIDS—A contrarian view. JAP 106: 1761‐1762, 2009.
 53. Lijowska AS , Reed NW , Chiodini BA , Thach BT . Sequential arousal and airway‐defensive behavior of infants in asphyxial sleep environments. J Appl Phys 83(1): 219‐228, 1997.
 54. Lindgren C , Jing L , Graham B , Grögaard J , Sundell H . Respiratory syncytial virus infection reinforces reflex apnea in young lambs. Pediatr Res 31(4 Pt 1): 381‐5, 1992.
 55. Lipsett LP . Crib death: A behavioral phenomenon? Curr Dir Psychol Sci 12(5): 164‐170, 2003.
 56. Lombroso CT , Lerman P . Breathholding spells (cyanotic and pallid infantile syncope). Pediatrics 39(4): 563‐81, 1967.
 57. Maehlen J , Olsson T , Zachau A , Klareskog L , Kristensson K . Local enhancement of major histocompatibility complex (MHC) class I and II expression and cell infiltration in experimental allergic encephalomyelitis around axotomized motor neurons. J Neuroimmunol 23(2): 125‐32, 1989.
 58. Maulsby R , Kellaway P . Transient hypoxic crises in children. In: Kellaway P , Peterson I , editors. Neurological and Electoencephalographic Correlative Studies in Infancy. New York: Grune and Stratton, 1964.
 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): 1136‐41, 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.
 87. Stephenson JB . Reflex anoxic seizures (‘white breath‐holding’): Nonepileptic vagal attacks. Arch Dis Child 53(3): 193‐200, 1978.
 88. Steriade M , McCormick DA , Sejnowski TJ . Thalamocortical oscillations in the sleeping and aroused brain. Science 262(5134): 679‐85, 1993.
 89. Steriade M , Jones EG , Llinas R . Thalamic Oscillations in the Sleeping and Aroused Brain. New York: John Wiley and Sons, 1990.
 90. St‐Hilaire M , Duvareille C , Avoine O , Carreau AM , Samson N , Micheau P , Doueik A , Praud JP . Effects of postnatal smoke exposure on laryngeal chemoreflexes in newborn lambs. J Appl Physil 109(6): 1820‐1826, 2010.
 91. St‐Hilaire M , Samson N , Nsegbe E , Duvareille C , Moreau‐Bussière F , Micheau P , Lebon J , Praud JP . Postnatal maturation of laryngeal chemoreflexes in the preterm lamb. J Appl Physiol 102: 1492‐1538, 2007.
 92. Stoltenberg L , Sundar T , Almaas R , Storm H , Rognum TO , Saugstad OD . Changes in apnea and autoresuscitation in piglets after intravenous and intrathecal interleukin‐1 beta injection. J Perinat Med 22(5): 421‐32, 1994.
 93. Storey AT , Johnson P . Laryngeal water receptors initiating apnea in the lamb. Exp Neurol 47: 42‐55, 1975.
 94. Sullivan RM , Taborsky‐Barba S , Mendoza R , Itano A , Leon M , Cotman CW , Payne TF , Lott I . Olfactory classical conditioning in neonates. Pediatrics 87: 511‐518, 1991.
 95. Sunderland R , Emery JL . Febrile convulsions and cot death. Lancet 318: 176‐178, 1981.
 96. Tarullo AR , Balsam PD , Fifer WP . Sleep and infant learning. Infant Child Dev 1: 35‐46, 2011.
 97. Thach BT , Harris KA , Krous HF . Pulmonary arteriolar muscle thickening in sudden infant death syndrome. BMJ Case Rep 2009 (published online June 1, 2009).
 98. Thach BT , Kenney‐Hunt JP , Simon TC , Stratman JL , Thach SB , Harris KA , Saunders S , Cheverud JM . Sex‐specific quantitative trait loci linked to autoresuscitation failure in SWR/J mice. Heredity 103: 469‐475, 2009.
 99. Thach BT . The role of respiratory control disorders in SIDS. Respir Physiol Neuro 149: 343‐353, 2005.
 100. Thach B . Tragic and sudden death. Potential and proven mechanisms causing sudden infant death syndrome. EMBO Rep 9(2): 114‐8, 2008.
 101. Thach BT , Krous HF . A new mechanism for causing sudden unexplained death in infants. Am J Respir Crit Care Med 183: A1868, 2011.
 102. Thach WT , Goodkin HP , Keating JG . The cerebellum and the adaptive coordination of movement. Annu Rev Neurosci 15: 403‐42, 1992.
 103. Toppin VA , Harris MB , Kober AM , Leiter JC , St.‐John WM . Persistence of eupnea and gasping following blockade of both serotonin type 1 and 2 receptors in the in situ juvenite rat preparation. JAP 103: 220‐227, 2007.
 104. Tryba AK , Pena F , Ramirez JM . Gasping activity in vitro: A rhythm dependent on 5‐HT 2A receptors. J Neurosci 26(10): 2623‐2634, 2006.
 105. Vege A , Rognum TO , Scott H , Aasen AO , Saugstad OD . SIDS cases have increased levels of interleukin‐6 in cerebrospinal fluid. Acta Paediatr 84(2): 193‐6, 1995.
 106. Waters KA , Tinworth KD . Habituation of arousal responses after intermittent hypercapnic hypoxia in piglets. Am J Respir Crit Care Med 171(11): 1305‐11, 2005.
 107. Waters KA , Gonzalez A , Jean C , Mortielli A , Brouillette RT . Face‐straight‐down and face‐near‐straight‐down positions in healthy, prone‐sleeping infants. J Pediatr 128: 616‐625, 1996.
 108. Wulbrand H , McNamara F , Thach BT . Suppression of sigma spindle electroencephalographic activity as a measure of transient arousal after spontaneous and occlusion‐evoked sighs and startles. Pediatr Res 44(5): 767‐73, 1998.
 109. Wulbrand H , McNamara F , Thach BT . The role of arousal related brainstem reflexes in causing recovery from upper airway occlusion in infants. Sleep 31(6): 833‐40, 2008.
 110. Xia L , Leiter JC , Bartlett D . Gestational nicotine exposure exaggerates hyperthermic enhancement of laryngeal chemoreflex in rat pups. Respir Physiol Neurobiol 171: 17‐21, 2010.

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Article Title: Potential Central Nervous System Involvement in Sudden Unexpected Infant Deaths and the Sudden Infant Death Syndrome
 

How to Cite

Bradley T. Thach. Potential Central Nervous System Involvement in Sudden Unexpected Infant Deaths and the Sudden Infant Death Syndrome. Compr Physiol 2015, 5: 1061-1068. doi: 10.1002/cphy.c130052