- Email: [email protected]
A possible cause of Sudden Infant Death Syndrome
Medical Hypotheses 136 (2020) 109520
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A possible cause of Sudden Infant Death Syndrome Arnoldus Schytte Blix
⁎
T
Department of Arctic and Marine Biology, UiT – The Arctic University of Norway, Tromsø, Norway St. Catharine’s College, Cambridge CB2 1RL, UK
A B S T R A C T
It is suggested that an orienting response to loud sound causes apnea, which, in already asphyxic infants, triggers a maximal secondary chemoreceptor response, with massive vagal stimulation of the heart, which causes heart arrest.
Introduction
The hypothesis
Sudden Infant Death Syndrome (SIDS) is one of the leading causes of infant death in the post neonatal period [1,2]. So far, the most important advance in combating this disorder has been the discovery that the prone sleep position more than triples the risk for SIDS [3], and most authors seem to agree that asphyxia is a key component of the problem [4–6]. In asphyxic mammals including man, arterial hypoxia will activate the peripheral chemoreceptors and reflexly induce responses aimed at improved oxygen uptake, such as tachycardia and (assisted by the central chemoreceptors) increased ventilation. This is what is termed the primary chemoreceptor response. If apnea occurs, however, chemoreceptor stimulation activates responses aimed at reduced use of the oxygen stores, such as selective peripheral vasoconstriction and bradycardia [7]. This latter reaction is clearly displayed in diving animals [8–10] (Fig. 1A), and it has repeatedly been suggested that the ‘diving reflex’ may be the cause of SIDS [e.g. 11–13]. Another causative candidate for SIDS has been the ‘orienting reflex’. The classical description of the orienting reflex was given by Pavlov [14]: ‘A reflex which brings about the immediate response in man and animals to the slightest changes in the world around them, so that they immediately orientate their appropriate receptor-organ in accordance with the perceptible quality in the agent bringing about the change, making full investigation of it’. This orienting reflex is common to all mammals and birds and include both reduced breathing and bradycardia, even in human babies [15]. If the stimulus is severe, it might be replaced, or, evolve into a fear response, which, with cessation of breathing and profound bradycardia [e.g. 16], is reminiscent of the diving responses. Accordingly, Gabrielsen [17] and Kaada [18,19] has suggested that the ‘fear paralysis reflex’ may be a major trigger mechanism for SIDS.
Blix and Berg [20] exposed ducks to an altitude of 6000 m in a walkin low-pressure chamber, which gave a steady state arterial PO2 of 33 ± 3 mmHg. When, after a period of 5 min equilibration, the ducks were submerged at this altitude they responded with a fully developed bradycardia within 3 sec (Fig. 1B), whereas when PO2 was adjusted to sea level value at this altitude, the cardiovascular responses to submergence was as those obtained at sea level. I therefore suggest that SIDS may occur in response to an orienting response to loud sounds in already asphyxic neonates, in which apnea is incurred, and by which the secondary chemoreceptor response is expressed, and results in massive vagal simulation of the heart, ultimately causing cardiac arrest in some so disposed infants.
⁎
Supportive evidence SIDS has a unique age-at-death distribution with approximately 80% occurring in the first four months after birth with a peak at 2–3 months of age [2]. This hitherto unexplained feature of SIDS can be explained, at least in part, by the following: Andersen et al. [15] found that auditory stimulation (sudden 80 dB noise) elicited apnea and bradycardia in 58% of infants at 8–16 weeks (2–4 months) compared to 14% at 28–50 weeks. Fetal hemoglobin has higher affinity for oxygen than that of the adult, and the adult form replaces fetal hemoglobin over a period of 6 months, with hemoglobin values generally being at their lowest values at 2–3 months of age [21]. The peripheral chemoreceptors are not functional at birth, but their chemosensitivity starts to develop within the first 3 weeks after birth [22].
Address: Department of Arctic and Marine Biology, UiT – the Arctic University of Norway, NO-9037 Tromsø, Norway. E-mail address: [email protected].
https://doi.org/10.1016/j.mehy.2019.109520 Received 5 November 2019; Received in revised form 29 November 2019; Accepted 7 December 2019 0306-9877/ © 2019 Elsevier Ltd. All rights reserved.
Medical Hypotheses 136 (2020) 109520
A.S. Blix
Acknowledgements The author has benefited from discussions with Dr. Philip Oliver during the preparation of the manuscript. References [1] Hunt CE, Hauck FR. Sudden infant death syndrome. Can Med Assoc J 2006;174:1861–9. [2] Shapiro-Mendoza CK, Parks S, Lambert AE, Camperlengo L, Cottengim C, Olson, C. The epidemiology of sudden infant death syndrome and sudden unexpected infant deaths: Diagnostic shift and other temporal changes. In: Duncan JR Byard RW, editors. SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future. Adelaide: Univ. Adelaide Press; 2018. pp. 1–13. [3] Willinger M, Hoffman HJ, Hartford RB. Infant sleep position and risk for sudden infant death syndrome. Pediatrics 1994;93:814–9. [4] Chiodini BA, Thach BT. Impaired ventilation in infants sleeping facedown: Potential significance for sudden infant death syndrome. J Pediatr 1963;123:686–92. [5] Pasquale-Styles MA, Tackitt PL, Schmidt CJ. Infant death scene investigation and the assessment of potential risk factors for asphyxia: a review of 209 sudden unexpected infant deaths. J Forensic Sci 2007;52:924–9. [6] Kinney HC, Thach BT. The sudden infant death syndrome. N Engl J Med 2009;361:795–805. [7] Daly M de Burgh, Scott MJ. The cardiovascular responses to stimulation of the carotid body chemoreceptors in the dog. J Physiol 1963;165:179–97. [8] Blix AS, Folkow B. Cardiovascular adjustments to diving in mammals and birds. In: Shepard JT, Abboud FM, editors. Handbook of Physiology. The Cardiovascular System III. Peripheral Circulation and Organ Blood Flow. Bethesta: American Physiological Society. 1983. pp. 917-945. [9] Butler PJ, Jones DR. Physiology of diving birds and mammals. Physiol Rev 1997;77:837–99. [10] Blix AS. Adaptations to deep and prolonged diving in phocid seals. J Exp Biol 2018;221. [11] Lobban CDR. The oxygen-conserving dive reflex re-examined as the principal contributory factor in sudden infant death. Med Hypothesis 1995;44:273–7. [12] Matturri L, Ottaviani G, Lavezzi AM. Sudden infant death triggered by dive reflex. J Clin Pathol 2005;58:77–80. [13] Pedroso FS, Riesgo RS, Gatiboni T, Rotta NT. The diving reflex in healthy infants in the first year of life. J Child Nevrology 2012;27:168–71. [14] Sokolov EN. Higher nervous functions: the orienting reflex. Ann Rev Physiol 1963;25:545–80. [15] Andersen SH, Nicholaisen RB, Gabrielsen GW. Autonomic response to auditorystimulation. Acta Paediatr 1993;82:913–8. [16] Gabrielsen GW, Blix AS, Ursin H. Orienting and freezing responses in incubating ptarmigan hens. Physiol Behav 1985;34:925–34. [17] Gabrielsen GW. Passiv frykt – en mulig årsak til plutselig uventet spebarnsdød? (in Norwegian). Tidsskr Nor Laegeforen 1986;106:898–902. [18] Kaada B. The sudden infant death syndrome induced by ‘the fear paralysis reflex. Med Hypothesis 1987;22:347–56. [19] Kaada B. Fryktparalyse – fortsatt en potensiell årsak til krybbedød (in Norwegian). Tidsskr Nor Laegeforen 1995;115:848–52. [20] Blix AS, Berg T. Arterial hypoxia and the diving responses of ducks. Acta Physiol Scand 1974;92:566–8. [21] Oski FA. Clinical implications of the oxyhemoglobin dissociation curve in the neonatal period. Critical Care Med 1979;7:412–8. [22] Gauda EB, Carroll JL, Donnelly DF. Developmental maturation of chemosensitivity to hypoxia of peripheral arterial chemoreceptors. In: Gonzalez C, Nurse CA, Peers C. editors. Arterial Chemoreceptors. Advances in Experimental Medicine and Biology. Dordrecht: Springer; 2009.Vol 648. [23] Foss I, Flottorp G. A comparative study of the development of hearing and vision in various species commonly used in experiments. Acta Otolaryng 1974;77:202–14. [24] Sebastini L, Salamone D, Silvestri P, Simoni A, Ghelarducci B. Development of fearrelated heart rate responses in neonatal rabbits. J Autonomic Nervous Syst 1994;50:231–8.
Fig. 1. Effect of pre-dive stimulation of chemoreceptors on the development of diving responses in the duck. A: normal blood pressure record obtained at sea level. B: blood pressure response obtained in dive commenced at simulated altitude of 6000 m, resulting in pre-dive arterial partial pressure of O2 of 33 mmHg (4.4 kPa) without an increase in arterial partial pressure of CO2. Note the nearly immediate development of intense bradycardia response when the peripheral chemoreceptors are stimulated prior to dive (B) as compared with normal dive situation (A). (Ref. [20]).
Test of hypothesis This hypothesis can be tested, for instance, in neonate rabbits, after being made hypoxic by breathing hypoxic air, and thereupon startled by loud noises. Such animals start to hear from day 7 [23] and show orienting responses with bradycardia when aged 18 days [24].
Funding This work did not receive any financial support. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
2
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A possible cause of Sudden Infant Death Syndrome Arnoldus Schytte Blix
⁎
T
Department of Arctic and Marine Biology, UiT – The Arctic University of Norway, Tromsø, Norway St. Catharine’s College, Cambridge CB2 1RL, UK
A B S T R A C T
It is suggested that an orienting response to loud sound causes apnea, which, in already asphyxic infants, triggers a maximal secondary chemoreceptor response, with massive vagal stimulation of the heart, which causes heart arrest.
Introduction
The hypothesis
Sudden Infant Death Syndrome (SIDS) is one of the leading causes of infant death in the post neonatal period [1,2]. So far, the most important advance in combating this disorder has been the discovery that the prone sleep position more than triples the risk for SIDS [3], and most authors seem to agree that asphyxia is a key component of the problem [4–6]. In asphyxic mammals including man, arterial hypoxia will activate the peripheral chemoreceptors and reflexly induce responses aimed at improved oxygen uptake, such as tachycardia and (assisted by the central chemoreceptors) increased ventilation. This is what is termed the primary chemoreceptor response. If apnea occurs, however, chemoreceptor stimulation activates responses aimed at reduced use of the oxygen stores, such as selective peripheral vasoconstriction and bradycardia [7]. This latter reaction is clearly displayed in diving animals [8–10] (Fig. 1A), and it has repeatedly been suggested that the ‘diving reflex’ may be the cause of SIDS [e.g. 11–13]. Another causative candidate for SIDS has been the ‘orienting reflex’. The classical description of the orienting reflex was given by Pavlov [14]: ‘A reflex which brings about the immediate response in man and animals to the slightest changes in the world around them, so that they immediately orientate their appropriate receptor-organ in accordance with the perceptible quality in the agent bringing about the change, making full investigation of it’. This orienting reflex is common to all mammals and birds and include both reduced breathing and bradycardia, even in human babies [15]. If the stimulus is severe, it might be replaced, or, evolve into a fear response, which, with cessation of breathing and profound bradycardia [e.g. 16], is reminiscent of the diving responses. Accordingly, Gabrielsen [17] and Kaada [18,19] has suggested that the ‘fear paralysis reflex’ may be a major trigger mechanism for SIDS.
Blix and Berg [20] exposed ducks to an altitude of 6000 m in a walkin low-pressure chamber, which gave a steady state arterial PO2 of 33 ± 3 mmHg. When, after a period of 5 min equilibration, the ducks were submerged at this altitude they responded with a fully developed bradycardia within 3 sec (Fig. 1B), whereas when PO2 was adjusted to sea level value at this altitude, the cardiovascular responses to submergence was as those obtained at sea level. I therefore suggest that SIDS may occur in response to an orienting response to loud sounds in already asphyxic neonates, in which apnea is incurred, and by which the secondary chemoreceptor response is expressed, and results in massive vagal simulation of the heart, ultimately causing cardiac arrest in some so disposed infants.
⁎
Supportive evidence SIDS has a unique age-at-death distribution with approximately 80% occurring in the first four months after birth with a peak at 2–3 months of age [2]. This hitherto unexplained feature of SIDS can be explained, at least in part, by the following: Andersen et al. [15] found that auditory stimulation (sudden 80 dB noise) elicited apnea and bradycardia in 58% of infants at 8–16 weeks (2–4 months) compared to 14% at 28–50 weeks. Fetal hemoglobin has higher affinity for oxygen than that of the adult, and the adult form replaces fetal hemoglobin over a period of 6 months, with hemoglobin values generally being at their lowest values at 2–3 months of age [21]. The peripheral chemoreceptors are not functional at birth, but their chemosensitivity starts to develop within the first 3 weeks after birth [22].
Address: Department of Arctic and Marine Biology, UiT – the Arctic University of Norway, NO-9037 Tromsø, Norway. E-mail address: [email protected].
https://doi.org/10.1016/j.mehy.2019.109520 Received 5 November 2019; Received in revised form 29 November 2019; Accepted 7 December 2019 0306-9877/ © 2019 Elsevier Ltd. All rights reserved.
Medical Hypotheses 136 (2020) 109520
A.S. Blix
Acknowledgements The author has benefited from discussions with Dr. Philip Oliver during the preparation of the manuscript. References [1] Hunt CE, Hauck FR. Sudden infant death syndrome. Can Med Assoc J 2006;174:1861–9. [2] Shapiro-Mendoza CK, Parks S, Lambert AE, Camperlengo L, Cottengim C, Olson, C. The epidemiology of sudden infant death syndrome and sudden unexpected infant deaths: Diagnostic shift and other temporal changes. In: Duncan JR Byard RW, editors. SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future. Adelaide: Univ. Adelaide Press; 2018. pp. 1–13. [3] Willinger M, Hoffman HJ, Hartford RB. Infant sleep position and risk for sudden infant death syndrome. Pediatrics 1994;93:814–9. [4] Chiodini BA, Thach BT. Impaired ventilation in infants sleeping facedown: Potential significance for sudden infant death syndrome. J Pediatr 1963;123:686–92. [5] Pasquale-Styles MA, Tackitt PL, Schmidt CJ. Infant death scene investigation and the assessment of potential risk factors for asphyxia: a review of 209 sudden unexpected infant deaths. J Forensic Sci 2007;52:924–9. [6] Kinney HC, Thach BT. The sudden infant death syndrome. N Engl J Med 2009;361:795–805. [7] Daly M de Burgh, Scott MJ. The cardiovascular responses to stimulation of the carotid body chemoreceptors in the dog. J Physiol 1963;165:179–97. [8] Blix AS, Folkow B. Cardiovascular adjustments to diving in mammals and birds. In: Shepard JT, Abboud FM, editors. Handbook of Physiology. The Cardiovascular System III. Peripheral Circulation and Organ Blood Flow. Bethesta: American Physiological Society. 1983. pp. 917-945. [9] Butler PJ, Jones DR. Physiology of diving birds and mammals. Physiol Rev 1997;77:837–99. [10] Blix AS. Adaptations to deep and prolonged diving in phocid seals. J Exp Biol 2018;221. [11] Lobban CDR. The oxygen-conserving dive reflex re-examined as the principal contributory factor in sudden infant death. Med Hypothesis 1995;44:273–7. [12] Matturri L, Ottaviani G, Lavezzi AM. Sudden infant death triggered by dive reflex. J Clin Pathol 2005;58:77–80. [13] Pedroso FS, Riesgo RS, Gatiboni T, Rotta NT. The diving reflex in healthy infants in the first year of life. J Child Nevrology 2012;27:168–71. [14] Sokolov EN. Higher nervous functions: the orienting reflex. Ann Rev Physiol 1963;25:545–80. [15] Andersen SH, Nicholaisen RB, Gabrielsen GW. Autonomic response to auditorystimulation. Acta Paediatr 1993;82:913–8. [16] Gabrielsen GW, Blix AS, Ursin H. Orienting and freezing responses in incubating ptarmigan hens. Physiol Behav 1985;34:925–34. [17] Gabrielsen GW. Passiv frykt – en mulig årsak til plutselig uventet spebarnsdød? (in Norwegian). Tidsskr Nor Laegeforen 1986;106:898–902. [18] Kaada B. The sudden infant death syndrome induced by ‘the fear paralysis reflex. Med Hypothesis 1987;22:347–56. [19] Kaada B. Fryktparalyse – fortsatt en potensiell årsak til krybbedød (in Norwegian). Tidsskr Nor Laegeforen 1995;115:848–52. [20] Blix AS, Berg T. Arterial hypoxia and the diving responses of ducks. Acta Physiol Scand 1974;92:566–8. [21] Oski FA. Clinical implications of the oxyhemoglobin dissociation curve in the neonatal period. Critical Care Med 1979;7:412–8. [22] Gauda EB, Carroll JL, Donnelly DF. Developmental maturation of chemosensitivity to hypoxia of peripheral arterial chemoreceptors. In: Gonzalez C, Nurse CA, Peers C. editors. Arterial Chemoreceptors. Advances in Experimental Medicine and Biology. Dordrecht: Springer; 2009.Vol 648. [23] Foss I, Flottorp G. A comparative study of the development of hearing and vision in various species commonly used in experiments. Acta Otolaryng 1974;77:202–14. [24] Sebastini L, Salamone D, Silvestri P, Simoni A, Ghelarducci B. Development of fearrelated heart rate responses in neonatal rabbits. J Autonomic Nervous Syst 1994;50:231–8.
Fig. 1. Effect of pre-dive stimulation of chemoreceptors on the development of diving responses in the duck. A: normal blood pressure record obtained at sea level. B: blood pressure response obtained in dive commenced at simulated altitude of 6000 m, resulting in pre-dive arterial partial pressure of O2 of 33 mmHg (4.4 kPa) without an increase in arterial partial pressure of CO2. Note the nearly immediate development of intense bradycardia response when the peripheral chemoreceptors are stimulated prior to dive (B) as compared with normal dive situation (A). (Ref. [20]).
Test of hypothesis This hypothesis can be tested, for instance, in neonate rabbits, after being made hypoxic by breathing hypoxic air, and thereupon startled by loud noises. Such animals start to hear from day 7 [23] and show orienting responses with bradycardia when aged 18 days [24].
Funding This work did not receive any financial support. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
2