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Hypoxic Ischemic Encephalopathy (Asphyxia)
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The Newborn II
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Hypoxic Ischemic Encephalopathy (Asphyxia)
Alfred W. Brann, Jr., M.D. *
Over the past century, numerous etiologies for central nervous system (eNS) pathology and neurologic dysfunction seen in children who are highrisk neonates have been defined. They include the following: 1. 2. 3. 4. 5. 6. 7. 8.
Chromosomal abnormalities Dysmorphic syndromes Drugs and toxins Infections Inherited metabolic diseases Trauma Intracranial hemorrhage Transient neonatal metabolic disorders Hypoxic ischemia Hypoglycemia Hyperbilirubinemia Hypematremia
The area of concentration of this article concerns the effects of hypoxic ischemia on the brain of the full-term fetus or neonate. Much has been and continues to be written about this area. In his landmark treatise of 1862, Little first made a causal link between suboptimal perinatal events and subsequent neurologic dysfunction and brain damage in both the premature and full-term infant.27 From this article and other classic retrospective clinical-neuropathologic studies using human autopsy material, the term birth injury was coined. Since its inception, this term has been used in a broad, nonselective manner to include both physical (birth trauma) and asphyxial (birth asphyxia) insults to the fetal brain during the birth process. Prior to the 1940s, birth trauma was thought to be the overriding etiologic and pathogenetic mechanism leading to most perinatally related brain damage. With improvement in the management of both dysfunctional *Professor of Pediatrics, and Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia
Pediatric Clinics of North America-Vol. 33, No.3, June 1986
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labor and abnormally sized and positioned fetuses, birth trauma to the nervous system has been almost totally reduced to brachial plexus and facial nerve injury. 39 Information about the specific effect of birth asphyxia on the fetus or neonate has been possible only since the development of techniques for determining blood pH and blood gases. Articles began to appear in the 1940s that strongly suggested a causal relationship between perinatal asphyxia and certain types and patterns of neuropathologic changes in the brain. In a second landmark article, Stewart Clifford described newborns who died after cesarean delivery because of premature separation of the placenta.1O At the time of death these infants were found to have brain swelling and cerebral necrosis. There was no evidence for birth trauma in these infants, and \lsphyxia was suggested as the etiology of the central nervous system injury, based on abnormal acid-base and blood gas determinations. Another set of articles also suggested strongly that asphyxia during the perinatal period led to the development of ulegyria in children who, as neonates, survived a perinatal insult. ll. 21 Recent human and animal studies have permitted a clearer distinction to be made between the effects of asphyxia and trauma on the fetal or neonatal nervous system. Neonatal hypoxic ischemic encephalopathy (HIE) is the term used most frequently to designate the clinical and neuropathologic findings thought to occur in the full-term infant following either intrapartum or neonatal asphyxia. The magnitude of the problem that neonatal HIE poses may not be appreciated fully. Three important factors contribute to this problem. First, more children with cerebral palsy (CP) are full-term infants than are premature infants. Even though the incidence of cerebral palsy is lower among full-term infants (3.38/1000 live births) versus preterm infants (90/1000 live births), this lower incidence is applied to a denominator that includes 92 per cent of the births in this country.36 Second, more asphyxiated full-term infants survive than do asphyxiated preterm infants. 31 Third, the HIE problem is compounded by the apparent lack of a significant reduction in the types of CP seen in full-term infants. A comprehensive population-based Swedish study showed that a decrease in the total CP incidence from 1954 to 1974 was due to a reduction of spastic diplegia in neonates weighing less than 2500 gm.23 Data from the Swedish study does not show any reduction in the incidence of the types of CP seen in fullterm infants. Thus, in the absence of data to the contrary, there is presently no reason to believe that the problem of the full-term asphyxiated neonate in the United States differs from that of these infants in Sweden. CLINICAL FEATURES In the past, the clinical course of the full-term infant who experienced intrapartum asphyxia was thought primarily to reflect altered brain function. It is now known, however, that because of the variable involvement of different organ systems, such infants can have quite different clinical courses. The variation in clinical signs is due in part to the ability of the
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fetus to redistribute blood flow to protect vital organs,4O as well as the difficulty in accurately establishing the length, severity, and acuteness of onset of the asphyxial episode. In addition, there may be unidentified factors in the mother, fetus, or neonate that can influence the occurrence or severity of asphyxia. This varied clinical course was documented in a retrospective study of 6045 consecutive deliveries. 47 Fifty-three full-term infants had an Apgar score of 5 or less at 1 minute and 5 minutes, and were thought to have suffered intrapartum asphyxia. Eighteen infants had no apparent disease throughout their hospitalization; however, thirty-five infants had at least one or as many as five abnormal organ systems. Nineteen of the thirty-five infants had more than one abnormal system. The 35 affected infants with low Apgar scores had problems (in order of decreasing frequency) with their pulmonary, cardiovascular, eNS, gastrointestinal, and renal systems. None of the infants in this study had clinically significant coagulation problems, although disorders of hemostasis have been described. Nine of these thirty-five died during the neonatal period. The most common cause of death was persistent pulmonary hypertension, which occurred in four infants. No one system or group of systems appeared to be the primary target of the intrapartum asphyxial episode. Only one third of the infants had clinical signs that suggested eNS involvement. Only two of the nine infants who expired, died from eNS disturbances. These two infants had massive brain swelling with cortical necrosis. From either the intrapartum course or the status of the neonate in the delivery room, it was not possible to predict whether the eNS or any other organ system was going to be affected. The functional state of the nervous system in an asphyxiated full-term neonate during the first week of life is characteristic enough to be termed HIE. 44, 56 Data indicate that full-term neonates at risk of developing longterm neurologic sequelae from an intrapartum asphyxial episode will demonstrate signs of neurologic dysfunction. at least within the first week of life, most usually within the first 12 hours after birth. Such a neonate mayor may not have a low Apgar score. 16, 17 The major signs of eNS dysfunction include seizures, abnormalities in state of consciousness, tone, posture, reflexes, respiratory pattern, oculovestibular response, autonomic function, and anterior fontanel. 29, 36, 39, 43, 56 As the physician attempts to assess the relative risk of a neonate to develop cerebral palsy, some obstetric complications can be considered as possible risk factors. Numerous prenatal and intrapartum events have been described as placing the fetus at an increased risk for experiencing intrapartum asphyxia. These conditions fall into three general categories: 1) altered placental exchange, 2) altered maternal blood flow to the placenta, or 3) reduced maternal arterial oxygen saturation. In a prospective study, the relative risk of cerebral palsy in infants weighing 2500 gm or more following certain obstetric events was described in relation to the Apgar scores. 37 The 18 obstetric complications evaluated in this study were: placenta previa, abruptio placentae, breech delivery, face or brow presentation, cord prolapse, placental infarction (2 + ), toxemia, lowest fetal heart rate « 100 beats per min), oxytocin augmentation, nuchal
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cord, meconium, uterine dysfunction, forceps use (mid- or high), second stage of labor longer than 59 minutes, chorioamnionitis, prolonged rupture of membranes (> 24 hrs), short cord « 40 cm), and polyhydraminos. Infants whose births were associated with these "anoxigenic" obstetric complications were at no greater risk for developing cerebral palsy than were infants whose births were uncomplicated, if their 5-minute Apgar scores were 7 or higher. This group comprised about 62 per cent of the study group and accounted for less than its proportional share of CPo There was an increased risk for cerebral palsy when the infant born with an obstetric complication had a 5-minute Apgar score less than or equal to 3. This group of patients accounted for only 1.5 per cent of the population, but accounted for 17 per cent of infant deaths and 13 per cent of CP infants in the study population. These data show that an obstetric complication per se does not increase the infant's risk for CP unless the complication is associated with a significantly low Apgar score. The low Apgar score indicates an abnormal condition but does not imply any specific etiology. Low scores can be due to anyone of the following six major causes: asphyxia, drugs, trauma, hypovolemia, infection, or anomalies. In a low Apgar score ascribed to asphyxia, signs known to occur during intrapartum asphyxia should be present whereas the other causes of low Apgar scores are eliminated. Data now show that a score of 0 to 3 at 5 minutes is a significantly low Apgar score. 36 Infants who have Apgar scores of 7 to 10 have been found to be at very low risk for an abnormal transition to extrauterine life and for later abnormal neurologic development. The score range of 0 to 3 is "significant" because of the higher mortality and CNS morbidity among infants with this score than among infants with scores of 4 to 6 or 7 to 10. 34 The longer the score is low, the greater is its significance. 34 An infant with a 0 to 3 score at 1 minute has a mortality of 5 per cent to 10 per cent, which rises to approximately 53 per cent if that score is maintained for 20 minutes. In full-term surviving neonates with an Apgar score of 0 to 3 at 5 minutes, the incidence of CP is approximately 1 per cent. If this score is sustained for 15 minutes, 9 per cent of the survivors will have CP, with a dramatic rise to 57 per cent for infants who sustain an Apgar score of 0 to 3 for 20 minutes. The Apgar score may indicate asphyxia, but not duration of the asphyxial episode. Some estimate of the duration of the episode may be estimated from observing the newborn. When a low Apgar score occurs, infants tend to lose these functions, in order: their color, respirations, tone, reflexes, and heart rate. Following effective resuscitation, these functions tend to reappear in the following order: heart rate, reflexes, color, respirations, and tone. The time required for tone and respirations to return may indicate the severity or duration of the asphyxial insult to the CNS. Delay of greater than 2 hours in return of tone is associated with an increased incidence of HIE as well as significant neurologic sequelae in surviving neonates. 8 The mean age at onset of spontaneQus respirations in an infant asphyxiated during labor and delivery is significantly greater in neonates who developed seizures, a major sign in HIE. 31 Other delivery room observations that may help estimate the length or severity of the
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intrapartum asphyxial episode are: delay m return of heart rate if resuscitation efforts are considered adequate, meconium present in the trachea, and meconium staining of the umbilical cord, skin, or nails. The last observation indicates previous exposure to meconium for at least 3 to 6 hours. 19 Neonatal seizures frequently are secondary to intrapartum asphyxia. 7, 8 Seizures have been reported in 30 per cent to 69 per cent of infants with abnormal neurologic examinations after an intrauterine asphyxial episode (see Table 1). Typically, seizure onset has been reported to occur at 12 to 24 hours after delivery. If signs other than tonic clonic movements are used to identify a seizure, however, seizure onset may be as early as 2 to 6 hours. Seizures per se are not associated exclusively with late neurologic sequelae; however, the seizure occurrence within the first 12 hours, the appearance of status or serial seizures, or a persistently abnormal electroencephalogram (EEG) (electrical silence, burst suppression, or low voltage background) are signs of significant neonatal neurologic dysfunction.28, 39. 56 Infants with HIE who have seizures as just described have a 30 per cent to 75 per cent likelihood of long-term neurologic sequelae. 18,31,45 Abnormalities in the level of consciousness are helpful in delineating the severity of an asphyxial insult and in predicting which infants may have neurologic sequelae if they survive. In a recent study,45 full-term asphyxiated infants who were felt to have an encephalopathy were grouped into three clinical states, according to the neonate's level of consciousness, neuromuscular control, complex reflexes, autonomic function, seizures, EEG findings, and duration of abnormality. Although all six of these factors were important in delineating the three states of encephalopathy, the level of consciousness seemed to be the primary determinant. The state 1 level of consciousness is hyperalertness; state 2, lethargy or obtundation; and state 3, stupor. Both the state of encephalopathy and duration of a given state were other factors that determined the severity of HIE and predictability of long-term outcome. Infants who did not enter state 3, and had signs of state 2 for fewer than 5 days appeared to be normal later in infancy. Infants who entered state 3, who had signs of state 2 for more than 7 days, or whose EEG failed to revert to normal either died or developed significant neurologic sequelae. These results have been confirmed in another study using the same scoring system, even without EEG criteria. 17 The incidence of moderate to severe long-term neurologic sequelae in asphyxiated, surviving full-term neonates varies from 4.7 per cent to 57.1 per cent, depending on the definition used for asphyxia (see Tables 1 and 2). The typical cluster of neurologic deficits in a severely affected child includes spastic quadriplegia, severe mental retardation, seizures, hearing deficits, and microcephaly. The full-term neonate at risk for developing long-term neurologic sequelae from an intrapartum asphyxial episode will demonstrate signs of neurologic dysfunction (HIE) in the first week of life. The value of HIE in identifying neonates at increased risk for later neurologic dysfunction has been confirmed by findings from the National Collaborative Perinatal Project (NCPP).36 Approximately 11 per cent of surviving children were suspected to have a brain abnormality during the nursery course. Of this group, 6 per cent died and 1 per cent later had
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cerebral palsy. Of infants who had a definite neurologic abnormality at time of discharge from the hospital, only 53 per cent died (0.5 per cent of surviving infants). CP occurred in 15.8 per cent of survivors; however, 85 per cent of surviving infants with definite neurologic abnormalities at the time of discharge did not have CP at follow-up. Among a group of full-term neonates with a history of an asphyxial episode and an abnormal neurologic examination during the first week of life, the incidence of early death was 7 per cent, and the incidence of neurologic handicaps was 28 per cent. When abnormalities of tone were isolated as a predictor of severe handicap in full-term neonates with a history and clinical course compatible with asphyxia, the risk for cerebral palsy among children surviving the neonatal period was 25 per cent. A chronologic combination of abnormal signs is more helpful than a single sign in predicting outcome. 45 , 58 The most helpful cluster of signs include an Apgar score of 3 or less obtained at 5 minutes or an Apgar score below 3 for 10 minutes or longer, together with other factors (e.g., reduced activity levels, tone, reduced consciousness lasting> 1 day, need for gavage feeding, hypotonia, or single or multiple episodes of apnea during the first week). The cluster may also include Sarnat State 3 or 2 lasting longer than 5 days, asymmetric neurologic signs, seizures with onset during the first day of life, and an overall impression of abnormal brain function during the time the infant waS in the nursery. More work is needed to define the predictive powers of the neonatal neurologic examination; however, an abnormal neurologic examination (as defined above) of a full-term infant with a history of probable intrapartum asphyxia is an extremely powerful tool in establishing the presence and severity of HIE, in predicting early death, or in identifying neonates who should be observed for later development of neurologic sequelae. As treatment for neonatal HIE is evolving and as potential treatments for children with early developmental delays are appearing, it becomes extremely important to identify the presence and severity of neonatal HIE.
PATHOLOGIC FEATURES From classic neuropathologic studies of brains from neonates who experienced an episode of "perinatal distress," three distinct sites of brain damage have been identified. 3, 55 These sites are the region of the subependymal germinal matrix, the periventricular white matter, and the cortical and subcortical gray matter. When babies with these lesions were classified by gestational age, however, it became apparent that there were differences in the loci of lesions seen in the preterm infant compared with those seen in the full-term infant. Although the topic of this discussion is HIE in the full-term infant, lesions seen in the preterm infant are mentioned to highlight the difference. The principal lesion seen in the preterm infant is located at the center of the hemisphere in the germinal matrix along the ventricular region, with sparing of the cortical mantle. The term subependymal germinal matrix hemorrhage/intraventricular hemorrhage (SE/IVH) describes this lesion.
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A second lesion, seen predominantly in preterm infants but also in full-term infants, occurs in the deep white matter of the periventricular region at the angles of the ventricle, superior to the germinal matrix. This cystic lesion has been called periventricular leukomalacia (PVL). In the full-term infant having experienced significant "perinatal distress," the lesions are located principally in the peripheral and dorsal areas of the cerebral cortex, involving necrosis of the gyri at the depths of sulci and the neuronal nuclei of the basal ganglia and brain stem. In some patients, cerebral necrosis is most severe in the region of the postcentral gyrus similar to that found in the full-term newborn monkey following experimentally produced intrapartum asphyxia. 5. 6, 32 Neonatal HIE, the term used to identify the encephalopathy in the full-term infant after either intrapartum or neonatal asphyxia has occurred, results in this latter pattern of brain lesions along with a particular set of signs of neonatal neurologic dysfunction. Although areas of petechial periventricular hemorrhage and leukomalacia can also be seen, the pattern of cerebral damage in the fullterm infant usually does not include SE/IVH. Those full-term infants who survive the perinatal asphyxial episode and neonatal period primarily will have two neuropathologic conditions-ulegyria and status marmoratus of the basal ganglia. The reader is referred to Gilles for a detailed description and excellent discussion of the pathologic changes in the nervous system following perinatal insult. 20
PATHOGENESIS Based on animal data and clinical knowledge from human studies, a proposed pathogenesis for HIE in the full-term infant and its sequelae in the surviving neonate is outlined in Figure l. This diagram has been derived from data from two rhesus monkey models termed prolonged partial asphyxia (developed by Brann and Myers 5, 6, 32), and acute total asphyxia (developed by Windle42) as well as other animal and human data. 41 These two models closely replicate the two very different types of perinatal asphyxial events that occur most frequently in the human fetus or neonate-an acute asphyxial episode resulting from cord prolapse,26 and a prolonged partial asphyxial episode resulting from a placental abruption.lO Prolonged partial asphyxia of 1 to 3 hours in the monkey fetus produces a clinical course in the newborn monkey similar to that seen in the depressed newborn human following a placental abruption. 5 , 6, 32 Seizures occur in approximately 50 per cent of the monkeys within the first 24 hours of life. The spectrum of brain lesions in the cortex are similar to those in neonates who die following intrapartum asphyxia, as well as in children or adults said to have "cerebral palsy" secondary to a perinatal insult. The surviving monkey, unlike the human, has no motor deficit, despite significant brain lesions in the association areas of the cortex. Cytotoxic brain edema occurs in the neonatal period. 42 Cerebral blood flow (CBF) studies in the monkey show that the brain is abnormal at birth as demonstrated by the focal areas of ischemia. 4 These studies from the animal model strongly suggest that
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Intrapartum Asphyxia
Redistribution of Organ Flow Lung Kidney GI Tract
Heart Brain Adrenal
Variable Organ Effect Brain-l"onnal
(I)
(20)
Brain-Ulegyria
(3)
(4)
Figure 1. FetaVneonatal response to intrapartum asphyxia.
prolonged partial asphyxia from any cause in the fetus, in the absence of fetal circulatory collapse or fetal head compression, can cause cytotoxic edema and impaired CBF, leading to cerebral necrosis or ulegyria. Acute total asphyxia of 8 to 10 minutes produces in the monkey a longterm neurologic dysfunction similar to that seen in patients with spastic quadriplegia. 43 In the neonatal period, neither seizures nor brain swelling are seen. The neuropathologic findings occur primarily in the nuclei located in the brain stem, thalamus, and basal ganglia, with sparing of the cerebral cortex. The clinical spectrum and neuropathologic findings in monkeys from these two animal models, when combined, closely replicate short-term and long-term clinical and neuropathologic findings that usually occur in the human after perinatal asphyxia has occurred. In most cases, the total perinatal insult in humans most likely results from a partial prolonged asphyxial episode combined with a terminal acute asphyxial episode. The clinical course and the extent of neuropathologic changes in a neonate can vary depending on the acuteness of onset, as well as on the length and the severity of the asphyxial episode. The entire sequence of events leading to the various types of neuropathologic outcomes is not totally clear from current data, although the points represented in the diagram of the proposed pathogenesis (see Fig. 1) have been demonstrated in either animal or human studies. The diagram of proposed pathogenesis (see Fig. 1) is drawn from top to bottom as though the intrapartum asphyxial episode were a continuum, with the outcomes on the right side of the figure. Many newborns having low Apgar scores following intrapartum asphyxial episodes have no evidence of HIE (Fig. 1, step 1). This has been seen in asphyxiated infants who succumb because of other dysfunctions, such as persistent fetal circulation. 47
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The lack of CNS findings could be explained by the increased per cent of cardiac output to the brain, thus attempting to maintain adequate tissue oxygenation and preventing tissue ischemia. If the intrauterine asphyxial episode continues and homeostatic mechanisms that maintain brain oxygenation begin to fail, a cascade of events begins that leads to tissue ischemia, the central event in the pathogenesis of neonatal HIE and subsequent development of atrophic cortical sclerosis. 31 , 41, 43 The factors that lead to this tissue ischemia include abnormal ion homeostasis (especially calcium), energy failures, cellular acidosis, and blood-brain barrier alteration. 41 The length of time required for tissue ischemia to cause tissue death in the cerebral cortex is uncertain. Recent data indicate that brain cells are more resistant to ischemia than was previously thought. 41 It is conceivable that if the intrauterine asphyxial episode is relieved and the neonate is treated appropriately after the development of only mild multifocal tissue ischemia, the brain in the surviving infant could escape tissue necrosis (Fig. 1, step 2). If the intrapartum insult is not extremely severe or is quickly terminated, small areas of multifocal tissue necrosis do occur; they may not lead to significant areas of vasogenic edema with the development of severely increased intracranial pressure. Brain repair processes convert these areas of multifocal tissue necrosis into areas of ulegyria, as described in the monkey brain. The extent and pattern of ulegyria depend on the degree and location of cerebral necrosis (Fig. 1, step 3). If the intrapartum episode is severe and prolonged, multifocal areas of tissue ischemia located at the depths of sulci and within neuronal nuclei spread to the entire cerebral hemisphere. 43 The existing tissue ischemia, if unrelieved, leads to tissue necrosis. Vasogenic edema occurs following disruption of the tight junctions of the capillary endothelium, with leakage of osmotic materials into the interstitial tissues of the brain, pulling water from the intravascular space. 22 As the multifocal areas of necrotic brain coalesce, and significant increases in intracranial pressure occur in association with vasogenic edema, the brain swells progressively. This produces measurable increases in intracranial pressure. From animal data it is known that when intracranial pressure reaches one half to two thirds of the mean arterial pressure, reduced CBF causes tissue ischemia, especially in areas of cortex at depths of sulci. 2 The triad of multifocal tissue necrosis, vasogenic edema, and brain swelling with increasing intracranial pressure, leads to an ever-increasing oxygen debt in the brain, almost total tissue necrosis, and death (Fig. 1, step 4). In some asphyxiated neonates, increased intracranial pressure or brain edema at autopsy are not observed. This finding may be due to compensation by redistribution of blood How to protect the brain, whereas inadequate oxygen is supplied to the lung, kidney, or gastrointestinal (GI) tract. This may lead to death secondary to dysfunction of these organs. The absence of edema may be related to the type and length of the asphyxial episode. There is consistent absence of brain swelling in the monkey experiencing acute total asphyxia; however, there can be enough neuronal necrosis confined to the brain stem and basal ganglia to cause death from impaired respiratory control.
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Table 1. Incidence of Seizures in Full-term Asphyxiated Infants
RERFERENCE
Brown, 19748 Scott, 197646 Sarnat, 197645 DeSouza, 1978 '2 Mulligan, 1980'" Finer, 1981'7 Finer, 1983'6 Ergander, 1983 15
DEFINITION OF ASPHYXIA
0-2 at 1 min or 0-4 at 5 min or IPPV* o at 1 min or 0-2 at 20 min IPPV 0-4 at 1 or 5 min o at 1 min or onset of breathing after 5 min IPPV more than 1 min 0-3 at 5 min 0-5 at 5 min or IPPV 0-3 at 5 min
INCIDENCE OF SEIZURES (PERCENT)
MORTALITY (PERCENT)
51
22
48 52
52 10
42 52 68 69 30
4 19 7 0 21
*IPPV, intermittent positive-pressure ventilation. (Table courtesy of N. Finer.)
Unknown or poorly quantitated factors leading to thromboembolism and cerebral infarction may playa key role in the pathogenesis of ulegyria both with and without brain swelling during the neonatal period.
TREATMENT Although recent textbooks of neonatal-perinatal medicine include the management of an infant with symptoms of HIE, data from randomized clinical trials cannot yet recommend known efficacious therapy for the management from birth of an infant at high risk for HIE. At least three questions surround the appropriate prospective therapeutic management of such a neonate. First, can the asphyxiated neonate whose CNS is altered enough to develop HIE be identified within the first 2 to 6 hours after birth? Second, is there a critical time after which treatment is ineffective in eliminating or significantly reducing permanent brain damage in this infant? Third, what is the appropriate prospective intervention for this asphyxiated neonate? If an abnormal patient cannot be recognized, therapy cannot be initiated to alleviate the condition. Current data support the position that the full-term neonate who has had a history of fetal distress, with either an I\pgar score of less than or equal to 3 at 15 or 20 minutes, failure to have spontaneous and sustained respiration by 5 minutes, or altered tone or level of consciousness during the first 2 to 6 hours of life, is at great risk for having HIE. This neonate, who probably has focal areas of brain ischemia at birth similar to those seen in the fetal monkey following prolonged partial asphyxia,43 has a 50 per cent chance of having seizures,39 and at least a 20 per cent chance of having long-term neurologic sequelae. 36 Some neonates who subsequently develop neurologic sequelae and a clinical course of HIE have presented with an Apgar score of 7 to 10; however, these neonates sometimes have had an intrapartum course suggestive of asphyxia. It is extremely important in such cases to be sure that the
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Table 2. Incidence of Moderate or Severe Long-term Neurologic Sequelae (LTNS)* in Surviving Full-term Asphyxiated Infants
REFERENCE
Drage, 196613 Dweck, 19741• Brown, 19747 Steiner, 197550 Sarnat, 197645 Scott, 197646 Thomson, 1977"" DeSouza, 19781• Nelson, 1977"" Nelson, 1979"" Nelson, 198135 Mulligan, 1980'l1 Fitzhardinge, 198p· Finer, 198p· Storz, 198251 Finer, 19831• Ergander, 198315 Robertson" (unpublished)" Overall
DEFINITION OF ASPHYXIA
0-3 at 1 min 0-3 at 5 min 0-3 at 1 min 0-2 at 1 min or 0-4 at 5 min or IPPVt 0-1 at 15 min 0-4 at 1 or 5 min o at 1 min or 1-2 at 20 min IPPV o at 1 min or 0-3 at 5 min o at 1 min or onset of breathing after 5 min 0-3 at 5 min 0-3 at 10 min 0-3 at 15 min 0-3 at 20 min IPPV> 1 min 0-5 at 5 min or IPPV > 2 min 0-3 at 5 min 0-5 at 5 min or IPPV 0-5 at 5 min or IPPV 0-3 at 5 min 0-5 at 1 or 5 min IPPV
LTNSIN SURVIVORS (PER CENT)
MORTALITY (PERCENT)
3.6 7.4 33.0
23 50 61
26.0 28.0 31.0
22 44 10
25.0 10.3
52 50
8.0 4.7 16.7 36.0 57.128.6 27 47 28 22 16.3 22 14.7 23.4
4 15.5 34.4 52.5 5940.3 19 7 0 21 3.5 29
*Cerebral palsy or mental retardation. tIPPY, intermittent positive pressure ventilation. (Table courtesy of N. Finer.)
neurologic dysfunction seen in the first 2 to 6 hours after birth is not secondary to an etiology other than intrapartum asphyxia. Data indicate that a neonate experiencing intrapartum asphyxia sufficient to lead to longterm neurologic sequelae will have clinically recognizable neurologic dysfunction during the first 24 hours of life (see Tables 1 and 2). The question of a critical intervention time relates to the state of the asphyxial process in which the neonate presents. If the neonate is born after a prolonged intrapartum asphyxial episode, when vasogenic edema and increased intacranial pressure are far advanced, no therapeutic intervention is likely to be effective. Animal data show that earlier and more accurate detection of intrapartum asphyxia leads to delivery of a newborn without clinically apparent disease or very early stages of HIE, however.5. 6. 32 Thus, based on both human and animal data, intervention seems theoretically justified. 41 The third question relates to the appropriate prospective intervention for the asphyxiated neonate. To alleviate or reduce brain damage secondary to HIE, the therapeutic management should be directed first at eliminating the hypoxia and then at reducing brain ischemia and edema or reducing the metabolic requirements of the brain. A number of therapeutic modali-
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ties, including steroids,1 diuretics,58 mannitol,29 and barbiturates, 24. 30. 38. 48. 49 have been suggested. At the present time, barbiturates appear to hold the theoretical edge as the first agent to be used in a randomized clinical trial. Phenobarbital is the barbiturate of choice, primarily because of its ability to reduce seizures, especially in a brain that has lost its ability to auto regulate its energy requirements following asphyxia. Barbiturates also may positively influence a reduction in catecholomine secretion,49 toxic free radicals,48 cerebral edema, 30. 38 and general metabolic activity. 30. 3B At present we have made strides toward early identification of the infant with HIE, although we are currently unable to determine the length, severity, and acuteness of onset of that infant's asphyxial episode with certainty. Although phenobarbital is the drug of choice at the present time for research evaluation, data do not exist to support its current clinical use prospectively to prevent seizures. New insights into the pathophysiology of brain ischemia should lead to new proposed therapies, especially as more understanding is gained regarding metabolism of calcium and membrane phospholipid, prostaglandin, thromboxane, and leukotrienes. 41 Thus to reduce the total number of patients with CP in the United States, a concerted effort must be made not only on specific drug therapy for the full-term asphyxiated infant, but also an effort should be made regarding accurately identifying the full-term fetus at risk for experiencing suboptimal tissue oxygenation. This will permit the timely delivery, with capable persons in attendance of the fetus, who can appropriately assess, resuscitate, and stabilize the neonate.
REFERENCES 1. Anderson, D. C., and Cranford, R. E.: Corticosteroids in ischemic stroke. Current Concepts of Cerebrovascular Disease-Stroke, 10:68-71, 1979. 2. Baldy-Mouliner, M., and Frerebeau, P.: Blood How of the cerebral cortex in intracranial hypertension. Scand. J. Chn. Lab. Invest., 102:(Suppl.), VG, 1968. 3. Banker, B. P.: The neuropathological effects of anoxia and hypoglycemia in the newborn. Dev. Med. Child. Neurol., 9:544-550, 1967. 4. Bondareff, W., Myers, R D., and Brann, A. W.: Brain extracellular space in monkey fetuses subjected to prolonged partial asphyxia. Exp. Neurol., 28:167-178, 1970. 5. Brann, A. W., and Myers, R E.: Central nervous system findings in the newborn monkey following severe in utero partial asphyxia. Neurology, 25:327-338, 1975. 6. Brann, A. W., Myers, R. E., and DiGiacomo, R: The effects of halothane-induced maternal hypotension on the fetus. In Med Primator 1970. Proc of the Second Conference of Experimental Medical and Surgery in Primates. Basel, Switzerland; S Karger, 1971. 7. Brown, J. K., Cockburn, F., and Forfar, J. 0.: Clinical and chemical correlations in convulsions. Lancet, i: 135, 1972. 8. Brown, J. K., Parvis, R. J., and Forfar, J. D., Cochburn, F.: Neurological aspects of perinatal asphyxia. Develop. Med. Child. Neurol., 16:567-580, 1974. 9. Clark, D. B.: Abnormal neurologic signs in the neonate: Physical diagnosis of the newly born. In Kay, J. (ed.): Report of the 46th Ross Conference on Pediatric Research. Columbus, Ohio; 1964. . 10. Clifford, S. H.: The effects of asphyxia on the newborn infant. J. Pediatr., 18:567-578, 1941. 11. Courville, C. B.: Birth and brain damage. Pasadena, California; 1971.
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12. DeSouza, S., and Richards, B.: Neurological sequelae in newborn babies after perinatal asphyxia. Arch. Dis. Child., 53:564, 1978. 13. Drage, J. S., and Kennedy, C.: The Apgar scores as an index of infant morbidity. Develop. Med. Child. Neurol., 8:141, 1966. 14. Dweck, H. S., and Huggins, W.: Developmental sequelae in infants having suffered severe perinatal asphyxia. Am. J. Obstet. Gynecol., 119:811, 1974. 15. Ergander, V., and Erikson, M.: Severe neonatal asphyxia. Acta Paediatr. Scand., 72:321, 1983. 16. Finer, N. N., Robertson, C. M., Peters, K. L., et al.: Factors affecting outcome in hypoxic-ischemic encephalopathy in term infants. Am. J. Dis. Child., 137:21, 1983. 17. Finer, N. N., Robertson, C. M., Richards, R. T., etal.: Hypoxic-ischemic encephalopathy in term infants: Perinatal factors and outcome. Pediatrics, 98:112-117, 1981. 18. Fit;iliardinge, P. M., and Flodmark, 0.: The prognostic value of computerized tomography as an adjunct to assessment of the term infant with postasphyxial encephalopathy. J. Pediatr., 99:777, 1981. 19. Fiyikura, T., and Klionsky, B.: The significance of meconium staining. Am. J. Obstet. Gynecol., 121 :45-50, 1975. 20. Freeman, J. M. (ed.): Prenatal and Perinatal Factors Associated With Brain Disorders. Washington, D.C.; NIH Publications 85-1149, 1985. 21. Friedman, S. P., and Courville, C. B.: Atrophic lobar sclerosis of early childhood (Ulegyria): Report of two verified cases with particular reference to their asphyxial etiology. Bull. Los Angeles Neurol. Soc., 6:32-45, 1941. 22. Goldstein, G. W.: PathQgenesis of brain edema and hemorrhage: Role of the brain capillary. Pediatrics, 64:357-360, 1979. 23. Hagberg, B.: Epidemiological and preventive aspects of cerebral palsy and severe mental retardation in Sweden. Eur. J. Pediatr. Res., 7:691, 1971. 24. Katzman, R., Clasen, R., Klatzo, I., et al.: Brain edema in stroke: Report of Joint Committee for Stroke Resources. Stroke, 8:512-540, 1977. 25. Koops, B. L., and Harmon, R. J.: Studies on long-term outcome in newborns with birth weights under 1500 grams. Adv. Behav. Pediatr., 1:1-28, 1980. 26. Leech, R. W., and Alvord, E. C.: Anoxic ischemia encephalopathy in the human neonatal period: The significance of brain stem involvement. Arch. Neurol., 34:109-113, 1977. 27. Little, W. J.: On the influence of abnormal parturition, difficult labours, premature birth, and asphyxia neonatorum on the mental and physical condition of the child, especially in relation to deformities. Trans. Obstet. Soc. Lond., 3:293-346, 1861. 28. MacDonald, H. M., Mulligan, J. C., Allen, A. C., et al.: Neonatal asphyxia. I: Relationship of obstetric and neonatal complications to neonatal mortality in 38,405 consecutive deliveries. J. Pediatr., 96:898-909, 1980. 29. Marchal, C., Leveau, P., Genet, M., et al.: Traitement des souHTances cerebrales neonatales: Action des perfusions repeties de mannitol. Pediatrie, 27:709-719, 1972. 30. Marsh, M. L., Marshall, L. F., and Shapiro, H. M.: Neurosurgical intensive care. AnestheSiology, 47:149-163, 1977. 31. Mulligan, J. C., Painter, M. J., O'Donoghue, P. A., etal.: Neonatal asphyxia. II: Neonatal mortality and long-term sequelae. J. Pediatr., 96:903-907, 1980. 32. Myers, R. E.: Experimental models of perinatal brain damage: Relevance to human pathology. Intrauterine Asphyxia and the Developing Fetal Brain. Chicago; Year Book Medical, 1977. 33. Nelson, K. B., and Broman, S. H.: Perinatal risk factors in children with serious motor and mental handicaps. Ann. Neurol., 2:371, 1977. 34. Nelson, K. B., and Ellenberg, J. H.: Apgar scores as predictors of cerebral palsy. Pediatrics, 68:36-44, 1981. 35. Nelson, K. B., and Ellenberg, J. H.: Apgar scores as predictors of chronic neurologic disabilities. Pediatrics, 68:36, 1981. 36. Nelson, K. B., and Ellenberg, J. H.: Neonatal signs and predictors of cerebral palsy. Pediatrics, 64:225-232, 1979. 37. Nelson, K. B., and Ellenberg, J. H.: Obstetric complications as risk factors for cerebral palsy or seizure disorder. J.A.M.A., 1983. 38. Nordstrom, C. H., Rehncuoma, S., and Siesjo, B. K.: Effects of phenobarbital on cerebral ischemia. Part II: Restriction of cerebral energy state as well as glycolytic metabolites,
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citric acid cycle intermediates, and associated amino acids after pronounced incomplete ischemia. Stroke, 9:335-343, 1978. Painter, M. J., and Bergman, I.: Obstetrical trauma to the neonatal central nervous system and peripheral nervous system. Sem. Perinatol., 6:89, 1982. Peeters, L. H., Sheldon, R. E., Jones, M. D., et al.: Blood flow to fetal organs as a function of arterial oxygen content. Am. J. Obstet. Gynecol., 135:1071-1078,1979. Raichle, M. E.: The pathophysiology of brain ischemia. Ann. Neurol., 13:1-10, 1983. Ranck, J. B., and Windle, W. F.: Brain damage in the monkey, Maraca mulatta by asphyxia neonatorum. Exp. Neurol., 1:130-154, 1959. Reivich, M., Brann, A. W., Shapiro, H., and Myers, R. E.: Regional cerebral blood flow during intrauterine prolonged partial asphyxia. In Myers, S. S., Reivich, M., Erickhorn, O. (eds.): Research on the cerebral circulation. Fifth Intl Salzburg Conf. Springfield, Illinois; Charles C Thomas, 1972. Robertson, C. M.: Unpublished data. Sarnat, H. B., Sarnat, M. S.: Neonatal encephalopathy follOwing fetal distress. A clinical and electroencephalographic study. Arch. Neurol., 33:696--705, 1976. Scott, H.: Outcome of very severe birth asphyxia. Arch. Dis. Child., 51:712,1976. Sexson, W. R., Sexson, S. B., Rawson, J. E., et al.: The multisystem involvement of the asphyxiated newborn. Pediatr. Res., 10:432-439, 1976. Smith, D. S., and Rehncuoma, B. K.: Barbiturates as protective agents in brain ischemia and as free-radical scavengers in vitro. Acta Physiol. Scand., 492: 129, 1980. Steen, P. A., and Michenfelder, J. D.: Mechanisms of barbiturate protection. AnestheSiology, 53:183-185, 1980. Steiner, H., and Neligan, G.: Perinatal cardiac arrest: Quality of survivors. Arch. Dis. Child., 50:696, 1975. Storcz, J., and Mestyan, J.: Long-term prognosis ofasphyxic neonates from an intensive care unit: Intrauterine retarded infants at high risk of cerebral palsy. Acta Paediatr. Acad. Sci. Hungavicae, 23:361, 1982. Terplan, K. L.: Histopathologic brain changes in 1,152 cases of the perinatal and early infancy period. Biol. Neonate, 11:348-353, 1967. Thomson, A. J., and Searle, M.: Quality of survival after severe birth asphyxia. Arch. Dis. Child., 50:620, 1977. Todd, M. M., Chadwich, H. S., Shapiro, H. M., et al.: The neurologic effects of thiopental therapy following experimental cardiac arrest in cats. Anesthesiology, 57:76--86, 1982. Towbin, A.: Central nervous system damage in the human fetus and newborn infant: Mechanical and hypoxic injury incurred in the fetal-neonatal period. Am. J. Dis. Child., 119:259, 1970. Volpe, J. J.: Neonatal seizures. Clin. Perinatol., 4:43-63,1977. Wilkenson, H. A., Wepsic, J. J., and Austin, B. S.: Diuretic synergy in the treatment of acute experimental cerebral edema. J. Neurosurg., 34:203-208, 1971. Ziegler, A. L., Calame, A., Marchand, C., et al.: Cerebral distress in full-term newborns and its prognostic value. A follow-up study of 90 infants. Helv. Paediatr. Acta, 31: 299-317, 1976.
Department of Pediatrics Emory University School of Medicine Atlanta, Medicine, Atlanta, Georgia
The Newborn II
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Hypoxic Ischemic Encephalopathy (Asphyxia)
Alfred W. Brann, Jr., M.D. *
Over the past century, numerous etiologies for central nervous system (eNS) pathology and neurologic dysfunction seen in children who are highrisk neonates have been defined. They include the following: 1. 2. 3. 4. 5. 6. 7. 8.
Chromosomal abnormalities Dysmorphic syndromes Drugs and toxins Infections Inherited metabolic diseases Trauma Intracranial hemorrhage Transient neonatal metabolic disorders Hypoxic ischemia Hypoglycemia Hyperbilirubinemia Hypematremia
The area of concentration of this article concerns the effects of hypoxic ischemia on the brain of the full-term fetus or neonate. Much has been and continues to be written about this area. In his landmark treatise of 1862, Little first made a causal link between suboptimal perinatal events and subsequent neurologic dysfunction and brain damage in both the premature and full-term infant.27 From this article and other classic retrospective clinical-neuropathologic studies using human autopsy material, the term birth injury was coined. Since its inception, this term has been used in a broad, nonselective manner to include both physical (birth trauma) and asphyxial (birth asphyxia) insults to the fetal brain during the birth process. Prior to the 1940s, birth trauma was thought to be the overriding etiologic and pathogenetic mechanism leading to most perinatally related brain damage. With improvement in the management of both dysfunctional *Professor of Pediatrics, and Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia
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labor and abnormally sized and positioned fetuses, birth trauma to the nervous system has been almost totally reduced to brachial plexus and facial nerve injury. 39 Information about the specific effect of birth asphyxia on the fetus or neonate has been possible only since the development of techniques for determining blood pH and blood gases. Articles began to appear in the 1940s that strongly suggested a causal relationship between perinatal asphyxia and certain types and patterns of neuropathologic changes in the brain. In a second landmark article, Stewart Clifford described newborns who died after cesarean delivery because of premature separation of the placenta.1O At the time of death these infants were found to have brain swelling and cerebral necrosis. There was no evidence for birth trauma in these infants, and \lsphyxia was suggested as the etiology of the central nervous system injury, based on abnormal acid-base and blood gas determinations. Another set of articles also suggested strongly that asphyxia during the perinatal period led to the development of ulegyria in children who, as neonates, survived a perinatal insult. ll. 21 Recent human and animal studies have permitted a clearer distinction to be made between the effects of asphyxia and trauma on the fetal or neonatal nervous system. Neonatal hypoxic ischemic encephalopathy (HIE) is the term used most frequently to designate the clinical and neuropathologic findings thought to occur in the full-term infant following either intrapartum or neonatal asphyxia. The magnitude of the problem that neonatal HIE poses may not be appreciated fully. Three important factors contribute to this problem. First, more children with cerebral palsy (CP) are full-term infants than are premature infants. Even though the incidence of cerebral palsy is lower among full-term infants (3.38/1000 live births) versus preterm infants (90/1000 live births), this lower incidence is applied to a denominator that includes 92 per cent of the births in this country.36 Second, more asphyxiated full-term infants survive than do asphyxiated preterm infants. 31 Third, the HIE problem is compounded by the apparent lack of a significant reduction in the types of CP seen in full-term infants. A comprehensive population-based Swedish study showed that a decrease in the total CP incidence from 1954 to 1974 was due to a reduction of spastic diplegia in neonates weighing less than 2500 gm.23 Data from the Swedish study does not show any reduction in the incidence of the types of CP seen in fullterm infants. Thus, in the absence of data to the contrary, there is presently no reason to believe that the problem of the full-term asphyxiated neonate in the United States differs from that of these infants in Sweden. CLINICAL FEATURES In the past, the clinical course of the full-term infant who experienced intrapartum asphyxia was thought primarily to reflect altered brain function. It is now known, however, that because of the variable involvement of different organ systems, such infants can have quite different clinical courses. The variation in clinical signs is due in part to the ability of the
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fetus to redistribute blood flow to protect vital organs,4O as well as the difficulty in accurately establishing the length, severity, and acuteness of onset of the asphyxial episode. In addition, there may be unidentified factors in the mother, fetus, or neonate that can influence the occurrence or severity of asphyxia. This varied clinical course was documented in a retrospective study of 6045 consecutive deliveries. 47 Fifty-three full-term infants had an Apgar score of 5 or less at 1 minute and 5 minutes, and were thought to have suffered intrapartum asphyxia. Eighteen infants had no apparent disease throughout their hospitalization; however, thirty-five infants had at least one or as many as five abnormal organ systems. Nineteen of the thirty-five infants had more than one abnormal system. The 35 affected infants with low Apgar scores had problems (in order of decreasing frequency) with their pulmonary, cardiovascular, eNS, gastrointestinal, and renal systems. None of the infants in this study had clinically significant coagulation problems, although disorders of hemostasis have been described. Nine of these thirty-five died during the neonatal period. The most common cause of death was persistent pulmonary hypertension, which occurred in four infants. No one system or group of systems appeared to be the primary target of the intrapartum asphyxial episode. Only one third of the infants had clinical signs that suggested eNS involvement. Only two of the nine infants who expired, died from eNS disturbances. These two infants had massive brain swelling with cortical necrosis. From either the intrapartum course or the status of the neonate in the delivery room, it was not possible to predict whether the eNS or any other organ system was going to be affected. The functional state of the nervous system in an asphyxiated full-term neonate during the first week of life is characteristic enough to be termed HIE. 44, 56 Data indicate that full-term neonates at risk of developing longterm neurologic sequelae from an intrapartum asphyxial episode will demonstrate signs of neurologic dysfunction. at least within the first week of life, most usually within the first 12 hours after birth. Such a neonate mayor may not have a low Apgar score. 16, 17 The major signs of eNS dysfunction include seizures, abnormalities in state of consciousness, tone, posture, reflexes, respiratory pattern, oculovestibular response, autonomic function, and anterior fontanel. 29, 36, 39, 43, 56 As the physician attempts to assess the relative risk of a neonate to develop cerebral palsy, some obstetric complications can be considered as possible risk factors. Numerous prenatal and intrapartum events have been described as placing the fetus at an increased risk for experiencing intrapartum asphyxia. These conditions fall into three general categories: 1) altered placental exchange, 2) altered maternal blood flow to the placenta, or 3) reduced maternal arterial oxygen saturation. In a prospective study, the relative risk of cerebral palsy in infants weighing 2500 gm or more following certain obstetric events was described in relation to the Apgar scores. 37 The 18 obstetric complications evaluated in this study were: placenta previa, abruptio placentae, breech delivery, face or brow presentation, cord prolapse, placental infarction (2 + ), toxemia, lowest fetal heart rate « 100 beats per min), oxytocin augmentation, nuchal
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cord, meconium, uterine dysfunction, forceps use (mid- or high), second stage of labor longer than 59 minutes, chorioamnionitis, prolonged rupture of membranes (> 24 hrs), short cord « 40 cm), and polyhydraminos. Infants whose births were associated with these "anoxigenic" obstetric complications were at no greater risk for developing cerebral palsy than were infants whose births were uncomplicated, if their 5-minute Apgar scores were 7 or higher. This group comprised about 62 per cent of the study group and accounted for less than its proportional share of CPo There was an increased risk for cerebral palsy when the infant born with an obstetric complication had a 5-minute Apgar score less than or equal to 3. This group of patients accounted for only 1.5 per cent of the population, but accounted for 17 per cent of infant deaths and 13 per cent of CP infants in the study population. These data show that an obstetric complication per se does not increase the infant's risk for CP unless the complication is associated with a significantly low Apgar score. The low Apgar score indicates an abnormal condition but does not imply any specific etiology. Low scores can be due to anyone of the following six major causes: asphyxia, drugs, trauma, hypovolemia, infection, or anomalies. In a low Apgar score ascribed to asphyxia, signs known to occur during intrapartum asphyxia should be present whereas the other causes of low Apgar scores are eliminated. Data now show that a score of 0 to 3 at 5 minutes is a significantly low Apgar score. 36 Infants who have Apgar scores of 7 to 10 have been found to be at very low risk for an abnormal transition to extrauterine life and for later abnormal neurologic development. The score range of 0 to 3 is "significant" because of the higher mortality and CNS morbidity among infants with this score than among infants with scores of 4 to 6 or 7 to 10. 34 The longer the score is low, the greater is its significance. 34 An infant with a 0 to 3 score at 1 minute has a mortality of 5 per cent to 10 per cent, which rises to approximately 53 per cent if that score is maintained for 20 minutes. In full-term surviving neonates with an Apgar score of 0 to 3 at 5 minutes, the incidence of CP is approximately 1 per cent. If this score is sustained for 15 minutes, 9 per cent of the survivors will have CP, with a dramatic rise to 57 per cent for infants who sustain an Apgar score of 0 to 3 for 20 minutes. The Apgar score may indicate asphyxia, but not duration of the asphyxial episode. Some estimate of the duration of the episode may be estimated from observing the newborn. When a low Apgar score occurs, infants tend to lose these functions, in order: their color, respirations, tone, reflexes, and heart rate. Following effective resuscitation, these functions tend to reappear in the following order: heart rate, reflexes, color, respirations, and tone. The time required for tone and respirations to return may indicate the severity or duration of the asphyxial insult to the CNS. Delay of greater than 2 hours in return of tone is associated with an increased incidence of HIE as well as significant neurologic sequelae in surviving neonates. 8 The mean age at onset of spontaneQus respirations in an infant asphyxiated during labor and delivery is significantly greater in neonates who developed seizures, a major sign in HIE. 31 Other delivery room observations that may help estimate the length or severity of the
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intrapartum asphyxial episode are: delay m return of heart rate if resuscitation efforts are considered adequate, meconium present in the trachea, and meconium staining of the umbilical cord, skin, or nails. The last observation indicates previous exposure to meconium for at least 3 to 6 hours. 19 Neonatal seizures frequently are secondary to intrapartum asphyxia. 7, 8 Seizures have been reported in 30 per cent to 69 per cent of infants with abnormal neurologic examinations after an intrauterine asphyxial episode (see Table 1). Typically, seizure onset has been reported to occur at 12 to 24 hours after delivery. If signs other than tonic clonic movements are used to identify a seizure, however, seizure onset may be as early as 2 to 6 hours. Seizures per se are not associated exclusively with late neurologic sequelae; however, the seizure occurrence within the first 12 hours, the appearance of status or serial seizures, or a persistently abnormal electroencephalogram (EEG) (electrical silence, burst suppression, or low voltage background) are signs of significant neonatal neurologic dysfunction.28, 39. 56 Infants with HIE who have seizures as just described have a 30 per cent to 75 per cent likelihood of long-term neurologic sequelae. 18,31,45 Abnormalities in the level of consciousness are helpful in delineating the severity of an asphyxial insult and in predicting which infants may have neurologic sequelae if they survive. In a recent study,45 full-term asphyxiated infants who were felt to have an encephalopathy were grouped into three clinical states, according to the neonate's level of consciousness, neuromuscular control, complex reflexes, autonomic function, seizures, EEG findings, and duration of abnormality. Although all six of these factors were important in delineating the three states of encephalopathy, the level of consciousness seemed to be the primary determinant. The state 1 level of consciousness is hyperalertness; state 2, lethargy or obtundation; and state 3, stupor. Both the state of encephalopathy and duration of a given state were other factors that determined the severity of HIE and predictability of long-term outcome. Infants who did not enter state 3, and had signs of state 2 for fewer than 5 days appeared to be normal later in infancy. Infants who entered state 3, who had signs of state 2 for more than 7 days, or whose EEG failed to revert to normal either died or developed significant neurologic sequelae. These results have been confirmed in another study using the same scoring system, even without EEG criteria. 17 The incidence of moderate to severe long-term neurologic sequelae in asphyxiated, surviving full-term neonates varies from 4.7 per cent to 57.1 per cent, depending on the definition used for asphyxia (see Tables 1 and 2). The typical cluster of neurologic deficits in a severely affected child includes spastic quadriplegia, severe mental retardation, seizures, hearing deficits, and microcephaly. The full-term neonate at risk for developing long-term neurologic sequelae from an intrapartum asphyxial episode will demonstrate signs of neurologic dysfunction (HIE) in the first week of life. The value of HIE in identifying neonates at increased risk for later neurologic dysfunction has been confirmed by findings from the National Collaborative Perinatal Project (NCPP).36 Approximately 11 per cent of surviving children were suspected to have a brain abnormality during the nursery course. Of this group, 6 per cent died and 1 per cent later had
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cerebral palsy. Of infants who had a definite neurologic abnormality at time of discharge from the hospital, only 53 per cent died (0.5 per cent of surviving infants). CP occurred in 15.8 per cent of survivors; however, 85 per cent of surviving infants with definite neurologic abnormalities at the time of discharge did not have CP at follow-up. Among a group of full-term neonates with a history of an asphyxial episode and an abnormal neurologic examination during the first week of life, the incidence of early death was 7 per cent, and the incidence of neurologic handicaps was 28 per cent. When abnormalities of tone were isolated as a predictor of severe handicap in full-term neonates with a history and clinical course compatible with asphyxia, the risk for cerebral palsy among children surviving the neonatal period was 25 per cent. A chronologic combination of abnormal signs is more helpful than a single sign in predicting outcome. 45 , 58 The most helpful cluster of signs include an Apgar score of 3 or less obtained at 5 minutes or an Apgar score below 3 for 10 minutes or longer, together with other factors (e.g., reduced activity levels, tone, reduced consciousness lasting> 1 day, need for gavage feeding, hypotonia, or single or multiple episodes of apnea during the first week). The cluster may also include Sarnat State 3 or 2 lasting longer than 5 days, asymmetric neurologic signs, seizures with onset during the first day of life, and an overall impression of abnormal brain function during the time the infant waS in the nursery. More work is needed to define the predictive powers of the neonatal neurologic examination; however, an abnormal neurologic examination (as defined above) of a full-term infant with a history of probable intrapartum asphyxia is an extremely powerful tool in establishing the presence and severity of HIE, in predicting early death, or in identifying neonates who should be observed for later development of neurologic sequelae. As treatment for neonatal HIE is evolving and as potential treatments for children with early developmental delays are appearing, it becomes extremely important to identify the presence and severity of neonatal HIE.
PATHOLOGIC FEATURES From classic neuropathologic studies of brains from neonates who experienced an episode of "perinatal distress," three distinct sites of brain damage have been identified. 3, 55 These sites are the region of the subependymal germinal matrix, the periventricular white matter, and the cortical and subcortical gray matter. When babies with these lesions were classified by gestational age, however, it became apparent that there were differences in the loci of lesions seen in the preterm infant compared with those seen in the full-term infant. Although the topic of this discussion is HIE in the full-term infant, lesions seen in the preterm infant are mentioned to highlight the difference. The principal lesion seen in the preterm infant is located at the center of the hemisphere in the germinal matrix along the ventricular region, with sparing of the cortical mantle. The term subependymal germinal matrix hemorrhage/intraventricular hemorrhage (SE/IVH) describes this lesion.
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A second lesion, seen predominantly in preterm infants but also in full-term infants, occurs in the deep white matter of the periventricular region at the angles of the ventricle, superior to the germinal matrix. This cystic lesion has been called periventricular leukomalacia (PVL). In the full-term infant having experienced significant "perinatal distress," the lesions are located principally in the peripheral and dorsal areas of the cerebral cortex, involving necrosis of the gyri at the depths of sulci and the neuronal nuclei of the basal ganglia and brain stem. In some patients, cerebral necrosis is most severe in the region of the postcentral gyrus similar to that found in the full-term newborn monkey following experimentally produced intrapartum asphyxia. 5. 6, 32 Neonatal HIE, the term used to identify the encephalopathy in the full-term infant after either intrapartum or neonatal asphyxia has occurred, results in this latter pattern of brain lesions along with a particular set of signs of neonatal neurologic dysfunction. Although areas of petechial periventricular hemorrhage and leukomalacia can also be seen, the pattern of cerebral damage in the fullterm infant usually does not include SE/IVH. Those full-term infants who survive the perinatal asphyxial episode and neonatal period primarily will have two neuropathologic conditions-ulegyria and status marmoratus of the basal ganglia. The reader is referred to Gilles for a detailed description and excellent discussion of the pathologic changes in the nervous system following perinatal insult. 20
PATHOGENESIS Based on animal data and clinical knowledge from human studies, a proposed pathogenesis for HIE in the full-term infant and its sequelae in the surviving neonate is outlined in Figure l. This diagram has been derived from data from two rhesus monkey models termed prolonged partial asphyxia (developed by Brann and Myers 5, 6, 32), and acute total asphyxia (developed by Windle42) as well as other animal and human data. 41 These two models closely replicate the two very different types of perinatal asphyxial events that occur most frequently in the human fetus or neonate-an acute asphyxial episode resulting from cord prolapse,26 and a prolonged partial asphyxial episode resulting from a placental abruption.lO Prolonged partial asphyxia of 1 to 3 hours in the monkey fetus produces a clinical course in the newborn monkey similar to that seen in the depressed newborn human following a placental abruption. 5 , 6, 32 Seizures occur in approximately 50 per cent of the monkeys within the first 24 hours of life. The spectrum of brain lesions in the cortex are similar to those in neonates who die following intrapartum asphyxia, as well as in children or adults said to have "cerebral palsy" secondary to a perinatal insult. The surviving monkey, unlike the human, has no motor deficit, despite significant brain lesions in the association areas of the cortex. Cytotoxic brain edema occurs in the neonatal period. 42 Cerebral blood flow (CBF) studies in the monkey show that the brain is abnormal at birth as demonstrated by the focal areas of ischemia. 4 These studies from the animal model strongly suggest that
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Intrapartum Asphyxia
Redistribution of Organ Flow Lung Kidney GI Tract
Heart Brain Adrenal
Variable Organ Effect Brain-l"onnal
(I)
(20)
Brain-Ulegyria
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(4)
Figure 1. FetaVneonatal response to intrapartum asphyxia.
prolonged partial asphyxia from any cause in the fetus, in the absence of fetal circulatory collapse or fetal head compression, can cause cytotoxic edema and impaired CBF, leading to cerebral necrosis or ulegyria. Acute total asphyxia of 8 to 10 minutes produces in the monkey a longterm neurologic dysfunction similar to that seen in patients with spastic quadriplegia. 43 In the neonatal period, neither seizures nor brain swelling are seen. The neuropathologic findings occur primarily in the nuclei located in the brain stem, thalamus, and basal ganglia, with sparing of the cerebral cortex. The clinical spectrum and neuropathologic findings in monkeys from these two animal models, when combined, closely replicate short-term and long-term clinical and neuropathologic findings that usually occur in the human after perinatal asphyxia has occurred. In most cases, the total perinatal insult in humans most likely results from a partial prolonged asphyxial episode combined with a terminal acute asphyxial episode. The clinical course and the extent of neuropathologic changes in a neonate can vary depending on the acuteness of onset, as well as on the length and the severity of the asphyxial episode. The entire sequence of events leading to the various types of neuropathologic outcomes is not totally clear from current data, although the points represented in the diagram of the proposed pathogenesis (see Fig. 1) have been demonstrated in either animal or human studies. The diagram of proposed pathogenesis (see Fig. 1) is drawn from top to bottom as though the intrapartum asphyxial episode were a continuum, with the outcomes on the right side of the figure. Many newborns having low Apgar scores following intrapartum asphyxial episodes have no evidence of HIE (Fig. 1, step 1). This has been seen in asphyxiated infants who succumb because of other dysfunctions, such as persistent fetal circulation. 47
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The lack of CNS findings could be explained by the increased per cent of cardiac output to the brain, thus attempting to maintain adequate tissue oxygenation and preventing tissue ischemia. If the intrauterine asphyxial episode continues and homeostatic mechanisms that maintain brain oxygenation begin to fail, a cascade of events begins that leads to tissue ischemia, the central event in the pathogenesis of neonatal HIE and subsequent development of atrophic cortical sclerosis. 31 , 41, 43 The factors that lead to this tissue ischemia include abnormal ion homeostasis (especially calcium), energy failures, cellular acidosis, and blood-brain barrier alteration. 41 The length of time required for tissue ischemia to cause tissue death in the cerebral cortex is uncertain. Recent data indicate that brain cells are more resistant to ischemia than was previously thought. 41 It is conceivable that if the intrauterine asphyxial episode is relieved and the neonate is treated appropriately after the development of only mild multifocal tissue ischemia, the brain in the surviving infant could escape tissue necrosis (Fig. 1, step 2). If the intrapartum insult is not extremely severe or is quickly terminated, small areas of multifocal tissue necrosis do occur; they may not lead to significant areas of vasogenic edema with the development of severely increased intracranial pressure. Brain repair processes convert these areas of multifocal tissue necrosis into areas of ulegyria, as described in the monkey brain. The extent and pattern of ulegyria depend on the degree and location of cerebral necrosis (Fig. 1, step 3). If the intrapartum episode is severe and prolonged, multifocal areas of tissue ischemia located at the depths of sulci and within neuronal nuclei spread to the entire cerebral hemisphere. 43 The existing tissue ischemia, if unrelieved, leads to tissue necrosis. Vasogenic edema occurs following disruption of the tight junctions of the capillary endothelium, with leakage of osmotic materials into the interstitial tissues of the brain, pulling water from the intravascular space. 22 As the multifocal areas of necrotic brain coalesce, and significant increases in intracranial pressure occur in association with vasogenic edema, the brain swells progressively. This produces measurable increases in intracranial pressure. From animal data it is known that when intracranial pressure reaches one half to two thirds of the mean arterial pressure, reduced CBF causes tissue ischemia, especially in areas of cortex at depths of sulci. 2 The triad of multifocal tissue necrosis, vasogenic edema, and brain swelling with increasing intracranial pressure, leads to an ever-increasing oxygen debt in the brain, almost total tissue necrosis, and death (Fig. 1, step 4). In some asphyxiated neonates, increased intracranial pressure or brain edema at autopsy are not observed. This finding may be due to compensation by redistribution of blood How to protect the brain, whereas inadequate oxygen is supplied to the lung, kidney, or gastrointestinal (GI) tract. This may lead to death secondary to dysfunction of these organs. The absence of edema may be related to the type and length of the asphyxial episode. There is consistent absence of brain swelling in the monkey experiencing acute total asphyxia; however, there can be enough neuronal necrosis confined to the brain stem and basal ganglia to cause death from impaired respiratory control.
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Table 1. Incidence of Seizures in Full-term Asphyxiated Infants
RERFERENCE
Brown, 19748 Scott, 197646 Sarnat, 197645 DeSouza, 1978 '2 Mulligan, 1980'" Finer, 1981'7 Finer, 1983'6 Ergander, 1983 15
DEFINITION OF ASPHYXIA
0-2 at 1 min or 0-4 at 5 min or IPPV* o at 1 min or 0-2 at 20 min IPPV 0-4 at 1 or 5 min o at 1 min or onset of breathing after 5 min IPPV more than 1 min 0-3 at 5 min 0-5 at 5 min or IPPV 0-3 at 5 min
INCIDENCE OF SEIZURES (PERCENT)
MORTALITY (PERCENT)
51
22
48 52
52 10
42 52 68 69 30
4 19 7 0 21
*IPPV, intermittent positive-pressure ventilation. (Table courtesy of N. Finer.)
Unknown or poorly quantitated factors leading to thromboembolism and cerebral infarction may playa key role in the pathogenesis of ulegyria both with and without brain swelling during the neonatal period.
TREATMENT Although recent textbooks of neonatal-perinatal medicine include the management of an infant with symptoms of HIE, data from randomized clinical trials cannot yet recommend known efficacious therapy for the management from birth of an infant at high risk for HIE. At least three questions surround the appropriate prospective therapeutic management of such a neonate. First, can the asphyxiated neonate whose CNS is altered enough to develop HIE be identified within the first 2 to 6 hours after birth? Second, is there a critical time after which treatment is ineffective in eliminating or significantly reducing permanent brain damage in this infant? Third, what is the appropriate prospective intervention for this asphyxiated neonate? If an abnormal patient cannot be recognized, therapy cannot be initiated to alleviate the condition. Current data support the position that the full-term neonate who has had a history of fetal distress, with either an I\pgar score of less than or equal to 3 at 15 or 20 minutes, failure to have spontaneous and sustained respiration by 5 minutes, or altered tone or level of consciousness during the first 2 to 6 hours of life, is at great risk for having HIE. This neonate, who probably has focal areas of brain ischemia at birth similar to those seen in the fetal monkey following prolonged partial asphyxia,43 has a 50 per cent chance of having seizures,39 and at least a 20 per cent chance of having long-term neurologic sequelae. 36 Some neonates who subsequently develop neurologic sequelae and a clinical course of HIE have presented with an Apgar score of 7 to 10; however, these neonates sometimes have had an intrapartum course suggestive of asphyxia. It is extremely important in such cases to be sure that the
461
HyPOXiC ISCHEMIC ENCEPHALOPATHY (ASPHYXIA)
Table 2. Incidence of Moderate or Severe Long-term Neurologic Sequelae (LTNS)* in Surviving Full-term Asphyxiated Infants
REFERENCE
Drage, 196613 Dweck, 19741• Brown, 19747 Steiner, 197550 Sarnat, 197645 Scott, 197646 Thomson, 1977"" DeSouza, 19781• Nelson, 1977"" Nelson, 1979"" Nelson, 198135 Mulligan, 1980'l1 Fitzhardinge, 198p· Finer, 198p· Storz, 198251 Finer, 19831• Ergander, 198315 Robertson" (unpublished)" Overall
DEFINITION OF ASPHYXIA
0-3 at 1 min 0-3 at 5 min 0-3 at 1 min 0-2 at 1 min or 0-4 at 5 min or IPPVt 0-1 at 15 min 0-4 at 1 or 5 min o at 1 min or 1-2 at 20 min IPPV o at 1 min or 0-3 at 5 min o at 1 min or onset of breathing after 5 min 0-3 at 5 min 0-3 at 10 min 0-3 at 15 min 0-3 at 20 min IPPV> 1 min 0-5 at 5 min or IPPV > 2 min 0-3 at 5 min 0-5 at 5 min or IPPV 0-5 at 5 min or IPPV 0-3 at 5 min 0-5 at 1 or 5 min IPPV
LTNSIN SURVIVORS (PER CENT)
MORTALITY (PERCENT)
3.6 7.4 33.0
23 50 61
26.0 28.0 31.0
22 44 10
25.0 10.3
52 50
8.0 4.7 16.7 36.0 57.128.6 27 47 28 22 16.3 22 14.7 23.4
4 15.5 34.4 52.5 5940.3 19 7 0 21 3.5 29
*Cerebral palsy or mental retardation. tIPPY, intermittent positive pressure ventilation. (Table courtesy of N. Finer.)
neurologic dysfunction seen in the first 2 to 6 hours after birth is not secondary to an etiology other than intrapartum asphyxia. Data indicate that a neonate experiencing intrapartum asphyxia sufficient to lead to longterm neurologic sequelae will have clinically recognizable neurologic dysfunction during the first 24 hours of life (see Tables 1 and 2). The question of a critical intervention time relates to the state of the asphyxial process in which the neonate presents. If the neonate is born after a prolonged intrapartum asphyxial episode, when vasogenic edema and increased intacranial pressure are far advanced, no therapeutic intervention is likely to be effective. Animal data show that earlier and more accurate detection of intrapartum asphyxia leads to delivery of a newborn without clinically apparent disease or very early stages of HIE, however.5. 6. 32 Thus, based on both human and animal data, intervention seems theoretically justified. 41 The third question relates to the appropriate prospective intervention for the asphyxiated neonate. To alleviate or reduce brain damage secondary to HIE, the therapeutic management should be directed first at eliminating the hypoxia and then at reducing brain ischemia and edema or reducing the metabolic requirements of the brain. A number of therapeutic modali-
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ties, including steroids,1 diuretics,58 mannitol,29 and barbiturates, 24. 30. 38. 48. 49 have been suggested. At the present time, barbiturates appear to hold the theoretical edge as the first agent to be used in a randomized clinical trial. Phenobarbital is the barbiturate of choice, primarily because of its ability to reduce seizures, especially in a brain that has lost its ability to auto regulate its energy requirements following asphyxia. Barbiturates also may positively influence a reduction in catecholomine secretion,49 toxic free radicals,48 cerebral edema, 30. 38 and general metabolic activity. 30. 3B At present we have made strides toward early identification of the infant with HIE, although we are currently unable to determine the length, severity, and acuteness of onset of that infant's asphyxial episode with certainty. Although phenobarbital is the drug of choice at the present time for research evaluation, data do not exist to support its current clinical use prospectively to prevent seizures. New insights into the pathophysiology of brain ischemia should lead to new proposed therapies, especially as more understanding is gained regarding metabolism of calcium and membrane phospholipid, prostaglandin, thromboxane, and leukotrienes. 41 Thus to reduce the total number of patients with CP in the United States, a concerted effort must be made not only on specific drug therapy for the full-term asphyxiated infant, but also an effort should be made regarding accurately identifying the full-term fetus at risk for experiencing suboptimal tissue oxygenation. This will permit the timely delivery, with capable persons in attendance of the fetus, who can appropriately assess, resuscitate, and stabilize the neonate.
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Department of Pediatrics Emory University School of Medicine Atlanta, Medicine, Atlanta, Georgia