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Sudden infant death syndrome: can gastroesophageal reflux cause sudden infant death?
Sudden Infant Death Syndrome: Can Gastroesophageal Reflux Cause Sudden Infant Death? Bradley T. Thach, MD
Although gastric contents in the airways and lungs of sudden infant death syndrome (SIDS) victims is commonly found during postmortem examination, its significance as a sole or contributory cause of death has long been controversial. Currently, most authorities view such aspiration as resulting from “agonal” processes and, therefore, irrelevant to cause of death. Recent clinical and experimental evidence indicates that infants who are near death because of a variety of conditions, frequently “autoresuscitate,” which produces rapid and complete recovery. In animal models, aspiration of water or saline into the airways has been shown to prevent autoresuscitation. In light of these findings, aspiration of gastric contents should be reconsidered as a contributory cause of many SIDS deaths. Am J Med. 2000;108(4A): 144S–148S. © 2000 by Excerpta Medica, Inc.
From the Department of Pediatrics, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, Missouri, USA. Supported by National Institutes of Health Grant HED 10993. Requests for reprints should be addressed to Bradley T. Thach, MD, Department of Pediatrics, 1 Children’s Place, St. Louis, Missouri 63110. 144S © 2000 by Excerpta Medica, Inc. All rights reserved.
T
he purpose of this brief review is to reexamine a longstanding controversy in forensic medicine: the significance of gastroesophageal reflux and resultant pulmonary aspiration in cases of sudden and otherwise unexplained deaths. The presence of gastric contents in the lungs and airways is common in deaths caused by a wide variety of disorders, including those in which death occurs suddenly and for no apparent reason.1– 4 In former times,the sudden and unexpected death of young infants frequently was attributed to aspiration of a regurgitated feeding.3,5,6 Presence of gastric material in the lungs occurs in 20% to 30% of routine sudden infant death syndrome (SIDS) autopsies.4,7–9 Use of special histologic techniques indicates a much higher incidence, 30% to 60%.3,10 Currently, however, the finding of regurgitated milk in the lungs of SIDS victims generally is considered of little relevance to the cause of death.1,5,6,11,12 There are two primary reasons for this view. The first of these dates from the early 1970s when renewed attention was given to SIDS, its cause, and diagnosis. The belief that SIDS could be attributed to a single cause emerged as a predominant theory. Accordingly, if a potential causal factor was not present in all SIDS cases, it could no longer be considered “the cause” of SIDS. The second, and more compelling, reason for disregarding evidence of aspiration in the postmortem findings can be attributed to the work of Gardner and others during the late 1950s. This work is fully discussed below. More recent findings from different fields suggest a need to reevaluate the role of aspiration in deaths, at least as far as SIDS and other forms of sudden death are concerned. Reevaluation is needed for two reasons. First, in contrast with the “single-cause” hypothesis, it is now apparent that multiple SIDS risk factors likely interact in combination. Elimination of one or more of these risks (e.g., prone sleep position) has been followed by significant reductions in SIDS rates, however, without the complete elimination of SIDS.13–15 A “triple risk” model has been proposed in which congenital or acquired risk factors interact with environmental “triggering” factors primarily during the critical developmental period when most SIDS cases occur.16 Also, certain theoretically distinct diseases may be virtually indistinguishable from other forms of SIDS. From these perspectives, a “single cause” hypothesis would appear to be outmoded. There is 0002-9343/00/$20.00 PII S0002-9343(99)00354-X
A Symposium: Gastroesophageal Reflux and Sudden Infant Death Syndrome/Thach
a second reason for reevaluating the causal role of “agonal” aspiration in the sequence of events leading to death. This comes from new insights into the final common pathway in the process of dying and the remarkable capacity for “autoresuscitation” to fully reverse this pathway often within seconds before actual death. These issues are further discussed below.
FORENSIC STUDIES OF GASTROESOPHAGEAL REFLUX AND ASPIRATION In the late 1950s the several studies conducted by Gardner on aspiration pneumonia and its significance in forensic medicine soon became regarded as the definitive work in this field.3 Gardner reviewed his own extensive clinical experience as well as prior work. He concluded that in a substantial number of autopsies of individuals, whose deaths were clearly caused by well-substantiated mechanisms, such as trauma or myocardial infarction, there was evidence of recently aspirated gastric material in the airways. In such cases it seemed clear that aspiration played a secondary role, if any at all, in the deaths. Gardner proposed that such aspiration in some cases may be the result of “agonal” regurgitation during the final stages of death. However, he also suspected that “aspiration” can occur even after death, as a consequence of manipulation of the body in the process of transportation. To test this hypothesis, he introduced barium into the stomachs of adult subjects shortly after their deaths. In 7 of 10 bodies so treated, he found evidence of barium in the airways and lungs when the postmortem examination was performed. This finding suggested that a combination of the postmortem relaxation of esophageal sphincters and the differential pressure produced in the abdomen and chest during transportation of the body caused passage of material from the stomach into the lungs. Gardner further showed that inflammatory changes resulting from such postmortem “aspiration” can occur in lung tissue for several hours after death, making it impossible to use microscopic findings to determine when aspiration occurred. The realization that “aspiration” can occur after death further compounded the already existing controversy over the significance of gastric material found in the lungs of individuals after death. Many pathologists previously had concluded that “agonal” aspiration of gastric contents during the final stages of dying is common.3,5,9 Although the origins of this theory are obscure, presumably agonal aspiration can be the combined result of relaxation of esophageal sphincters, suppression of upper airway protective reflexes, and terminal inspiratory efforts. This might occur as a natural consequence of hypoxemia and failing circulation in the final minutes before death. Despite these significant hindrances to making a definitive diagnosis of aspiration as a cause of death, Gardner and subsequent investigators believed that aspiration of
gastric contents, in fact, could be a primary cause of death, particularly in weak, debilitated, or neurologically impaired individuals.3 Bernard Knight, who succeeded Gardner as an authority in this field, concluded that the only hope a pathologist had for distinguishing such fatal aspiration cases from those in which insignificant agonal or postmortem aspiration occurred lay in obtaining a strong clinical history supporting the diagnosis: “the standard of proof required before one can confidently state that aspiration of stomach contents is the cause of death, is usually beyond the grasp of any pathologist if he does not have unequivocal clinical corroboration.”4 In SIDS cases, in particular, this inability to distinguish significant from insignificant aspiration troubled both Gardner and Knight. Gardner and, later, Knight adopted a pragmatic position in SIDS cases that had evidence of aspiration. They took the view that if SIDS is a diagnosis in which cause of death is unknown, one need not emphasize the possible causal role of aspiration, because introducing aspiration as a diagnostic possibility could be interpreted to suggest negligence on the part of the infant caretaker. It is of particular interest that Gardner made a strong distinction between this essentially pragmatic position and his underlying beliefs concerning the relevance of aspiration to cause of death in SIDS cases: “Aspiration of vomit is often dismissed as an agonal phenomenon [in SIDS]. Sometimes this may be so, but more often it is the coup de grace in an ill patient who might otherwise have a chance of survival.”3 Gardner’s cautionary note soon was forgotten and, with rare exceptions,17 forensic experts continue to view presence of intrapulmonary gastric fluid in SIDS as an “agonal” phenomenon with little or no significance in the events leading to the infant’s death.1,5,6,11,12
RECENT DEVELOPMENTS RELEVANT TO THE ROLE OF REGURGITATION AND ASPIRATION IN SIDS Progress during the past 10 years suggests that a reassessment of the potential role of aspiration in SIDS is appropriate. During this time, it has become apparent that young infants are prone to a variety of conditions that result in transient but severe episodes of hypoxemia and/or ischemia.18 Such events are extremely common within the first few minutes after birth. Later in the life of the infant, hypoxic episodes may appear in the form of prolonged apneic spells. These include apnea of prematurity, laryngeal chemoreflex apnea, obstructive sleep apnea, and “breathholding” apneic episodes.18,19 Other cardiovascular events, such as transient arrythmias or asystoles, have similar consequences. Not infrequently, such episodes progress to a point where loss of consciousness and a state of marked cardiovascular and neural depression suddenly occurs. This has been termed “hypoxic coma.”20,21 In most cases, cardiovascular and neural recov-
March 6, 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108 (4A)
145S
A Symposium: Gastroesophageal Reflux and Sudden Infant Death Syndrome/Thach
Figure 1. Polygraphic recordings from mice showing plethysmographic documented respiration and pharyngeal pressure recordings. Tracings begin at onset of hypoxic coma, which has been produced by sudden exposure to N2 gas. A small catheter is placed in the animal’s pharynx, and simultaneously the chamber is flushed with air. (A) Catheter placement alone. Note onset of gasps (G) that rapidly give way to eupneic breaths, at which time complete neurologic recovery occurs in this unanesthetized mouse. Then, a small bolus of fluid is infused into the airway to elicit swallows (Sw). (B) A similar procedure, except that the catheter is placed and a water fluid bolus is infused at the beginning of hypoxic coma. Note repeated swallows, prolongation of coma as compared with A, indicated by delayed eupnea onset. (Reproduced with permission from J Appl Physiol.24)
ery occurs rapidly and spontaneously after the onset of gasping respirations that reoxygenate the body. This mode of spontaneous recovery has been termed “autoresuscitation.”21 Such episodes are marked by loss of reflexes, muscle tone, apnea, bradycardia, and cyanosis or palor and formerly were known as “near miss SIDS.” They currently are termed “apparent life-threatening episodes”(ALTEs).18 The fact that prognosis is very good in the vast majority of infants with ALTEs is evidence of the efficiency and efficacy of autoresuscitation as a protective physiologic mechanism. Very recent studies of apnea monitor event recordings of infants dying of SIDS who were being monitored at the time of death have indicated that, in the majority of SIDS deaths, terminal gasping respirations are present.22,23 This suggests that SIDS, in part at least, represents a fail146S March 6, 2000 THE AMERICAN JOURNAL OF MEDICINE威
ure of the autoresuscitation mechanism to produce recovery. When gasping fails to produce recovery, common reasons for failure include underlying impairment of circulatory or pulmonary function.21 Were “agonal” regurgitation and aspiration to occur during hypoxic coma caused by apnea or other mechanisms, it conceivably could interfere with autoresuscitation and result in a SIDS death. To clarify further the potential adverse effects of gastroesophageal reflux and aspiration on the outcome of autoresuscitation, we developed an animal model in which hypoxic coma is rapidly induced in mice by sudden exposure to anoxic gas (N2).24 When the mouse became unconscious, a small bolus of fluid (water or saline, 0.05 mL) was delivered by cannula into the animal’s pharynx, and then room air was made available for the mouse to
Volume 108 (4A)
A Symposium: Gastroesophageal Reflux and Sudden Infant Death Syndrome/Thach
Figure 2. The same experimental situation as in Figure 1. In this case, however, the mouse does not swallow. The reason for absence of reflex swallowing is unclear. Note occurrence of gasps (G) that produce little or no movement of air into the chest but can be recorded as small deflections in pharyngeal pressure in the fluid-filled pharynx. This animal’s death is indicated by the last gasp. One presumes that failure to swallow caused persistence of water and persistent airway obstruction. (Reproduced with permission from J Appl Physiol.24)
breathe. Although most other reflexes were absent during hypoxic coma, fluid in the mouse’s pharynx produced swallowing. Swallowing was more frequent with water than with saline, indicating the presence of the laryngeal chemoreflex even at this very depressed level of neurologic function (Figure 1).19 Both saline and water boluses delayed recovery by autoresuscitation. Gasping duration was prolonged in each case. Saline boluses were cleared from the pharyngeal and nasal airway more slowly than water, and, likely as a consequence of this, recovery was less rapid with saline than with water. When swallowing was altogether absent, as occasionally occurred in some mice, or when swallowing was suppressed by phenobarbital anesthesia, autoresuscitation usually failed. These mice continued to gasp, but recovery did not occur. The mechanism for this failure appeared to be obstruction of the large or small airways by saline or water, as suggested by absent airflow to the lungs (Figure 2). These studies, therefore, showed that even small amounts of chemically innocuous fluid can delay or prevent autoresuscitation. In summary, postmortem evidence of gastric contents in airways and lungs long has been held to be a finding of little significance. As regards SIDS, the distinction between “we don’t know if this finding is relevant to cause of death” and “this finding is clearly not relevant to cause of death” has been blurred. Recent evidence indicates that autoresuscitation produced by “agonal” gasping is not infrequent in infants and young children as part of an efficient survival mechanism in the face of acute hypoxemia/hypoperfusion. Furthermore, the observation that even relatively benign fluids in the upper airway can impair autoresuscitation in an animal model suggests that the finding of pulmonary aspiration in a case of sudden infant death may indicate a cause for failed autoresuscitation and so may be very relevant to the causal sequence
of events leading to death. Although in the absence of conclusive evidence it is still quite appropriate to regard aspiration as an undetermined factor in SIDS, it is conceivable that increased attention given to its documentation and correlation with other pathologic and historic findings could lead to further insights into the mechanisms of SIDS deaths. Such renewed attention might one day indicate that “agonal” aspiration is the “coup de grace” that determines the death of many infants, as Gardner originally believed it to be.
REFERENCES 1. Knight B. Forensic Pathology, 2nd ed. New York: Oxford University Press, 1996:450. 2. DiMaio DJ. Forensic Pathology. New York: Elsevier, 1989: 217. 3. Gardner AMN. Aspiration of food and vomit. Q J Med. 1958;27:227–242. 4. Knight BH. The significance of the postmortem discovery of gastric contents in the air passages. Forensic Sci. 1975;6: 229 –234. 5. Camps FE. In: Camps FE, Carpenter RG, eds. Sudden and Unexpected Deaths in Infancy (cot deaths): Session I. Bristol, UK: John Wright and Sons, 1972:1–2. 6. Guntheroth WG. Crib Death: The Sudden Infant Death Syndrome. Mount Kisco, NY: Futura, 1989:140. 7. Valdes-DaPena MA. Sudden and unexpected death in infancy: a review of the world literature 1954 –1966. Pediatrics. 1967;39:123–138. 8. Werne J, Garrow I. Sudden apparently unexplained death during infancy. I. Pathologic finding in infants found dead. Arch Pathol. 1953;29:633– 675. 9. Simpson K. Pathology of sudden death. Lancet. 1947;ii: 745–747. 10. Coombs RRA. In: Camps FE, Carpenter RG, eds. Sudden and Unexpected Deaths in Infancy (cot deaths): Session I. Bristol, UK: John Wright and Sons, 1972:21. 11. Smialek JE, Smilaek PZ, Spitz WU. Accidental bed deaths
March 6, 2000
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A Symposium: Gastroesophageal Reflux and Sudden Infant Death Syndrome/Thach
12.
13.
14.
15. 16.
17. 18.
in infants due to unsafe sleeping situations. Clin Pediatr. 1977;16:1031–1036. James D, Berry PJ, Fleming P, Hathaway M. Surfactant abnormality and the sudden infant death syndrome: a primary or secondary phenomenon? Arch Dis Child. 1990;65: 774 –778. Mitchell EA, Brunt JM, Everand C. Reduction in mortality from sudden infant death syndrome in New Zealand: 1986 – 92. Arch Dis Child. 1994;70:291–294. Dwyer T, Ponsonby AL, Blizzard L, Newman N, Cochvane JA. The contribution of changes in the prevalence of prone sleeping position to the decline in sudden infant death syndrome in Tasmania. JAMA. 1995;273:783–789. Dwyer T, Ponsonby AL. The decline of SIDS: a success story for epidemiology. Epidemiology. 1996;7:3323–3325. Filiano JJ, Kinney HC. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model. Biol Neonate. 1994;65:1947–1997. Rammer L. Pathological definition of SIDS. Acta Paediatr. 1993;389:48 – 49. Thach BT. Apnea and the sudden infant death syndrome.
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19.
20. 21.
22.
23.
24.
In: Saunders NA, Sullivan C, eds. Sleep and Breathing (Biology of the Lung Series, C. Lenfant, ed). New York: Marcel Dekker, 1994. Thach BT. Reflux associated apnea in infants: evidence for a laryngeal chemoreflex. Am J Med. 1997(suppl. 5A):S120 – S124. Guntheroth WG, Kawabori I. Hypoxic apnea and gasping. J Clin Invest. 1975;56:1371–1377. Thach BT, Jacobi MS, Gershan WM. Control of breathing during asphyxia and autoresuscitation. In: Haddad G, Farber JP, eds. Developmental Neurobiology of Breathing. New York: Marcel Dekker, 1991. Poets CF, Meny RG, Chobanian MR, Bonofiglo RE. Gasping and other cardio-respiratory patterns during sudden infant deaths. Pediatr Res. 1999;45:350 –354. Sridhar R, Thach BT, Kelly D, Henslee JA. Competency of autoresuscitation mechanisms in sudden infant death. Pediatr Res. 1999; 45:365A. (Abstr.) Khurana A, Thach BT. Effects of upper airway stimulation on swallowing, gasping, and autoresuscitation in hypoxic mice. J Appl Physiol. 1996;80:472– 477.
Volume 108 (4A)
Although gastric contents in the airways and lungs of sudden infant death syndrome (SIDS) victims is commonly found during postmortem examination, its significance as a sole or contributory cause of death has long been controversial. Currently, most authorities view such aspiration as resulting from “agonal” processes and, therefore, irrelevant to cause of death. Recent clinical and experimental evidence indicates that infants who are near death because of a variety of conditions, frequently “autoresuscitate,” which produces rapid and complete recovery. In animal models, aspiration of water or saline into the airways has been shown to prevent autoresuscitation. In light of these findings, aspiration of gastric contents should be reconsidered as a contributory cause of many SIDS deaths. Am J Med. 2000;108(4A): 144S–148S. © 2000 by Excerpta Medica, Inc.
From the Department of Pediatrics, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, Missouri, USA. Supported by National Institutes of Health Grant HED 10993. Requests for reprints should be addressed to Bradley T. Thach, MD, Department of Pediatrics, 1 Children’s Place, St. Louis, Missouri 63110. 144S © 2000 by Excerpta Medica, Inc. All rights reserved.
T
he purpose of this brief review is to reexamine a longstanding controversy in forensic medicine: the significance of gastroesophageal reflux and resultant pulmonary aspiration in cases of sudden and otherwise unexplained deaths. The presence of gastric contents in the lungs and airways is common in deaths caused by a wide variety of disorders, including those in which death occurs suddenly and for no apparent reason.1– 4 In former times,the sudden and unexpected death of young infants frequently was attributed to aspiration of a regurgitated feeding.3,5,6 Presence of gastric material in the lungs occurs in 20% to 30% of routine sudden infant death syndrome (SIDS) autopsies.4,7–9 Use of special histologic techniques indicates a much higher incidence, 30% to 60%.3,10 Currently, however, the finding of regurgitated milk in the lungs of SIDS victims generally is considered of little relevance to the cause of death.1,5,6,11,12 There are two primary reasons for this view. The first of these dates from the early 1970s when renewed attention was given to SIDS, its cause, and diagnosis. The belief that SIDS could be attributed to a single cause emerged as a predominant theory. Accordingly, if a potential causal factor was not present in all SIDS cases, it could no longer be considered “the cause” of SIDS. The second, and more compelling, reason for disregarding evidence of aspiration in the postmortem findings can be attributed to the work of Gardner and others during the late 1950s. This work is fully discussed below. More recent findings from different fields suggest a need to reevaluate the role of aspiration in deaths, at least as far as SIDS and other forms of sudden death are concerned. Reevaluation is needed for two reasons. First, in contrast with the “single-cause” hypothesis, it is now apparent that multiple SIDS risk factors likely interact in combination. Elimination of one or more of these risks (e.g., prone sleep position) has been followed by significant reductions in SIDS rates, however, without the complete elimination of SIDS.13–15 A “triple risk” model has been proposed in which congenital or acquired risk factors interact with environmental “triggering” factors primarily during the critical developmental period when most SIDS cases occur.16 Also, certain theoretically distinct diseases may be virtually indistinguishable from other forms of SIDS. From these perspectives, a “single cause” hypothesis would appear to be outmoded. There is 0002-9343/00/$20.00 PII S0002-9343(99)00354-X
A Symposium: Gastroesophageal Reflux and Sudden Infant Death Syndrome/Thach
a second reason for reevaluating the causal role of “agonal” aspiration in the sequence of events leading to death. This comes from new insights into the final common pathway in the process of dying and the remarkable capacity for “autoresuscitation” to fully reverse this pathway often within seconds before actual death. These issues are further discussed below.
FORENSIC STUDIES OF GASTROESOPHAGEAL REFLUX AND ASPIRATION In the late 1950s the several studies conducted by Gardner on aspiration pneumonia and its significance in forensic medicine soon became regarded as the definitive work in this field.3 Gardner reviewed his own extensive clinical experience as well as prior work. He concluded that in a substantial number of autopsies of individuals, whose deaths were clearly caused by well-substantiated mechanisms, such as trauma or myocardial infarction, there was evidence of recently aspirated gastric material in the airways. In such cases it seemed clear that aspiration played a secondary role, if any at all, in the deaths. Gardner proposed that such aspiration in some cases may be the result of “agonal” regurgitation during the final stages of death. However, he also suspected that “aspiration” can occur even after death, as a consequence of manipulation of the body in the process of transportation. To test this hypothesis, he introduced barium into the stomachs of adult subjects shortly after their deaths. In 7 of 10 bodies so treated, he found evidence of barium in the airways and lungs when the postmortem examination was performed. This finding suggested that a combination of the postmortem relaxation of esophageal sphincters and the differential pressure produced in the abdomen and chest during transportation of the body caused passage of material from the stomach into the lungs. Gardner further showed that inflammatory changes resulting from such postmortem “aspiration” can occur in lung tissue for several hours after death, making it impossible to use microscopic findings to determine when aspiration occurred. The realization that “aspiration” can occur after death further compounded the already existing controversy over the significance of gastric material found in the lungs of individuals after death. Many pathologists previously had concluded that “agonal” aspiration of gastric contents during the final stages of dying is common.3,5,9 Although the origins of this theory are obscure, presumably agonal aspiration can be the combined result of relaxation of esophageal sphincters, suppression of upper airway protective reflexes, and terminal inspiratory efforts. This might occur as a natural consequence of hypoxemia and failing circulation in the final minutes before death. Despite these significant hindrances to making a definitive diagnosis of aspiration as a cause of death, Gardner and subsequent investigators believed that aspiration of
gastric contents, in fact, could be a primary cause of death, particularly in weak, debilitated, or neurologically impaired individuals.3 Bernard Knight, who succeeded Gardner as an authority in this field, concluded that the only hope a pathologist had for distinguishing such fatal aspiration cases from those in which insignificant agonal or postmortem aspiration occurred lay in obtaining a strong clinical history supporting the diagnosis: “the standard of proof required before one can confidently state that aspiration of stomach contents is the cause of death, is usually beyond the grasp of any pathologist if he does not have unequivocal clinical corroboration.”4 In SIDS cases, in particular, this inability to distinguish significant from insignificant aspiration troubled both Gardner and Knight. Gardner and, later, Knight adopted a pragmatic position in SIDS cases that had evidence of aspiration. They took the view that if SIDS is a diagnosis in which cause of death is unknown, one need not emphasize the possible causal role of aspiration, because introducing aspiration as a diagnostic possibility could be interpreted to suggest negligence on the part of the infant caretaker. It is of particular interest that Gardner made a strong distinction between this essentially pragmatic position and his underlying beliefs concerning the relevance of aspiration to cause of death in SIDS cases: “Aspiration of vomit is often dismissed as an agonal phenomenon [in SIDS]. Sometimes this may be so, but more often it is the coup de grace in an ill patient who might otherwise have a chance of survival.”3 Gardner’s cautionary note soon was forgotten and, with rare exceptions,17 forensic experts continue to view presence of intrapulmonary gastric fluid in SIDS as an “agonal” phenomenon with little or no significance in the events leading to the infant’s death.1,5,6,11,12
RECENT DEVELOPMENTS RELEVANT TO THE ROLE OF REGURGITATION AND ASPIRATION IN SIDS Progress during the past 10 years suggests that a reassessment of the potential role of aspiration in SIDS is appropriate. During this time, it has become apparent that young infants are prone to a variety of conditions that result in transient but severe episodes of hypoxemia and/or ischemia.18 Such events are extremely common within the first few minutes after birth. Later in the life of the infant, hypoxic episodes may appear in the form of prolonged apneic spells. These include apnea of prematurity, laryngeal chemoreflex apnea, obstructive sleep apnea, and “breathholding” apneic episodes.18,19 Other cardiovascular events, such as transient arrythmias or asystoles, have similar consequences. Not infrequently, such episodes progress to a point where loss of consciousness and a state of marked cardiovascular and neural depression suddenly occurs. This has been termed “hypoxic coma.”20,21 In most cases, cardiovascular and neural recov-
March 6, 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108 (4A)
145S
A Symposium: Gastroesophageal Reflux and Sudden Infant Death Syndrome/Thach
Figure 1. Polygraphic recordings from mice showing plethysmographic documented respiration and pharyngeal pressure recordings. Tracings begin at onset of hypoxic coma, which has been produced by sudden exposure to N2 gas. A small catheter is placed in the animal’s pharynx, and simultaneously the chamber is flushed with air. (A) Catheter placement alone. Note onset of gasps (G) that rapidly give way to eupneic breaths, at which time complete neurologic recovery occurs in this unanesthetized mouse. Then, a small bolus of fluid is infused into the airway to elicit swallows (Sw). (B) A similar procedure, except that the catheter is placed and a water fluid bolus is infused at the beginning of hypoxic coma. Note repeated swallows, prolongation of coma as compared with A, indicated by delayed eupnea onset. (Reproduced with permission from J Appl Physiol.24)
ery occurs rapidly and spontaneously after the onset of gasping respirations that reoxygenate the body. This mode of spontaneous recovery has been termed “autoresuscitation.”21 Such episodes are marked by loss of reflexes, muscle tone, apnea, bradycardia, and cyanosis or palor and formerly were known as “near miss SIDS.” They currently are termed “apparent life-threatening episodes”(ALTEs).18 The fact that prognosis is very good in the vast majority of infants with ALTEs is evidence of the efficiency and efficacy of autoresuscitation as a protective physiologic mechanism. Very recent studies of apnea monitor event recordings of infants dying of SIDS who were being monitored at the time of death have indicated that, in the majority of SIDS deaths, terminal gasping respirations are present.22,23 This suggests that SIDS, in part at least, represents a fail146S March 6, 2000 THE AMERICAN JOURNAL OF MEDICINE威
ure of the autoresuscitation mechanism to produce recovery. When gasping fails to produce recovery, common reasons for failure include underlying impairment of circulatory or pulmonary function.21 Were “agonal” regurgitation and aspiration to occur during hypoxic coma caused by apnea or other mechanisms, it conceivably could interfere with autoresuscitation and result in a SIDS death. To clarify further the potential adverse effects of gastroesophageal reflux and aspiration on the outcome of autoresuscitation, we developed an animal model in which hypoxic coma is rapidly induced in mice by sudden exposure to anoxic gas (N2).24 When the mouse became unconscious, a small bolus of fluid (water or saline, 0.05 mL) was delivered by cannula into the animal’s pharynx, and then room air was made available for the mouse to
Volume 108 (4A)
A Symposium: Gastroesophageal Reflux and Sudden Infant Death Syndrome/Thach
Figure 2. The same experimental situation as in Figure 1. In this case, however, the mouse does not swallow. The reason for absence of reflex swallowing is unclear. Note occurrence of gasps (G) that produce little or no movement of air into the chest but can be recorded as small deflections in pharyngeal pressure in the fluid-filled pharynx. This animal’s death is indicated by the last gasp. One presumes that failure to swallow caused persistence of water and persistent airway obstruction. (Reproduced with permission from J Appl Physiol.24)
breathe. Although most other reflexes were absent during hypoxic coma, fluid in the mouse’s pharynx produced swallowing. Swallowing was more frequent with water than with saline, indicating the presence of the laryngeal chemoreflex even at this very depressed level of neurologic function (Figure 1).19 Both saline and water boluses delayed recovery by autoresuscitation. Gasping duration was prolonged in each case. Saline boluses were cleared from the pharyngeal and nasal airway more slowly than water, and, likely as a consequence of this, recovery was less rapid with saline than with water. When swallowing was altogether absent, as occasionally occurred in some mice, or when swallowing was suppressed by phenobarbital anesthesia, autoresuscitation usually failed. These mice continued to gasp, but recovery did not occur. The mechanism for this failure appeared to be obstruction of the large or small airways by saline or water, as suggested by absent airflow to the lungs (Figure 2). These studies, therefore, showed that even small amounts of chemically innocuous fluid can delay or prevent autoresuscitation. In summary, postmortem evidence of gastric contents in airways and lungs long has been held to be a finding of little significance. As regards SIDS, the distinction between “we don’t know if this finding is relevant to cause of death” and “this finding is clearly not relevant to cause of death” has been blurred. Recent evidence indicates that autoresuscitation produced by “agonal” gasping is not infrequent in infants and young children as part of an efficient survival mechanism in the face of acute hypoxemia/hypoperfusion. Furthermore, the observation that even relatively benign fluids in the upper airway can impair autoresuscitation in an animal model suggests that the finding of pulmonary aspiration in a case of sudden infant death may indicate a cause for failed autoresuscitation and so may be very relevant to the causal sequence
of events leading to death. Although in the absence of conclusive evidence it is still quite appropriate to regard aspiration as an undetermined factor in SIDS, it is conceivable that increased attention given to its documentation and correlation with other pathologic and historic findings could lead to further insights into the mechanisms of SIDS deaths. Such renewed attention might one day indicate that “agonal” aspiration is the “coup de grace” that determines the death of many infants, as Gardner originally believed it to be.
REFERENCES 1. Knight B. Forensic Pathology, 2nd ed. New York: Oxford University Press, 1996:450. 2. DiMaio DJ. Forensic Pathology. New York: Elsevier, 1989: 217. 3. Gardner AMN. Aspiration of food and vomit. Q J Med. 1958;27:227–242. 4. Knight BH. The significance of the postmortem discovery of gastric contents in the air passages. Forensic Sci. 1975;6: 229 –234. 5. Camps FE. In: Camps FE, Carpenter RG, eds. Sudden and Unexpected Deaths in Infancy (cot deaths): Session I. Bristol, UK: John Wright and Sons, 1972:1–2. 6. Guntheroth WG. Crib Death: The Sudden Infant Death Syndrome. Mount Kisco, NY: Futura, 1989:140. 7. Valdes-DaPena MA. Sudden and unexpected death in infancy: a review of the world literature 1954 –1966. Pediatrics. 1967;39:123–138. 8. Werne J, Garrow I. Sudden apparently unexplained death during infancy. I. Pathologic finding in infants found dead. Arch Pathol. 1953;29:633– 675. 9. Simpson K. Pathology of sudden death. Lancet. 1947;ii: 745–747. 10. Coombs RRA. In: Camps FE, Carpenter RG, eds. Sudden and Unexpected Deaths in Infancy (cot deaths): Session I. Bristol, UK: John Wright and Sons, 1972:21. 11. Smialek JE, Smilaek PZ, Spitz WU. Accidental bed deaths
March 6, 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108 (4A)
147S
A Symposium: Gastroesophageal Reflux and Sudden Infant Death Syndrome/Thach
12.
13.
14.
15. 16.
17. 18.
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